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Lulli, M.;  Napoli, C.;  Landini, I.;  Mini, E.;  Lapucci, A. Non-Coding RNAs in Colorectal Cancer. Encyclopedia. Available online: (accessed on 15 April 2024).
Lulli M,  Napoli C,  Landini I,  Mini E,  Lapucci A. Non-Coding RNAs in Colorectal Cancer. Encyclopedia. Available at: Accessed April 15, 2024.
Lulli, Matteo, Cristina Napoli, Ida Landini, Enrico Mini, Andrea Lapucci. "Non-Coding RNAs in Colorectal Cancer" Encyclopedia, (accessed April 15, 2024).
Lulli, M.,  Napoli, C.,  Landini, I.,  Mini, E., & Lapucci, A. (2022, November 17). Non-Coding RNAs in Colorectal Cancer. In Encyclopedia.
Lulli, Matteo, et al. "Non-Coding RNAs in Colorectal Cancer." Encyclopedia. Web. 17 November, 2022.
Non-Coding RNAs in Colorectal Cancer

Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Despite the advances in the knowledge of pathogenetic molecular mechanisms and the implementation of more effective drug treatments, the overall survival rate of patients remains unsatisfactory. The high death rate is mainly due to metastasis of cancer in about half of the cancer patients and the emergence of drug-resistant populations of cancer cells. Improved understanding of cancer molecular biology has highlighted the role of non-coding RNAs (ncRNAs) in colorectal cancer development and evolution. ncRNAs regulate gene expression through various mechanisms, including epigenetic modifications and interactions of long non-coding RNAs (lncRNAs) with both microRNAs (miRNAs) and proteins, and through the action of lncRNAs as miRNA precursors or pseudogenes. LncRNAs can also be detected in the blood and circulating ncRNAs have become a new source of non-invasive cancer biomarkers for the diagnosis and prognosis of colorectal cancer, as well as for predicting the response to drug therapy.

long non-coding RNAs colorectal cancer gene regulation

1. Introduction

Colorectal cancer (CRC) is one of the third most frequent and lethal cancer worldwide and the second leading cause of cancer-related deaths globally [1]. Most patients have metastases at diagnosis (approximately 20%) or develop them later because of the natural history of the disease (approximately 25%) [2]. Despite the availability of both cytotoxic chemotherapeutic and targeted agents, administered based on the knowledge of some tumor biomarkers, drug treatment response needs improvement because both intrinsic and acquired resistance mechanisms are responsible for treatment failure. Therefore, there is a clinical need to improve the understanding of the biological processes in CRC that are responsible for gene deregulation, heterogeneity, and escape during immunosurveillance and tumor growth control by drug treatment; thus, revealing the role of novel pathogenic determinants and their application as biomarkers for disease characterization, prediction of therapeutic drug response, and prognosis, is crucial [3].

