Crosstalk between non-coding RNAs and programmed cell death in colorectal cancer: implications for targeted therapy

Abstract

Background

Colorectal cancer (CRC) remains one of the most common causes of cancer-related mortality worldwide. Its progression is influenced by complex interactions involving genetic, epigenetic, and environmental factors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been identified as key regulators of gene expression, affecting diverse biological processes, notably programmed cell death (PCD).

Objective

This review aims to explore the relationship between ncRNAs and PCD in CRC, focusing on how ncRNAs influence cancer cell survival, proliferation, and treatment resistance.

Methods

A comprehensive literature analysis was conducted to examine recent findings on the role of ncRNAs in modulating various PCD mechanisms, including apoptosis, autophagy, necroptosis, and pyroptosis, and their impact on CRC development and therapeutic response.

Results

ncRNAs were found to significantly regulate PCD pathways, impacting tumor growth, metastasis, and treatment sensitivity in CRC. Their influence on these pathways highlights the potential of ncRNAs as biomarkers for early CRC detection and as targets for innovative therapeutic interventions.

Conclusion

Understanding the involvement of ncRNAs in PCD regulation offers new insights into CRC biology. The targeted modulation of ncRNA-PCD interactions presents promising avenues for personalized cancer treatment, which may improve patient outcomes by enhancing therapeutic effectiveness and reducing resistance.

Introduction

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths overall, the leading cause in men under 50, and the third most commonly diagnosed cancer [1]. Various epidemiological factors, including Survival Rates, Age and Gender, Racial and Ethnic Disparities, Geographical Variations, Lifestyle Factors, and Molecular and Genetic Factors influence CRC prognosis [2]. The overall 5-year survival rate for CRC is approximately 65% [3]. Global CRC prognosis has improved due to advancements in screening and treatment, though significant survival disparities persist between high-income and low-income regions. Survival rates vary widely, highlighting the critical need for equitable, early detection efforts [1, 4].

Despite progress in traditional treatments like surgery, radiotherapy, and chemotherapy, alongside newer approaches such as immunotherapy and targeted therapy, the prognosis for CRC remains grim [5, 6]. Furthermore, traditional therapies often lack the selectivity required to target just cancer cells, causing harm to healthy organs. Persistently high rates of chemoresistance, recurrence, and metastasis underscore the need to explore novel pathogenic mechanisms, which could potentially lead to advanced targeted and combination therapies in the future.

The development of colorectal adenomas and invasive adenocarcinomas in healthy colonic epithelial cells over time results from a confluence of genetic, epigenetic, and environmental variables, ultimately leading to CRC [7]. Targeting ncRNAs is a viable option because of their capacity to influence gene expression and cellular processes that are related to cancer development and programmed cell death. By altering ncRNA pathways, it may be feasible to overcome resistance, increase treatment specificity, and lessen unwanted effects, offering a more precise and personalized [8].

Programmed cell death (PCD) plays a pivotal role in the development and homeostasis of cells in the human body. This crucial biological process involves the removal of damaged cells at risk of tumorigenicity [9]. Activation of PCD occurs in response to stress signals, initiating a cascade of complex transcriptional responses and protein posttranslational modifications that orchestrate cell demise [9, 10]. Over the past few decades, numerous forms of PCD, including apoptosis, autophagy, ferroptosis, pyroptosis, necroptosis, cuproptosis, NETosis, anoikis, and disulfidptosis, have been identified and are observed to undergo alterations in cancers [11].

ncRNAs, such as microRNAs (miRNAs), lncRNAs, and circular RNAs (circRNAs), lacking protein-coding functions, have been demonstrated to exert regulatory effects on PCD, influencing various cellular processes [10, 12]. It is well-established that ncRNAs are crucial regulators of a wide array of cellular processes through their control over target gene expression [13]. miRNAs inhibit gene expression by specifically binding to messenger RNAs (mRNAs), preventing their translation. lncRNAs and circRNAs typically function as "sponges" for miRNAs, thereby modulating gene expression indirectly. Additionally, these ncRNAs can influence the expression of target genes by affecting the binding of transcription factors to promoters. Given their essential roles, dysregulation of ncRNAs is a major contributor to cancer progression [14, 15].

This review aims to understand the interactions between ncRNAs and PCD in CRC and offers promising insights into targeted therapeutic strategies. By unraveling these molecular relationships, it may be possible to develop novel therapeutic approaches aimed at reactivating cell death pathways, specifically in cancer cells, ultimately improving treatment outcomes for CRC patients.

Pathogenesis of colorectal cancer

The pathogenesis of CRC arises from complex interactions among genetic mutations, environmental influences, and microbial factors, all of which contribute to the disease's complexity and heterogeneity. Understanding these interactions is vital for advancing CRC prevention and treatment strategies [16].

Progress in molecular techniques has led to the realization of the pathogenesis of hereditary and sporadic CRC syndromes. This progress has allowed us to categorize the improvement of CRC into two separate pathways: the serrated and genetically independent pathways. The conventional pathway contains the adenoma-to-carcinoma sequence. The conventional pathway is identified by genetic mutations in tumor protein p53 (p53), Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), and Adenomatous Polyposis Coli (APC), but the serrated pathway is recognized for modifications in MutL Homolog 1 (MLH1) methylation, CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A), and v-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) [17,18,19].

Despite the widespread acceptance of the adenoma-carcinoma sequence and serrated pathways, inflammation has increasingly been implicated in CRC. Inflammatory bowel disease (IBD), containing Crohn’s disease and ulcerative colitis, has long been related to a bigger risk of CRC. Helicobacter Pylori, which causes chronic inflammation, has also been related to a moderate increase in CRC risk [20]. In addition to ulcerative colitis, an inflammatory hepatobiliary disease, significantly increases the risk of CRC by approximately fourfold [21]. Colitis-related CRC has been associated with p53, KRAS, and APC mutations. However, these mutations are less frequent than those associated with sporadic CRC [22, 23]. Mutations in hMSH2, which contribute to hereditary nonpolyposis CRC, were reported to be more recurrent in ulcerative colitis patients who developed CRC than in patients who did not develop CRC [24].

An important aspect of CRCis the upregulation of genes that transform normal glandular epithelial cells into invasive adenocarcinomas. Vogelstein and Fearon's classic and seminal tumor development model suggested the polyp to cancer development process. It includes three steps: a step that starts the arrangement of benign neoplasms (adenomas and sessile serrated polyps) taken after by a step that stimulates the progression to more histologically advanced neoplasms; and after that, a step that changes the tumors to invasive carcinoma [25]. Since this model was first suggested, we have learned a lot about the molecular pathogenesis of CRC. This has caused many changes to be made to the first Vogelstein and Fearon model. For example, the first version of the model suggested that only tubulovillous and tubular adenomas could develop into invasive adenocarcinoma. Nowadays, we know that serrated polyps containing traditional serrated adenomas and sessile serrated adenomas/polyps can also lead to malignant conversion [26, 27]. A different pathway to malignancy is Serrated polyps. Some microvesicular hyperplastic polyps, can develop into serrated neoplasms (serrated adenomas/polyps or traditional serrated adenomas). Some of these serrated neoplasms can then develop into CRC[28]. Premalignant serrated polyps more regularly develop with the proximal colon [29] and are related to the CpG Island Methylator Phenotype, a phenotype realized by having an extraordinarily high frequency of aberrantly methylated CpG dinucleotides. Conversely, routine tubular adenomas turn out to be more frequently started by biallelic inactivation of the APCtumor-suppressor gene and show chromosome instability (CIN), which is a shape of genomic imbalances that are realized by aneuploidy and losses and gains of a huge part of chromosomes or entire chromosomes [30, 31]. Furthermore, other molecular changes, like mutations in BRAFV600E, are usually seen more regularly in tumors that progress through the serrated neoplasia pathway [30]. Therefore, our knowledge of the process that leads to polyps to cancer in the colon is that it is different and that one of the major differences between the pathways at the molecular level is the noticeable type of genomic and epigenomic instability involved. We still know little about the pathogenesis of CRC. Much research and work are still needed to determine its exact pathogenesis.

ncRNAs: biogenesis and role in cancer

Despite proteins serving as crucial entities in genetic information, it is noteworthy that less than 2% of the genome is dedicated to coding for proteins. The transcripts beyond this fraction are termed ncRNAs [32]. Based on their location, structure, and length, ncRNAs have been categorized into different classes, such as miRNAs, lncRNAs, and circRNAs. miRNAs are small, highly conserved single-stranded RNAs, approximately 21–22 nucleotides (nt) in length. The biogenesis of miRNAs is a multistep process involving transcription by RNA polymerase II or III into primary miRNAs, which are then cleaved into precursor miRNAs (pre-miRNAs) by the nuclear ribonuclease Drosha. These pre-miRNAs, around 70 nts long, are exported to the cytoplasm by exportin-5 and subsequently cleaved by Dicer into double-stranded miRNAs, from which the passenger strand is degraded. The mature miRNA strand is incorporated into the Argonaute (AGO) protein within the RNA-induced silencing complex (RISC), where it mediates translational repression by binding to complementary sequences in target mRNAs to destroy targeted mRNA [33]. Besides targeting mRNAs, miRNAs also interact with other ncRNAs, such as lncRNAs and circRNAs, and compete with endogenous RNAs (ceRNAs) to regulate shared RNA transcripts.

In contrast, circRNAs and lncRNAs are longer than 200 nt, but they differ in structure, circRNAs are ring-like, while lncRNAs are linear. Both circRNAs and lncRNAs can be transcribed from various genomic regions, including intergenic regions, introns, exons, or 5′/3′-untranslated regions. They can also fold into complex secondary structures, allowing them to interact with proteins, RNA, and DNA [34]. circRNAs and lncRNAs regulate gene expression in different ways. For example, they can act as miRNA decoys to stop the targeted mRNA from deteriorating. They can also modify transcription factors to bind to promoters, thereby regulating the expression of specific genes [35]. Additionally, they can act as scaffolds to regulate protein–protein interactions and the associated downstream signaling pathways. Recent studies have indicated the role of circRNAs and lncRNAs in the epigenetic modulation of chromatin to control gene expression [8, 36] (Fig. 1).

Fig. 1

Overview of microRNA (miRNA) biogenesis and functional mechanisms. The biogenesis of miRNAs begins with the transcription of primary miRNA transcripts by RNA polymerases II and III. These primary miRNAs are then processed in the nucleus by the ribonuclease Drosha into precursor miRNAs (pre-miRNAs) that possess a characteristic stem-loop structure. The pre-miRNAs are subsequently exported from the nucleus to the cytoplasm by exportin-5. Once in the cytoplasm, the enzyme Dicer cleaves the pre-miRNAs to produce double-stranded miRNAs. Helicase enzymes then unwind these double strands, leading to the degradation of the passenger strand. At the same time, the mature miRNA strand is incorporated into the Argonaute (AGO) protein within the RNA-induced silencing complex (RISC). Within RISC, miRNAs can regulate gene expression by binding to complementary sequences in target mRNAs, thereby repressing translation. Beyond mRNAs, miRNAs also modulate the expression of other ncRNA, such as lncRNAs and circRNAs. Furthermore, ceRNAs can affect RNA transcript levels by sequestering shared miRNAs, thereby influencing gene regulatory networks

It has been indicated that ncRNAs can play roles in oncogenic processes. For instance, an oncogenic miRNA called miR-10b is necessary for tumor growth in glioblastomas and is overexpressed compared to ordinary brain tissue [37]. One of the most greatly researched oncogenic lncRNAs is HOTAIR, which was initially identified as a gene regulator of the HOX gene family, which controls cellular identity [38]. HOTAIR overexpression, probably by tumor invasiveness and rising metastasis, has been related to bad outcomes in breast and several other cancers [39]. circRNAs can also function similarly to lncRNAs by sponging miRNAs, as in the case of circCCDC66, which has oncogenic tasks in CRC[40].

ncRNAs also can play a role in the tumor suppressive process. For example, usually, miR-16-1 and miR-15a play a role as tumor suppressors, but their deletion, or mutated, is associated with the improvement of chronic lymphocytic leukemia (CLL), which is the most prevalent form of leukemia [41, 42]. A lncRNA with known tumor suppressive roles is GAS5, which is usually downregulated in cancers, with straight in vivo experimental indication in glioblastoma and breast cancer models [43, 44]. circHIPK3, another ncRNA, inhibits tumor growth in bladder cancer [45].

Recent research has demonstrated the significance of ncRNAs in regulating cancer cell signaling, cancer progression, and the tumor microenvironment (TME) through exosomes [46, 47]. Exosomes, a type of extracellular vesicles, play a major role in starting an intercellular communication network between stromal cells, tumor immune, and cancer cells [48]. It has been established that exosomes carrying tumor-associated cargo, such as ncRNAs, have the potential to develop into new targets and biomarkers in the development of cancer therapy due to their critical roles in inducing therapeutic resistance, immune response, metastasis, and angiogenesis [48]. For instance, exosomes derived from oral squamous cell carcinoma (OSCC) cells usually have miR-29a-3p upregulated. By activating SOCS1/STAT6 signaling, exosomes enriched in miR-29a-3p distinguish unpolarized macrophages into the M2-subtype, which finally promotes tumor cell proliferation and invasion [49].

The study of steady changes in cellular activity is known as epigenetics. Epigenetic changes aren't irrevocable and do not alter the DNA sequence [50]. ncRNA-mediated regulation, histone modifications, and DNA methylation are a few instances of epigenetic events [51]. Within these epigenetic incidents, through the modification of stemness, deregulation of ncRNAs can also come through cancer cell development [52]. For years, they were regarded as genomic junk [53], but now it is understood that they have a role in the epigenetic regulation of gene expression. Changes in cell behavior and function are the outcome of the epigenetic regulation of genes by the ncRNA family [54]. The abnormal expression of ncRNAs in cancer helps cancer phenotypes like stemness [55, 56]. Numerous ncRNAs are either overexpressed or suppressed to manipulate gene expression to favor the stemness in cancer cells. For example, oncogenic miRNAs like miR-181 and miR-155 are deregulated in breast cancer and help with self-renewal [57]. Migration, invasion, breast cancer cell expansion, and higher proliferation are the results of features related to cancer stemness. The downregulation of tumor suppressors miR-192–5p and miR-206 in hepatocellular carcinoma results in cancer cell expansion and dedifferentiation, among other features associated with stemness. Other well-known miRNAs contributing to stemness include miR-613, miR-500a-3p, miR-494, miR-217, miR-194, miR-125b and miR-125 [58]. We also know that ncRNAs play roles in program cell death processes, which we will discuss further.

ncRNAs in colorectal cancer

Numerous studies have revealed that ncRNAs participate in various cellular processes, such as cell growth, apoptosis, differentiation, and gene expression. ncRNAs can modulate gene expression at different levels, such as transcription, splicing, translation, and epigenetics [32, 59]. For instance, lncRNAs can act as a mediator for the LSD1 complex, which is responsible for histone methylation and demethylation, respectively. Recruiting these complexes to specific genomic loci can alter the chromatin structure and gene expression in CRC [60].

CCAT1 and CCAT2 are lncRNAs linked to the development and progression of colorectal, gastric, liver, and breast cancers. CCAT1 enhances MYC expression and influences genes involved in cell growth and survival, with elevated levels found in these cancers. CCAT2 is linked to cancer aggressiveness through the WNT/β-catenin signaling pathway and MYC activation, with high levels observed in colorectal, breast, lung, and gastric cancers [61,62,63,64]. Both CCAT1 and CCAT2 contribute to poor cancer prognosis, making them potential biomarkers and therapeutic targets [61, 63].