2. LncRNAs in Initiation and Progression of CRC

CRC develops from normal mucosal epithelium to a benign adenoma and finally progresses to become a malignant tumor. The pathogenesis of CRC is a multi-step process driven by genetic and epigenetic alterations that perturb cellular physiology [4][5]. These alterations initiate an evolutionary process mainly characterized by the acquisition of hallmark capabilities for transforming CRC cells, such as sustaining proliferative signaling, evading growth suppressors, resisting apoptosis, enabling replicative immortality, and activating the epithelial-mesenchymal transition (EMT) program, angiogenesis, invasion, and metastasis. It has become clear in recent years that the alteration of numerous molecular mechanisms driven or coordinated by lncRNAs is directly involved in all of these cancer hallmarks. Considering the role of some lncRNAs in CRC initiation and progression, lncRNAs play a crucial role in the regulation of complex cellular processes, and the deregulation of a lncRNA can determine the phenotypic alteration of several tumor processes simultaneously, such as the induction of proliferation, invasive capacity, and metastasis of tumor cells.
Understanding the involvement of lncRNAs in tumorigenic signaling pathways, such as Wnt/β-catenin, epidermal growth factor receptor (EGFR)/insulin-like growth factor 1 receptor (IGF-1R), KRAS, phosphatidylinositol-3-kinase (PI3K), transforming growth factor-beta (TGF-β), p53, and EMT signaling pathways [6] can provide further insights into CRC pathogenesis.
Growing evidence indicates that the lncRNA regulator of reprogramming (lnc-ROR) regulates the progression of various cancers by promoting the proliferation, invasion, migration, and drug resistance of various cancer cells, including lung cancer, hepatocellular carcinoma, breast cancer, and CRC cells [7]. In CRC cell lines, lnc-ROR sponges miRNAs that regulate stem cell factors such as POU class 5 homeobox 1, Nanog, and SRY-box 2; it also reduces sensitivity to radiotherapy by deregulating the p53/miR-145 pathway [8]. Over-expression of lnc-ROR is also associated with the EMT pathway activation and metastases in CRC, and it down-regulates the expression of miR-6833-3p, thereby inhibiting the apoptosis-related protein SMC4 [9]. Deregulation of lncRNA expression occurs in a tissue- or organ-specific way [10][11][12] and appears to be strongly related to CRC onset and progression [13].
Deregulation of a lncRNA has been observed to be associated with the loss of imprinting of long QT intronic transcript 1 (LIT1/KCNQ1OT1) in CRC, indicating its potential as a useful marker for CRC diagnosis [14]. The oncogenic lncRNA HOX antisense intergenic RNA (HOTAIR) binds to polycomb repressive complex 2 (EZH2) and lysine-specific histone demethylase 1A (KDM1A) in the 5′ and 3′ regions and represses the transcription of the homeobox D cluster (HOXD) family genes in breast cancer progression and CRC by acting as a scaffold for histones [13]. The high expression of HOTAIR is significantly correlated with distant metastasis and poor prognosis in CRC patients [15], and it has not only been confirmed as a negative prognostic factor in primary tumors but also as a circulating biomarker in the blood of CRC patients [16].
Moreover, the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which acts as a predictive biomarker of metastasis in non-small cell lung cancer patients, has been described as a new prognostic marker in CRC patients [17][18]. The lncRNAs MALAT1, CCAT1, and PANDAR are up-regulated in the blood of CRC patients compared with that in healthy controls, suggesting their role as potential biomarkers for CRC prognosis [19].