It is demonstrated that lncRNA CCAT1, which can function as a sponge for miR-181b-5p, is an anti-tumor miRNA in CRC. By trapping these miRNAs, CCAT1 can enhance the expression of their target genes, such as c-Myc, which are tumorigenic in CRC [65, 66]. Gao et al. demonstrated that miR-96, a miRNA that is highly expressed in CRC cells, enhances their proliferation by targeting multiple tumor suppressor genes, such as TP53INP1, FOXO1, and FOXO3a [67]. Other studies have shown that ncRNAs stimulate angiogenesis and progression in CRC. For instance, lncRNA HOTAIR can change the chromatin structure and gene expression in CRC by bringing histone-modifying complexes to specific genomic regions [68]. Also, the lncRNA CCAT1 affects the expression of VEGF, a crucial factor for angiogenesis, by antagonizing microRNA-218. MicroRNA-218 is a tumor suppressor that can downregulate VEGF expression. CCAT1 interacts with microRNA-218 and blocks it from binding to VEGF mRNA, leading to increased VEGF protein levels [69].

Other studies have shown that ncRNAs from CRC cells activate cancer-associated fibroblasts (CAFs). CAFs can also release miR-1246 into CRC cells and stimulate cell migration by activating Wnt/β-catenin signaling related to CRC development. High miR-1246 expression also indicates poor prognosis in CRC patients [70, 71].

Studies have shown that epithelial CRC prevents myofibroblast differentiation by releasing extracellular vesicles (EVs) and transferring miR-200 (miR-200a/b/c-141) into recipient fibroblasts and by targeting zinc-finger E-box-binding (ZEB) [72]. SFRP1 protein, which is derived from myofibroblasts, may act as a potential inhibitor of CRC, and its absence may facilitate tumor proliferation in CRC [73].

It increases the expression or activity of tumor-suppressive ncRNAs that block CRC cell growth, survival, invasion, metastasis, and drug resistance. For instance, lncRNA MALAT1 can function as a sponge for cancer-promoting miRNAs, such as miR-20b, and inhibit the PI3K/AKT/mTOR pathway often altered in CRC. By using viral vectors, nanoparticles, or exosomes to deliver or overexpress MALAT1, it may be feasible to activate the tumor-suppressive function of MALAT1 [74]. In another example, lncRNA HOTAIR is involved in the regulation of epithelial-mesenchymal transition (EMT) and CRC metastasis by interacting with the polycomb repressive complex 2 (PRC2) and mediating the trimethylation of histone H3 at lysine 27 (H3K27me3) on the promoter regions of E-cadherin and other genes associated with epithelial phenotype, resulting in their transcriptional silencing [75].

ncRNAs have been demonstrated to be involved in the modulation of macrophage polarization in CRC in recent studies [76]. Macrophages can be polarized into two distinct phenotypes: M1 and M2. Pro-inflammatory and anti-tumor activities characterize M1 macrophages, while M2 macrophages are associated with anti-inflammatory and tumor-promoting functions [77]. ncRNAs can influence the polarization and activation of macrophages through their interactions with other molecules, such as transcription factors, cytokines, and miRNAs [78]. This results in enhanced M2 polarization and activation of macrophages and increased tumor growth [79]. For instance, miR-195-5p, a tumor suppressor miRNA, can block the GATA3-mediated secretion of IL-4 in CRC cells and consequently inhibit the polarization of M2-like tumor-associated macrophages by targeting the NOTCH2 gene. [80]. Zhao et al. confirmed that exosomal miR-934-induced M2 macrophage polarization facilitates CRC liver metastasis by activating the CXCL13/CXCR5 axis in CRC cells [81].

Some ncRNAs play a role in modulating the immune system with different mechanisms in CRC. For example, they can impair the immune response by affecting T cells. Zheng et al. demonstrated that the 3'-untranslated region (3'-UTR) of the calnexin (CANX) gene was a direct target of miR-148a-3p, which inhibited the expression of CANX protein by binding to its 3'-UTR. As a consequence, miR-148a-3p reduced the surface expression of major histocompatibility complex class I (MHC-I) molecules on CRC cells, which impaired the destruction of tumor cells by CD8 + T cells [82]. In the following sections, we will discuss the relationship between ncRNAs and PCD in CRC.

Apoptosis-related ncRNAs and colorectal cancer

The term apoptosis was created to define a type of cell death that "seems to perform a complementary but opposite role to mitosis in regulating cells from animal. The morphological characteristics of apoptosis indicate that it is an active, inherent phenomenon that can be suppressed or triggered by various pathological and physiological stimuli [83]. Nowadays, many diseases are related to altered cellular survival [84]. Many cancers are characterized by inhibited or decreased apoptosis [85]. Apoptosis, which rapidly eliminates damaged cells when something goes wrong in a cell, can stop the cancer development. Conversely, the injured cell can survive and transform into a cancer cell. Cancer cells are capable of avoiding apoptosis and dividing continuously. The tumor suppressor gene TP53, mutated in about fifty percent of human malignancies, plays a significant role in defending normal cells from transforming into cancers. Because of its remarkable ability to act as a highly sensitive stress input collector, the p53 tumor suppressor is a significant barrier to neoplastic changes and tumor development [86].

Apoptosis plays a crucial role in keeping colonic epithelia intact. A dynamic balance between the proliferation of cells at the base and apoptosis at the top of the crypt maintains the normal typical configuration of colonic crypts [87,88,89]. There is growing evidence that the equilibrium of apoptosis rate and cell growth becomes disturbed during the formation of CRC. Suppression and failure of apoptosis may disrupt epithelial cell homeostasis, leading to the development of CRC and suboptimal response to chemotherapy and radiation [90]. Mutation in the oncogenes (BRAF, PIK3CA, and KRAS) and tumor suppressor genes (TP53, APC, and DC4/SMAD4) can lead to an ineffective apoptosis mechanism. An early indicator of CRC formation is the inability to eliminate mutated cells, accompanied by the continuous increase in proliferation. The development of early adenoma, which could later transform into adenocarcinoma and ultimately late-stage CRC, is caused by the accumulation of mutated colonic cells [91].

In recent research, ncRNAs have been demonstrated to play a crucial regulatory role in initiating apoptosis[92]. ncRNAs, in particular lncRNAs, miRNAs, and circRNAs, are widespread regulators for various cancer hallmarks, including genomic instability, apoptosis, proliferation, metastasis, and invasion [8]. Apoptosis, cell proliferation, chemoresistance, invasion, and metastasis are correlated with high levels of lncRNAs expression or silencing in CRC [93]. Several miRNAs have been found to be apoptosis inhibitors or promoters in CRC. Moreover, miRNAs in CRC also act as a tumor suppressor [94].