Recently, Liu et al. [20] identified a competing endogenous RNA (ceRNA) regulatory network by bioinformatics analysis and experimental validation, in which 23 differentially expressed lncRNAs, 7 miRNAs, and 244 mRNAs act as regulatory axes associated with CRC tumorigenesis and prognosis. In the IGF2-AS/miR-150/IGF2 axis, the over-expression of miRNA150 down-regulates the expression of the lncRNA IGF2-AS, resulting in the over-expression of IGF2; however, IGF2-AS expression is positively correlated with IGF2 expression in CRC patients. Another lncRNA associated with the pathogenesis of CRC is plasmacytoma variant translocation 1 (PVT1); its up-regulation influences the down-regulation of miR-16-5p, which plays a significant role as a tumor suppressor in CRC [21]. The loss of PVT1 and miR-16-5p over-expression has been observed to drastically reduce the tumor volume in a mouse xenograft model. Furthermore, the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis is directly associated with CRC pathogenesis: PVT1 up-regulation induces the down-regulation of miR-16-5p, thereby reducing the binding of this miRNA to the mRNA VEGFA and up-regulating VEGFA, affecting VEGFR1 and AKT signaling [21]. Genome-wide association studies have identified a single nucleotide polymorphism at the PVT1 locus (8q24) that is closely associated with an increased risk of developing CRC [22]. The PVT1 locus drives the production of four miRNAs: miRNA-1204, miRNA-1205, miRNA-1206, and miRNA-1207-5p and -3p, some of which are important in the tumorigenic onset of CRC and gastric cancer [23][24][25][26].
Among the differentially expressed lncRNAs implicated in CRC progression, RP11-468E2.5 is less expressed in CRC samples than in paired normal mucosa, whereas its target genes STAT5A and STAT6 transcription factors are up-regulated [27]. Furthermore, the silencing of RP11-468E2.5 leads to an increase in the expressions of JAK2, STAT3, STAT5, STAT6, CCND1, and Bcl-2 and a decrease in P21 and P27 expressions, highlighting the effects of RP11-468E2.5 down-regulation on the activation of the JAK/STAT signaling pathway, which is driven by the increase of STAT5 and STAT6, promoting cell proliferation and inhibiting apoptosis in CRC [28].
The lncRNA MIR17HG is also associated with carcinogenesis and CRC progression [29]. MIR17HG induces NF-κB/RELA expression by sponging miR-375. RELA activates the transcription of MIR17HG by binding directly to its promoter region in a positive feedback loop [30]. Among the various miRNAs transcribed by MIR17HG, miR-17-5p reduces the expression of the tumor suppressor B-cell linker (BLNK), providing CRC cells greater capacity to migrate and invade. Furthermore, MIR17HG up-regulates PD-L1 expression, thus representing a potential target for immunotherapy.
The lncRNA MFI2-AS1 sponges miR-574-5, activating the expression of MYC binding protein (MYCBP) and thus promoting the proliferation and migration of CRC cells [31].
The lncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) is also closely associated with cell proliferation, migration, and invasion in both CRC cell lines and patients. Reduced expression levels of FEZF1-AS1 inhibit the activation of the EMT pathway and increase the expression levels of orthodenticle homeobox 1 (OTX1) [32]; thus, the FEZF1-AS1/OTX1/EMT axis is involved in CRC development. In addition, FEZF1-AS1 positively regulates the expression of NT5E by sponging miR-30a-5p.

3. Role of lncRNAs in CRC Drug Resistance

Positive or negative modulation of signaling pathways is the basis for maintaining cellular homeostasis, and alterations in these pathways can cause the development of diseases, such as cancer. LncRNAs are regulators of signaling pathways, and their deregulation may be closely related to the onset of cancer chemoresistance. This section highlights the results of various in vitro and in vivo studies related to the development of CRC chemoresistance associated with the deregulation of lncRNAs and their related signaling pathways. Several studies have been conducted regarding the potential contribution of lncRNAs to the onset of drug resistance in CRC [33]. The first example is the lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1), which is involved in the enhancement of methotrexate resistance. KCNQ1OT1 regulates the protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B) by sponging miR-760, thereby influencing the downstream cAMP responsive element binding protein 1 (CREB1) signaling pathway in CRC cells [34]. In addition, CREB1 is known as a proto-oncogenic transcription factor that modulates the expression of some crucial genes and miRNAs. Furthermore, KCNQ1OT1 up-regulation was observed to promote resistance to oxaliplatin in CRC cells and in an in vivo model by sponging miRNA-34a. This mechanism positively regulates the expression levels of the autophagy-related 4B cysteine peptidase (ATG4B) gene, a member of the autophagy protein family, which can enhance the protective autophagy pathway and chemoresistance [35]. Moreover, the group recently identified KCNQ1OT1 and the coding gene pinin, desmosome-associated protein (PNN) as predictive biomarkers of 5-fluorouracil response and outcome in stage III CRC patients. KCNQ1OT1 over-expression is associated with poor prognosis and the concomitant onset of resistance to 5-fluorouracil. Further studies are warranted to elucidate the signaling pathways influenced by KCNQ1OT1 activity and their potential correlations with drug resistance in CRC patients [36].
The lncRNA taurine up-regulated gene 1 (TUG1) is also associated with methotrexate resistance through its sponging activity on miRNA-186, which increases the expression of cytoplasmic polyadenylation element binding protein 2 (CPEB2) in colon cancer cell lines and in triple-negative breast cancer with increased metastasis [37]. In CRC cell lines, TGF-β promotes cell migration by up-regulating lncRNA TUG1 expression, while its knockdown inhibits migration, invasion, and the EMT pathway in CRC cells in vitro and reduces CRC lung metastasis in vivo [37]. This finding highlights the effects of TGF-β on metastasis via the TUG1/TWIST1/EMT signaling pathway in human CRC models [38].
Over-expression of XIST and ROR1 lncRNAs and concomitant down-regulation of miRNA-30a-5p also contribute to multidrug resistance in CRC cell lines and tissues [39].
Using RNA-Seq, RT-qPCR, and bioinformatics analysis, Zinovieva et al. identified five lncRNAs (LINC00973, LINC00941, CASC19, CCAT1, and BCAR4) in a murine CRC xenograft model as well as in HT-29 and HCT-116 CRC cell lines treated with 5-fluorouracil, oxaliplatin, and irinotecan at different concentrations and exposure times [40]. The most frequent changes were associated with LINC00973, which was most strongly and consistently increased in CRC cell lines treated with the aforementioned anticancer drugs. Recently, the lncRNA LINC00973 was characterized as a part of a ceRNA through its sponging activity on miRNA-7109-3p; this controls Siglec-15 expression, a critical immune suppressor, which is highly expressed in human cancer cells [41]. LINC00973 is also up-regulated in the cetuximab-resistant CRC cell line H508/CR; however, its silencing by a short interfering RNA (siRNA) reduces cell viability, increases apoptosis, and decreases glucose consumption and lactate secretion [42].
GIHCG, another important lncRNA, is over-expressed in several CRC cell lines and tissues; it promotes CRC cell proliferation and survival by inhibiting miR-200b/200a/429 expression and has been associated with resistance to 5-fluorouracil and oxaliplatin in CRC. High GIHCG expression is correlated with lymphovascular invasion, lymph node metastasis, and distant metastasis in CRC. Its over-expression also contributes to the resistance to anticancer drugs; patients with high expression levels of GIHCG show lower rates of overall survival and progression-free survival [43].
The lncRNA CACS15 is up-regulated in oxaliplatin-resistant CRC tissues and cells. It contributes to oxaliplatin resistance by positively regulating the expression levels of ABCC1 by sponging miR-145 [44]. CASC15 silencing overcomes oxaliplatin resistance in CRC by regulating the CASC15/miR-145/ABCC1 axis [45].
A lncRNA closely associated with resistance to 5-fluorouracil in CRC is H19 imprinted maternally expressed transcript (H19) through its sponging activity on miR-194-5p. This interaction leads to the up-regulation of SIRT1 and activation of the autophagic pathway, which may play a key role in drug resistance in several cancers, including CRC [46]. SIRT1, a member of the sirtuin family, removes acetyl groups from lysine residues of histones and non-histone proteins, driving gene expression and inducing several signaling pathways, including the autophagy pathway [47]. H19 also mediates resistance to methotrexate by modulating Wnt/β-catenin signaling in methotrexate-resistant CRC cell lines [48].