miRNAs

An oncogene called miR-135b-5p promotes tumor growth by boosting CRC cell proliferation and preventing apoptosis by inhibiting the TGF-signaling pathway [95]. Overexpression of miR-223 increases the cell cycle and prevents apoptosis in CRC cells [96]. miR-17-5 overexpression boosts the growth, anti-apoptosis, migration, and invasion of CRC cells, while miR-17-5p knockdown reduces cell growth, migration, and invasion but has little impact on apoptosis [97]. Yan and colleagues detected that the miR-4449/SOCS3/STAT3 axis played a critical role in the CRC cell’s growth and resistance to cell apoptosis [98]. Through suppressing the expression of the PTEN protein in CRC cells, miR-21-5p regulates malignant procedures such as proliferation, anti-apoptosis, cell cycle progression, and invasion [99]. miR-126, as a tumor suppressor miRNA, decreases mTOR expression, leading to an anticancer effect in CRC cells by mediating autophagy and apoptosis [100]. Ma et al. discovered that when miR-193a-3p was overexpressed, it enhanced cell apoptosis. On the other hand, when it was silenced, miR-193a-3p limited the apoptosis of CRC cells. miR-193a-3p exerted tumor-suppressing effects by altering the PAK3 signaling pathway [101]. Through the direct downregulation of ROCK1 and c-Met and their associated pathways, miR-148a can reduce CRC cells' angiogenesis and elevate their apoptosis[102]. MCM7's 3'UTR is a direct target of miR-107, which controls MCM7 expression. Additionally, MCM7 knockdown may influence CRC cell growth and apoptosis by the PAK2 pathway, and overexpressing PAK2 can reverse the biological impacts of MCM7 knockdown in CRC cell lines [103]. By targeting GREM2 via the TGF- pathway, miR-103a-3p downregulation decreases proliferation through the G1/S transition and boosts apoptosis in CRC cells [104]. Gao G et al. demonstrated that GA inhibited HT-29 cancer cell proliferation by inducing cell apoptosis by suppressing miR-21 expression [105]. The role of miR-451 in CRC is to inhibit growth and migration, enhance chemotherapeutic sensitivity, and induce apoptosis [106]. By targeting ING5, miR-196b-5p increases proliferation, migration, and invasion and suppresses apoptosis in CRC cells [107]. The suppression of miR-149 can reverse the impact caused by circRNA 100146 knockdown on CRC cell proliferation, apoptosis, migration, and invasion [108]. According to Lu et al.'s study, miR-338-3p overexpression decreased CRC cell proliferation and caused cell cycle arrest and apoptosis [109]. Xiao et al. showed that miR-4260 is a new oncomiR in CRC that boosts cell proliferation and migration and decreases apoptosis via 5-FU by directly targeting MCC [110]. MiR-296 inhibits CRC cell survival by increasing cell apoptosis. The deactivation of the AKT/STAT3 signaling pathway, which ARRB1 modulates, may be related to MiR-296-induced apoptosis in CRC [111]. The significant inhibition of miR-4262 production levels in CRC tissue enhances apoptosis and inhibits CRC proliferation [112]. Feng et al.'s study showed that BIK mRNA and protein levels were downregulated in malignant CRC cell lines. When miR486-3p was downregulated, it resulted in a significant increase in BIK mRNA levels. This increase suppressed cell proliferation, migration, and invasion and promoted apoptosis in CRC cells [113]. Ji and colleagues' study found that Melatonin reduced proliferation and viability while inducing apoptosis in CRC cells by stimulating the expression of the miR-34a/449a cluster [114]. The study by Zhou et al. demonstrated that miR-421 is highly expressed in CRC tissues, confirming that caspase-3 is a direct target of miR-42. Caspase-3 mRNA and protein levels are controlled in reverse by miR-421. These findings showed new signaling mechanisms in CRC and the significant role of miR-421 in apoptosis[115]. Table 1 presents a summary of Apoptosis-related ncRNAs and CRC.

Table 1 Apoptosis-related ncRNAs and colorectal cancer

lncRNAs

Jiang et al. research showed that increasing the levels of the lncRNA RP11-468E2.5 and suppressing the JAK/STAT signaling pathway by negatively targeting STAT5 and STAT6 inhibited CRC cell proliferation and increased apoptosis [116]. According to a study by Lin H et al., lncRNA SUMO1P3 boosted cell cycle and proliferation and suppressed apoptosis by silencing CPEB3 [117]. Ma et al. found that down-regulation of lncRNA BANCR elevated ADR sensitivity, inhibited proliferation and invasion, and facilitated apoptosis [118]. Yi and colleagues' research demonstrated that Lnc-S100B-2 was overexpressed in CRC. Lnc-S100B-2 expression could impact CRC cells' proliferation, apoptosis, and epithelial-mesenchymal transformation (EMT) [119]. Xiong et al. findings demonstrated that the primary role of lncRNA DANCR in CRC was controlling apoptosis [120]. The regulative impact of lnc-NEAT1 on CRC sensibility, apoptosis, and invasion can be changed by cleavage and polyadenylation-specific factor 4 (CPSF4) overexpression [121]. Inhibiting cell migration and growth, promoting apoptosis, and suppressing the proliferation of CRC cells are all effects of lncRNA GAS5 overexpression [122]. Chen et al. findings demonstrated that through sponging miR-519d-3p, lncRNA BLACAT1 could have a vital role in the growth, apoptosis, migration, invasion, and drug resistance of progression of CRC cells [123]. The increased expression of lncRNA CRLM1 in CRC cells represses apoptosis and promotes metastasis[124]. Yuan H and coworkers' results showed that lncRNA RPLP0P2 expression levels were related to the growth of CRC by boosting proliferation and metastasis and repressing apoptosis[125]. According to a study by Xu et al., RUNX1-activated lncRNA RNCR3 drove CRC cell growth and invasion while attenuating apoptosis. Although RUNX1 overexpression indeed increased lncRNA RNCR3 stages and AKT1 presentation, it substantially decreased miR-1301-3p presentation. These findings demonstrated that RUNX1/RNCR3/miR-1301-3p/AKT1 axis was implicated in CRC by regulating colon tumor growth, invasion, and apoptosis[126]. Lian and colleagues' study indicated that reduced expression of the lncRNA LINC00460 inhibited the growth of CRC cells and caused cell apoptosis[127]. Chen et al. findings showed that lncRNA RMST could act as an endogenous competitor for miR-27a-3p to inhibit the development of CRC. Also, overexpression of miR-27a-3p partially inverted the influences of lncRNA RMST overexpression on CRC cell apoptosis and growth[128]. Based on the findings of Guo et al., they found that lncRNA HCG11 overexpressed in CRC cell lines and approved that lncRNA HCG11 silence could enhance the apoptosis of CRC cells although suppressing cell growth, migration, and invasion[129]. Liang H et al. indicated that by targeting the miR-519b-3p/ZNF277 axis, lncRNA Duxap8 enhances CRC cell growth and suppresses apoptosis[130]. Table 2 presents a summary of the regulatory role of ncRNAs in the autophagy of CRC reported by studies.

Table 2 Regulatory role of ncRNAs in autophagy of colorectal cancer reported by studies

CircRNAs

In CRC cell lines, several circRNAs have been identified as key regulators of cancer cell behavior. A reduction in the expression of circRNA hsa_circ_0000523 (a.k.a. circ_006229) was observed across CRC cells, where it was found to inhibit the proliferation of SW620 and SW480 cells and enhance apoptosis. Knockdown of hsa_circ_0000523 has been linked to colorectal tumor formation through the release of miR-31, which activates the Wnt/β-catenin signaling pathway [131]. Similarly, the apoptosis potential of LoVo cells has been explored with the downregulation of circLMNB1, which was shown through flow cytometry and Hoechst staining to increase apoptosis, evidenced by elevated levels of Bax and caspase-3, two pro-apoptotic proteins. Overexpression of circLMNB1, in contrast, enhanced cell mobility [132]. Additionally, circCUL2 appears to regulate apoptosis through its influence on mitochondrial Bax and Bcl2 levels, with miR-208a-3p acting as a target that mediates the proliferative capacity of SW480 and SW620 cells [133]. Circ_0006174, elevated in CRC tissues, has been associated with larger tumor size and advanced cancer stages, promoting cancer cell activity while inhibiting apoptosis, as seen in HT-29 and DLD-1 cells [134]. Moreover, elevated hsa_circ_0064559 in CRC tumors has been found to enhance apoptosis by regulating apoptosis-related genes, highlighting its potential as a drug target and biomarker. Collectively, these findings underscore the complex role of circRNAs in modulating CRC progression and offer insights for potential therapeutic interventions [135].

In addition, circPDK1 overexpression in CRC malignancies has been observed to increase cell invasion, migration, the Warburg effect, and cell growth, while circPDK1 silencing promoted apoptosis. These effects were reversed by the depletion of miR-627-5p or CCND2, highlighting the functional impact of circPDK1 in CRC tissue [136]. Circ_0058123 was observed to increase RAC1 expression and reduce miR-939-5p in CRC cells and tissues, and its silencing restrained CRC cell functions, promoted apoptosis, and slowed tumor progression; these effects were reversed by a miR-939-5p inhibitor [137]. Downregulation of circ_0000370 reduced CRC cell growth, invasion, and migration while increasing apoptosis in cells, with in vivo studies confirming decreased tumor progression [138]. Similarly, silencing of circ_0000395 and circ_0001821 reduced CRC proliferation, invasion, and glycolytic capacity while promoting apoptosis [139, 140].

Other circRNAs, such as circ_0004585, were found overexpressed in CRC cells, especially in 5-FU-resistant tissues, where silencing increased 5-FU sensitivity and hindered CRC colony formation, invasion, and viability [141]. Downregulation of circ_0001535 prevented CRC cell migration, vessel formation, and proliferation while accelerating apoptosis, as observed through increased expression of miR-433-3p and inhibition of RBPJ [142]. Similarly, circ_0000467 downregulation reduced invasion, glycolysis, and migration while enhancing apoptosis in CRC cells, with this effect largely mediated through interactions with miR-330-5p [143]. Overexpression of circ_0001535 was noted in colon and rectum tissues, and its downregulation promoted apoptosis and decreased tumorigenic activities [144]. Elevated expression of circRAD23B was observed to accelerate CRC cell cycle progression and metastasis, with silencing of this circRNA reducing CRC proliferation and promoting apoptosis by activating the miR-1205/TRIM44 axis [145]. These findings underscore the multifaceted role of circRNAs in CRC progression, highlighting their potential as biomarkers and therapeutic targets.

Autophagy-related ncRNAs and colorectal cancer

The elimination of unneeded or malfunctioning cellular components is attributed to a cellular process called autophagy. This cellular process can be categorized into three types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) [146]. The process of macroautophagy is primarily facilitated by the autophagosome, which is the most frequent form of autophagy. Upon the fusion of the autophagosome and the lysosome, the resultant autolysosome acts as a site for lysosomal enzymes to degrade its contents into smaller biological molecules. These molecules are subsequently reused as fuel for cellular bioactivity or recycled by the cells [147].

Autophagy-related genes (ATGs) play a crucial role in regulating the development and turnover of autophagosomes [148]. These ATG-encoded products primarily function to enhance the buildup of a complex involving serine/threonine protein kinase and class III phosphatidylinositol 3-kinase (PI3K-III), thereby promoting the creation of autophagy vesicles and the assembly of the ATG5-ATG12/ATG16 junction system [149,150,151,152]. The Ser/Thr protein kinase complex comprises ATG13, focal adhesion kinase family interacting protein of 200 kDa (FIP200), ATG101, and ULK1 (unc-51 like autophagy activating kinase 1)/ULK2 protein kinases. The ULK complex is negatively regulated by the mammalian target of rapamycin (mTOR) and positively modulated by AMP-activated protein kinase (AMPK). It is also highly sensitive to amino acid deprivation and energy shortage [153].

Upstream factors such as protein kinase B (PKB/AKT) and mitogen-activated protein kinase (MAPK) are able to trigger mTOR activation, leading to the suppression of ULK. Conversely, AMPK and p53 can activate ULK by inhibiting mTOR. ULK1/ATG1 (or ULK2) can enhance the activity of hVps34 in the PI3K-III complex, which is crucial for autophagy initiated by Beclin1/ATG6 phosphorylation. This event results in recruiting other components, including Beclin1, p150, and ATG14 or UVRAG, into the complex. In addition, the production level of PIP3 is elevated, thereby promoting the ATG5-ATG12/ATG16 connection system to enter the growing autophagy vesicles [147].

The collaborative efforts of ATG4B and ATG7 result in the production of LC3-I (microtubule-associated protein light chain 3) from pro-LC3. The subsequent exposure of the C-terminal glycine of LC3-I leads to facilitating the conjugation of LC3-I with phosphatidylethanolamine (PE), which ultimately ends up in the generation of LC3-II. The latter is then incorporated into the expanding membrane. Consequently, LC3-II is widely acknowledged as an autophagosome marker [154]. The impact of autophagy on cancer cells manifests in various ways. Under specific circumstances, a number of autophagy genes may play a role in transforming normal cells into CRC. The initial autophagy marker that has been identified as participating in the development of CRC is LC3 [155].

For several years, there has been a prevailing debate surrounding the precise roles of autophagy in various types of cancer [156]. Although autophagy serves as a mechanism of equilibration and promotes anti-malignant effects by the clearance of unhealthy damaged particles, at the beginning of cancer, autophagy can facilitate the escape of cancerous cells from crisis conditions, such as hypoxia [157], starvation [158] and growth factor deprivation [159]. Several investigations have demonstrated that the upregulation of LC3-II, Beclin1, ATG 10, and ATG 5 in CRC is linked to metastasis and unfavorable prognosis for CRC patients [160,161,162,163]. Also, therapeutic agents can be more effective against CRC cells by inhibiting ATG4B and reducing autophagy [164]. A comparative clinical study revealed that, in contrast to CRC cells, the ATG4D gene is notably suppressed in the normal cells of advanced cancer patients [165]. In patients with CRC, ATG7 plays a key role in inhibiting the pathway that leads to cell death because reduced ATG7 expression induces apoptosis and improves chemotherapy [166]. knockdown of p62/sequestosome 1, which serves as a crucial receptor in directing ubiquitinated proteins toward the growing autophagosome [167], has been found to significantly decrease the autophagic process and impede the proliferation of CRC [168]. Increased radiosensitivity of CRC can achieved by concomitant administration of autophagy inhibitor chloroquine and mTOR inhibitor tesirolimus [163].

Pleckstrin homology-like domain family A member 2 (PHLDA2) has been identified as a promoter of CRC. Low levels of PHLDA2 cause a noticeable inhibition of CRC cell proliferation, migration, and invasion. in addition, this slight amount of PHLDA2 induced autophagy via the PI3K/AKT/GSK3β and PI3K/AKT/mTOR signaling pathways [169]. The involvement of ncRNAs in the autophagy process of CRC has been firmly established [170, 171].

miRNAs

Yang et al. showed that treating CAFs with a miR-31 mimic suppressed the expression of ATGs LC3, DRAM, ATG, and Beclin-1, improving CRC cells' radiation sensitivity co-cultured with CAFs. miR-31 has the ability to suppress autophagy in colorectal CAFs, influence the growth of CRC, and raise the radiation sensitivity of CRC cells co-cultured with CAF [172]According to Liu et al., overexpression of miR-93 decreased the effects of ionizing radiation (IR) on autophagy and increased the radiosensitivity of RC by suppressing its target gene, ATG12. [173]. By targeting ATG12, miR-214 has been demonstrated to greatly increase the radiosensitivity of CRC, prevent autophagy, and promote apoptosis [174]. Additionally, combining Bcl-2 and Beclin-1 can avoid the unwarranted activation of autophagy, whereas disrupting this connection may cause autophagy. [175, 176]. In hypoxic conditions, radiosensitivity has been demonstrated to decline partly due to autophagy. Based on this research, hypoxia-inducible factor-1a causes miR-210 to suppress the synthesis of Bcl-2 in CRC cells when the environment is hypoxic. This promotes autophagy and reduces radiosensitivity [177].

As an oncogenic factor in CRC, PIK3C3 knockdown increases drug sensitivity in CRC by damaging stem cells [178]. In order to mediate the development of CRC, PIK3C3 enhances autophagy levels. To suppress autophagy, miR-338-5p decreases the level of PIK3C3 expression, which increases survival and prognosis in patients with CRC [170]. One other cancer-causing factor in CRC is miR-125b, whose upregulation promotes metastasis in CRC cells by reducing CFTR and CGN levels [179]. Besides that, G-CSF increases miR-125b expression, which promotes CRC cell invasion [180]. The expression of miR-125b can be increased by the CXCL12/CXCR4 axis, which will speed up the progression of CRC by activating Wnt/β-catenin signaling and promoting autophagy [181]. The miRNA/autophagy axis also controls how CRC cells react to chemotherapy. The initiation of pro-survival autophagy may cause the insensitivity of CRC to 5-fluorouracil. To cause apoptosis by inhibiting autophagy, miR-22 reduces the expression level of BTG1, which affects drug resistance [182]. As a result, the miRNA/autophagy axis controls the development of CRC cells and how they react to treatment [183].

lncRNAs

According to increasing documentation, Autophagy is known to be a regulator of CRC development. The RSL1D1/RAN axis considerably enhances metastasis and proliferation of CRC cells by inhibiting autophagy [184]. IRF1 decreases the development of CRC by inhibiting the expression of ATG13, which mediates apoptosis and reduces autophagy [185]. Particularly, lncRNAs control autophagy to influence the development of CRC. The best-known controllers of autophagy are thought to be ATGs. lncRNAs tend to have an indirect effect on ATGs in controlling autophagy in CRC. ATG7 overexpression may act as a mediator for the induction of autophagy in the development of CRC [186].