The over-expression of the lncRNA small Cajal body-specific RNA 2 (SCARNA2) is positively correlated with drug resistance and bad prognosis in CRC patients; down-regulation of SCARNA2 by RNA silencing was found to restore the drug sensitivity in vitro.
SCARNA2 promotes drug resistance by suppressing the miR-342-3p target sequence to modulate EGFR and B-cell lymphoma 2 (Bcl2) expression in CRC cells, thus entering the miR-342-3p-EGFR/BCL2 pathway [49].
The lncRNA X-inactive specific transcript (XIST) promotes doxorubicin resistance by sponging miRNA-124 and up-regulates serum and glucocorticoid-inducible kinase 1 (SGK1) in CRC cells and tissues [50]. Knockdown of XIST reverts resistance to doxorubicin, reduces ABCB1 and GSTP1 expression levels, and enhances apoptosis. Over-expression of miRNA-124 suppresses XIST-mediated effects, restoring the sensitivity of CRC-doxorubicin-resistant cell lines [50]. Moreover, XIST is involved in 5-fluorouracil resistance by up-regulating thymidylate synthase (TYMS) expression levels in CRC cells [51].
Another lncRNA associated with resistance to chemotherapeutic agents in CRC is the lncRNA BRAF-activated non-protein coding RNA (BANCR), which is over-expressed in CRC patients. BANCR causes doxorubicin resistance by modulating the miRNA-203/chromosome segregation 1 like (CSE1L) complex in tumor cells [52].
The lncRNA urothelial carcinoma-associated-1 RNA (UCA1) is associated with resistance to cetuximab. An increase in UCA1 expression levels in cetuximab-resistant CRC patients was negatively correlated with survival time. Moreover, circulating UCA1 promotes metastasis through the miR-143/MYO6 axis. UCA1 also causes resistance to 5-fluororacil by sponging miRNA-204-5p; a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory pathway is involved in 5-fluorouracil-resistance in CRC patients [53][54][55].
The lncRNA small nucleolar RNA host gene 15 (SNHG15) is also associated with resistance to 5-fluorouracil in CRC. By analyzing RNA-seq data of tumor tissue and paired normal mucosa obtained from 456 CRC patients, it was found that over-expression of SNHG15 in tumors was highly correlated with poor patient outcomes. Higher SNHG15 expression in tumors with high levels of MYC expression and direct modulation of SNHG15 transcription by the oncogene MYC were also observed. The inhibition of SNHG15 causes changes in multiple relevant genes implicated in cancer progression, including MYC, NRAS, BAG3, and ERBB3. Many of these genes are functionally related to apoptosis-induced factor (AIF), a protein that specifically interacts with SNHG15, suggesting that SNHG15 acts, at least partly, by regulating AIF activity and promotes cell proliferation, invasion, and drug resistance in CRC [56].
Another lncRNA associated with oxaliplatin resistance and promotion of metastasis is colorectal neoplasia differentially expressed (CRNDE), which is over-expressed in CRC patients and cell lines. CRNDE acts as a ceRNA, sponging miR-136 and driving the reactivation of its target E2F transcription factor 1 (E2F1) [57].
HOTAIR has been investigated as a putative marker involved in 5-fluorouracil resistance by promoting TYMS expression. HOTAIR overexpression inhibits 5-fluorouracil-induced cytotoxicity in CRC cell lines. High levels of HOTAIR are associated with poor response to 5-fluorouracil-based chemotherapy in CRC patients. The mechanism of resistance is closely related to the role of HOTAIR in the negative regulation of miRNA-218 expression and activation of the NF-κB pathway in CRC patients [58].
Coffey et al. identified that the lncRNA mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) and two associated miRNAs, miR-100 and miR-125b, are over-expressed in cetuximab-resistant CRC patients and head and neck squamous cell cancer cell lines [59]. miRNA-100 and miRNA-125b can repress some Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, whereas Wnt inhibition in cetuximab-resistant cells restores cetuximab responsiveness. The mechanism of cetuximab resistance represents a double-negative feedback loop between MIR100HG and the transcription factor GATA6; although GATA6 represses MIR100HG, this is hampered by its targeting of miR-125b [59].
Over-expression of the lncRNA prostate cancer-associated Transcript-1 (PCAT-1) promotes prostate cancer cell proliferation through MYC and is closely associated with poor prognosis in CRC patients. Silencing PCAT-1 in CRC cells suppresses cell motility and invasiveness and increases the response to 5-fluorouracil treatment [60]. Another lncRNA closely related to 5-fluorouracil resistance in CRC is HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1); it is present in lower levels in 5-fluorouracil-resistant CRC tissues and cell lines (HCT116 and SW480). HOTAIRM1 can induce drug resistance, together with B-cell translocation gene 3 (BTG3), which is a target of miRNA-17-5p. BTG3 is a p53 target that binds to the transcription factor E2F1, inhibiting its expression. BTG3 suppresses AKT activity, which is frequently deregulated in many cancers [61]. Thus, the over-expression of miRNA-17-5p causes down-regulation of HOTAIRM1 and BTG3, resulting in increased resistance to 5-fluorouracil in CRC cells [62].


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Subjects: Oncology
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Update Date: 18 Nov 2022