Using RNA-seq analysis, Zhou et al. discovered that SP100-AS1 was overexpressed in the tissues of radioresistant CRC patients. Importantly, in vitro and in vivo cell proliferation, radioresistance, and tumor development were all expressively decreased by SP100-AS1 downregulation. ATG3 protein was also discovered to interact with and be stabilized by SP100-AS1 via the ubiquitination-dependent proteasome pathway. Additionally, it might act as a sponge for miR-622, that affected autophagic activity by targeting ATG3 mRNA [187].

However, SNHG8's position as an oncogenic factor is confirmed when its inhibition relates to miR-663 overexpression and CRC development reduction [188]. Based on the suppression of miR-588, SNHG8's role in CRC is associated with autophagy regulation. Then, to promote autophagy-induced CRC development, ATG7 expression rises [186]. Same with SNHG8, mounting studies demonstrated that HOTAIR, a lncRNA, had an oncogenic role in CRC. In order to promote FLT-1 expression in CRC carcinogenesis, HOTAIR participates in miR-211-5p sponging [189]. Furthermore, snail recruitment by HOTAIR has positive effects on EMT induction, decreasing HNF4 expression and increasing CRC attack [190]. The interplay between HOTAIR and ATG12 can define the response of CRC cells to radiation. In order to make CRC cells sensitive to radiotherapy, HOTAIR expression must be silenced. Radioresistance may be caused by autophagy induction by HOTAIR; the mechanism is that HOTAIR increases ATG12 expression by suppressing miR-93 to cause radioresistance via autophagy in CRC [173]. These studies demonstrate that the interaction between lncRNA and autophagy plays a role in the development of CRC [191].

CircRNAs

According to recent research, circRNAs exhibit aberrant expression in CRC, and they are good potential targets for cancer treatment. For example, circ-0052184 increases the expression of HOXA9 by acting as a ceRNA for miR-604 to promote CRC cell growth and invasion [192]. The role of circRNAs controls CRC cell growth and migration as well as patients' prognosis [193, 194]. CircRNAs that control autophagy are important in the realm of treating CRC. Circ-UBAP2 contributes to the development of CRC by promoting pro-survival autophagy. For CRC to proceed through autophagy, FOXO1 must be upregulated. Circ-UBAP2 upregulates FOXO1, which stimulates autophagy and promotes the development of cancer, by downregulating miR-582-5p [195]. In CRC cells, circRNAs control both autophagy and apoptosis. Circ-CUL2 inhibits the development of CRC; its upregulation can minimize tumor cell growth and invasion. When circ-CUL2 downregulates miR-208a-3p, it can cause PPP6C to overexpress, which causes the CRC to undergo autophagy and apoptosis [133].

In the course of treating CRC, the expression of circRNAs can be managed. Quercetin decreases the expression of Circ-0006990 in M2-polarized macrophages, which inhibits autophagy and facilitates the transition of these cells to M1-polarized macrophages [196]. Circ-BANP increases cell survival percentage and promotes cell autophagy, which decreases the susceptibility of CRC cells to radiation [197]. Zihao et al. discovered that recipient cells could acquire the oxaliplatin resistance-inducing properties of the elevated exosomal circATG4B produced from oxaliplatin-resistant CRC cells. Furthermore, circATG4B encodes a brand-new useful protein (circATG4B222aa) [198]. Inducing autophagy and oxaliplatin resistance in CRC cells both in vitro and in vivo was achieved by circATG4B-222aa but not by circATG4B itself. Additionally, they discovered that circATG4B222aa communicated with TMED10 in a competitive manner and served as a trap to stop binding TMED10 to ATG4B, increasing autophagy and causing drug resistance. Overall, this study showed a new molecular mechanism for how circRNAs acquired drug resistance in CRC. An essential biomarker that could serve as a targeted therapy for oxaliplatin-resistant CRC is the new circATG4B222aa [198].

Ferroptosis-related ncRNAs and colorectal cancer

Ferroptosis is a form of PCD that occurs as a result of the accumulation of iron-dependent lipid peroxides within cells brought about by a variety of factors, such as cysteine deficiency, loss of glutathione peroxidase 4 (GPX4) activity, and arachidonic (AA) peroxidation [199,200,201]. The clinical management of CRC can be improved through the activation of ferroptosis by diverse mechanisms such as elevating intracellular Fe2 + levels, the generation of reactive oxygen species (ROS), reducing the amount of the antioxidant glutathione (GSH), or inactivating GPX4 in CRC cells [202, 203].

The adjustment of redox homeostasis in cancer progression is a crucial aspect, and one protein that has received more attention is the NF-E2-related factor 2 (Nrf2). This protein mediates adaptation to oxidative stress caused by oncogenic stimulation [204]. The process of nuclear translocation and consequent activation of Nrf2 serves as a defensive mechanism for cancer cells against programmed cell death. This event also triggers cell proliferation, thus promoting tumor growth and survival [205]. In particular, ferroptosis has been linked to the development of Nrf2-mediated cancer, indicating its potential role in the carcinogenic process [206, 207].

The role of long intergenic non-protein coding RNA 239 (LINC00239) as a ferroptosis suppressor in CRC has been established. LINC00239 has been observed to stimulate the growth of CRC cells through its interaction with Kelch-like ECH-associated protein 1 (Keap1), which leads to instability in the structure of Keap1/Nrf2. Thus, the stability of the Nrf2 protein was elevated by LINC00239 by the inhibition of its ubiquitination, ultimately contributing to the advancement of CRC. It should be noted that Nrf2 is a regulator activating the transcription of LINC00239 in a manner that contributes positively to feedback. The combination of suppressing LINC00239 and inducing ferroptosis may hold great promise as a therapeutic method for patients with CRC [208]. The lncRNA named p53RRA has been identified to interact with G3BP1 and consequently enhance apoptosis and ferroptosis in lung cancer cells. This outcome is achieved through the sequestration of p53 in the nucleus by p53RRA [209]. The metastasis of CRC is facilitated by LINC00941, which works by stimulating the TGF-β/SMAD2/3 signaling pathway and obstructing the degradation of SMAD4 protein [210].

LINC00239 has been demonstrated to reduce levels of Fe2 + , ROS and lipid ROS, which is indicative of its participation in ferroptosis. In addition, the presence of LINC00239 has been shown to elevate the expression of various metabolic genes, like GPX4, which is connected to ferroptosis through its regulation of lipid ROS [208].

The participation of circRNAs in the process of ferroptosis can greatly influence the initiation and progression of CRC [211, 212]. XIAN and colleagues' study supports that circABCB10 predominantly interacts with C–C motif chemokine ligand 5 (CCL5) and miR-326. Downregulation of miR-326 can effectively target CCL5 and results in reducing the ferroptosis and apoptosis processes in CRC cells by the knockdown of circABCB10 [213].

LINC01606 acts as a booster of cancer by promoting the stemness and proliferation of tumor cells while also suppressing the occurrence of ferroptosis by Wnt/β‐catenin signaling. It has the potential to be a highly effective therapeutic target in the treatment of colon cancer. There is a safeguarding mechanism that protects colon cancer cells from ferroptotic cell death. This protection is achieved by increasing the formation of monounsaturated fatty acids via a positive feedback regulatory loop signaling called LINC01606–Wnt/β‐catenin–TFE3. This signaling actively blocks ferroptosis and promotes stemness [214].

The regulatory activity of MicroRNA‐15a‐3p (miR‐15a‐3p) has been detected in multiple cancer types. In the case of CRC, miR‐15a‐3p has a positive impact on ferroptosis regulation by means of its direct targeting of GPX4. Elevation in the levels of intracellular Fe2 + , ROS, and malondialdehyde (MDA) both in vitro and in vivo, are the consequences achieved by the upregulation of miR-15a-3p, which suppressed the expression of GPX4 through binding to its 3'-untranslated region. The findings show reduction in the sensitivity of CRC cells to GPX4 and erastin base on the suppression of miR-15a-3p. This highlight the regulatory role of miR-15a-3p in CRC cells ferroptosis by targeting GPX4 [215].

The tumor suppressor gene known as p53, or TP53, has been recognized to facilitate the occurrence of ferroptosis through a mechanism dependent on transcription. TP53 effectively restrains erastin-triggered ferroptosis by obstructing dipeptidyl-peptidase-4 (DPP4) activity through a transcription-independent manner. The absence of TP53 leads to the prevention of nuclear collection of DPP4 and consequently promotes DPP4-mediated lipid peroxidation at the plasma membrane. Ultimately, this cascade of events culminates in ferroptosis. These data unveil a direct molecular relationship between DPP4 and TP53 in the management of lipid metabolism and may provide a precision medicine method for the treatment of CRC by induction of the ferroptosis process [216].

The expression of circSTIL was found to be markedly elevated in CRC. Cell proliferation was detected to be suppressed during silencing of circSTIL in CRC cells while ferroptosis was induced. A noteworthy observation was that circSTIL presented competition with miR-431 for solute carrier family 7 member 11 (SLC7A11) binding. In addition, the cell phenotypes in CRC cells induced by circSTIL silencing were reversed by the suppression of miR-431 or overexpression of SLC7A11. The promotion of CRC cell proliferation and inhibition of the ferroptosis process in vitro by circSTIL was accomplished through the miR-431/SLC7A11 signaling pathway, which sheds light on the pathogenesis of CRC and identifies probable therapeutic targets for CRC patients [217].

When miR-545 was overexpressed, it effectively prevented the increase of MDA, ROS, and Fe2 + levels that were caused by erastin and Ras selective lethal 3 (RSL3). The overexpression of miR-545 also partially restored the survival rates of HT-29 and HCT-116 cells, which were reduced by erastin and RSL3. Transferrin (TF) was identified as a gene of interest targeted by miR-545. In order to ascertain whether miR-545 inhibits ferroptosis via TF, overexpression of TF was conducted in both HCT-116 and HT-29 cells. Upon examination, it was discovered that TF overexpression obstructed miR-545-mediated alterations in MDA, ROS, and Fe2 + concentrations in HCT-116 and HT-29 cells, leading to the apoptosis process in CRC cells. An experiment conducted in vivo demonstrated that the suppression of miR-545 led to a reduction in tumor growth in nude mice that were subjected to erastin therapy. These collective observations strongly suggest that miR-545 plays a critical role in promoting the survival of CRC cells by inhibiting transcription factor activity [218].

Several investigations have confirmed that miR-19a is detected as an oncogenic miRNA that accelerates the multi-steps of CRC cells metastasis. The miR-19a negatively regulates iron-responsive element-binding protein 2 (IREB2), which performs as an inducer of ferroptosis. It has been found that IREB2 is a direct target of miR-19a. Moreover, miR-19a suppresses ferroptosis by inhibiting IREB2 [219]. The miR-509-5p molecule exhibits tumor suppressor properties in CRC by regulating the expression of SLC7A11 and facilitating ferroptosis. Consequently, it represents a novel therapeutic object for the management of CRC [220].

The overexpression of OTUD6B-AS1, a lncRNA that contains the ovarian tumor domain 6B-antisense RNA1, has been shown to stabilize tripartite motif 16 (TRIM16) through its binding to human antigen R (HuR). Furthermore, this overexpression has also been found to increase GPX4-mediated ferroptosis, ultimately leading to the attenuation of CRC radioresistance [221]. The axis of circ_0007142/miR-874-3p/GDPD5 was found to have a notable impact on both tumorigenesis and ferroptosis in cells affected by CRC [222].

Pyroptosis-related ncRNAs and colorectal cancer

Pyroptosis, also called cellular inflammatory necrosis, stands out as an emerging facet of PCD in the intricate landscape of cancer [223]. The central player in this mechanism is the Gasdermin (GSDM) protein family, activated through cleavage by caspases and granzymes. This activation creates a cascade, resulting in membrane perforation, cellular swelling, and rupture, culminating in inflammatory responses [224]. In the realm of cancers like CRC, pyroptosis has been unveiled as a multifaceted contributor, impacting not only the genesis and progression of cancer but also shaping responses to treatment and prognostic outcomes [225]. Moreover, ncRNAs have been found to exert regulatory effects on the process of pyroptosis [226]. Cai et al. evaluated eight pyroptosis-associated lncRNAs, including LINC02381, LINC02798, Z99289.2, TEX41, FENDRR, MNX1-AS1, CCDC144NL-ASL, and NKILA. These lncRNAs exhibited the potential to predict treatment response and prognosis in individuals with CRC [227]. ceRNAs form a complex network where various RNA types, such as mRNAs and lncRNAs, compete for shared miRNA response elements. Specifically, lncRNAs serve as ceRNAs, capturing miRNAs and consequently affecting the expression of target mRNAs. This regulation plays a crucial role in controlling pyroptosis, influencing cancer development and the TME [228, 229]. Chen et al. assessed a ceRNA network based on 58 lncRNAs, 6 circRNAs, 25 pyroptosis-related genes, and 55 miRNAs. They revealed that KCNQ1OT1-miRNAs-SQSTM1 and HSA_CIRC_0001495-miRNAs-PTEN have potential regulatory sites and targets for regulating pyroptosis in colon adenocarcinoma [228]. The recent investigation illustrated that pyroptosis was instigated in a dose-dependent manner by ionizing radiation (IR). Furthermore, it identified that miR-448 targets the pyroptosis execution protein GSDME. The lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) was found to sponge miR-448, consequently influencing IR-induced pyroptosis and the vitality of human CRC cells by managing the expression, but not the initiation, of GSDME [230]. Pyroptosis-related lncRNAs have also been shown to have prognostic value in colon adenocarcinoma [231, 232]. While existing studies highlight the involvement of ncRNAs in the regulation of pyroptosis in CRC, the full scope of their role requires additional investigation for a comprehensive understanding.

Necroptosis-related ncRNAs and colorectal cancer

Necroptosis, also known as programmed necrosis, was first identified as a form of programmed death in 1988 and given a name in 2005 [233, 234]. Necroptosis is believed to play a key role in the control of tumors, including their spread, genesis, and immunity [235,236,237]. Necroptosis is a double-edged sword in tumor control; not only promotes metastasis and tumor development [238,239,240] but also inhibits it [241, 242]. When the apoptosis signal is missing, a regulated necrosis called necroptosis can be induced. DR family ligands and a variety of external and intracellular events that activate DR family ligands can both cause necroptosis [243]. Necroptosis is a critical factor in the growth promotion of several tumor types [244]. Necroptosis is a lytic kind of PCD that keeps active cells that have been prevented by apoptosis from destroying themselves. Necrotizing apoptosis is involved in destroying damaged or diseased cells in some degenerative or inflammatory disorders [245]. Necroptosis does not need the activation of caspase kinase, in contrast to apoptosis. The binding of a death receptor and ligand can cause necrotizing apoptosis when caspase inhibition is present [246]. The most well-understood types of controlled necroptosis are receptor-interacting protein kinase (RIP)1- and RIP3-mediated mixed lineage kinase domain (MLKD)-mediated necrosis [247]. Necroptosis is a novel target for molecular treatment since it has been demonstrated to contribute to the incidence and growth of the tumor. But it's still unclear how necroptosis relates to CRC [248].

PACER (p53-Activated Cell Death Enhancer in Response to DNA Damage) is a llncRNA that significantly regulates necroptosis, a form of PCD. It is transcriptionally activated by p53 in response to DNA damage, thereby enhancing p53 activity and indirectly influencing necroptosis [249]. PACER modulates the expression of receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3), essential for necrosome complex formation, allowing it to either promote or inhibit necroptosis based on the cellular context [250]. Additionally, PACER interacts with the NF-κB signaling pathway, impacting pro-survival gene expression. Its mechanisms include transcriptional regulation, post-transcriptional modifications, and modulation of protein–protein interactions. PACER's effects can vary in cancer cells—where it may enhance sensitivity to necroptosis-inducing agents—versus normal cells, where it likely helps maintain genomic stability [251]. Esra et al. demonstrated the critical regulatory roles that lncRNA PACER played in the regulation of the signaling pathway involved in necroptotic cell death. Notably, the absence of a necroptotic death signal in cancer cells may be due to the tumor promoter activity of PACER. Furthermore, it appears that RIP3 kinase plays a crucial role in PACER-associated necroptosis [243].

Eight important hub genes are found, and a ceRNA regulation network consisting of three mRNAs, five miRNAs, and one lncRNA is built. According to the immune infiltration study, the low-risk group had considerably higher immune-related scores than the high-risk group. Based on the risk score, necroptosis, and clinicopathological parameters (age and TNM stage), a nomogram of the model is created. The calibration curves suggest that the model can accurately forecast the CC 1-, 3-, and 5-year OS [244].

Evidence suggests that miR-29b-3p contributes to resistance to 5-fluorouracil (5-FU)-induced CRC necroptosis. Moreover, it has been demonstrated that miR-29b-3p targets the necroptosis TNF Receptor-Associated Factor 5 (TRAF5) regulatory component. The impact of miR-29b-3p on 5-FU-induced necroptosis may be reversed by rescue of TRAF5, which is compatible with the function of necroptostatin-1, a particular inhibitor of necroptosis. By controlling necroptosis, the miR-29b-3p/TRAF5 signaling axis is thought to play a crucial role in drug resistance in chemotherapy-treated CRC patients. The results of this investigation give us a new target for CRC interfere treatment. Additionally, they discovered that miR-29-3p lowered 5-FU's capacity to suppress tumor development in xenograft mice models in vivo and was resistant to 5-FU-induced necroptosis in vitro. Subsequent research revealed that miR-29-3p controlled medication resistance by suppressing the expression of TRAF5, the necroptosis regulatory component [252].

Necroptosis-related miRNAs have been employed by Huang et al. to predict the prognosis of patients with colon cancer, with mediocre results. Nevertheless, further research is needed to fully comprehend how lncRNAs and necroptosis interact in CRC, as their current understanding is inadequate. This work created a prognostic signature, categorized nine necroptosis-related lncRNAs (nrlncRNAs) based on risk ratings, and investigated how well the signature predicted immune infiltration and directed immunotherapy [248]. According to their research, a predictive signature derived from lncRNAs associated with necroptosis may be utilized to stratify individuals based on their likelihood of developing CRC and to understand the disease's underlying cause. LINC00513 functions as a positive regulator of interferon signaling pathways and is thought to have a role in systemic lupus erythematosus. The biological consequences of other nrlncRNAs not mentioned in the literature must be investigated. These nrlncRNAs and necroptotic genes interact closely, suggesting that they share some mechanisms in necroptotic pathways. Despite the fact that these lncRNAs' expressions all have a strong positive correlation with necroptotic genes, their varying impacts on prognosis are consistent with the paradoxical nature of necroptosis in malignancies [248].

DISC formation and early caspase-8 processing progress similarly via both DR4- and DR5-activated signaling in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells. In HT-29 cells, shRNA-mediated downregulation of DR4 or DR5 receptors suggested that DR5 had a greater role in TRAIL-induced apoptosis. In contrast to apoptosis, necroptotic signaling was triggered comparably by ligands specific to either DR4 or DR5. Auxiliary signaling pathways involving stress kinases or NF-κB were mostly activated in a DR5-dependent manner during apoptosis, and these ligands also activated these signaling pathways during necroptosis [253].

Disulfidptosis-related ncRNAs and colorectal cancer

Disulfidptosis, a recently identified form of PCD marked by disulfide stress due to the uptake of extracellular cysteine and excessive accumulation of intracellular cysteine, predominantly occurs in cells with elevated expression of solute carrier family 7 member 11 (SLC7A11) during glucose starvation and lacking repair mechanisms [254, 255]. Recent studies have demonstrated ncRNAs' regulatory effects in disulfidptosis regarding CRC [256,257,258,259]. For instance, Xue et al. constructed a risk model related to prognosis derived from four lncRNAs associated with disulfidptosis (ZEB1-AS1, SNHG16, SATB2-AS1, and ALMS1-IT1), which independently predicted prognosis of CRC cases and demonstrated noteworthy correlations with the tumor immune microenvironment, along with their responsiveness to immunotherapy and chemotherapy [260]. Altogether, grasping the complexities of disulfidptosis and its ties to the CRC remains an ongoing challenge, necessitating further investigation.

Conclusion

Figure 2 presents a summary of PCD (Autophagy, apoptosis, and ferroptosis-related ncRNA) in CRC. The diagram categorizes ncRNAs associated with various PCD pathways, including autophagy, pyroptosis, necroptosis, ferroptosis, disulfidptosis, and apoptosis, each represented in distinct sectors. Specific miRNAs, lncRNAs, and circRNAs that regulate or influence these processes are listed in each segment, highlighting their potential roles and interactions in modulating cell death mechanisms in CRC. Understanding these ncRNA-mediated interactions provides valuable insights into CRC progression and opens new avenues for developing targeted therapeutic strategies.

Fig. 2

Comprehensive overview of the classification of non-coding RNAs (ncRNAs) involved in different forms of programmed cell death (PCD) pathways in colorectal cancer (CRC). The circular diagram is divided into six sectors, each representing a specific PCD pathway, including autophagy, pyroptosis, necroptosis, ferroptosis, disulfidptosis, and apoptosis. Within each section, ncRNAs (including miRNAs, lncRNAs, and circRNAs) are displayed based on their regulatory roles in CRC-associated PCD pathways. The diagram uses red and blue arrows to indicate the functional impact of each ncRNA on PCD: red arrows signify ncRNAs that inhibit PCD pathways, thereby suppressing cell death, while blue arrows represent ncRNAs that enhance PCD pathways, promoting cell death. Understanding how these ncRNAs influence various PCD pathways provides insights into CRC biology and suggests potential therapeutic targets to selectively modulate cell death mechanisms for cancer treatment

ncRNAs have emerged as pivotal regulators of PCD pathways in CRC, influencing the progression, therapeutic response, and overall prognosis of the disease. By acting as molecular modulators, ncRNAs—especially miRNAs, lncRNAs, and circRNAs—can govern various forms of PCD, including apoptosis, autophagy, necroptosis, and ferroptosis, thereby affecting CRC cell fate and response to treatment. This literature review highlights the dual nature of ncRNAs in CRC; they can either promote tumorigenesis or function as tumor suppressors by interacting with PCD pathways and influencing the cellular microenvironment.

The interplay between ncRNAs and PCD in CRC offers substantial promise for the development of targeted therapies. Therapeutic strategies that modulate ncRNA expression to activate or inhibit specific PCD pathways could enhance treatment efficacy and reduce resistance to conventional therapies. Moreover, ncRNAs hold potential as biomarkers for CRC diagnosis and treatment monitoring, providing a pathway toward precision medicine.

In conclusion, the targeted modulation of ncRNAs presents a novel and promising strategy in CRC therapy. Future research should focus on further elucidating the specific molecular roles of ncRNAs in PCD, optimizing delivery methods for ncRNA-based therapies, and advancing clinical trials to validate these approaches. Ultimately, the integration of ncRNA knowledge into therapeutic strategies may improve CRC treatment outcomes and usher in a more personalized approach to cancer care.