Recent Insights into the Pathogenesis of Colorectal Cancer

Ajay Goel; Clement Richard Boland

Disclosures

Curr Opin Gastroenterol. 2012;26(1):47-52. 

In This Article

MicroRNAs and Colorectal Cancer

miRNAs constitute a class of unique, single-stranded, evolutionarily conserved, small (19–25 ribonucleotides), noncoding RNAs that function as posttranscriptional gene regulators. miRNAs have emerged as new molecular players in carcinogenesis, and deregulation of their expression has been linked to multiple human cancers.[21] miRNAs contribute to oncogenesis functioning either as tumor suppressors (tsmiRs) or tumor promoters (oncomiRs). miRNAs were first discovered in worms, and thus far approximately 550 human miRNAs have been identified.[22] Each miRNA can regulate the expression of several mRNA targets; however, identifying the relationship between miRNAs and their target genes has been a challenge. Much of the current knowledge in this regard comes from in-silico predictions, but given the burgeoning evidence that miRNAs play a critical role in cancer initiation and progression, there is a growing interest to identify the authentic, functional targets of miRNAs in human cancers. In the last few years, several miRNAs have been shown to be up or downregulated in CRC. In the last year, several publications[23–34,35••,36–41] have highlighted the functional role of miRNAs in CRC, as summarized in Table 2.

Differentially Expressed Micrornas in Colorectal Cancer

miRNA profiling of CRCs has identified several up and downregulated miRNAs, and of interest, expression of miR-31, miR-183, miR-17-5, miR-18a, miR-20a and miR-92 have been found to be significantly higher in CRC than normal tissues, whereas miR-143 and miR-145 are expressed at lower levels in CRCs.[23] Findings from this study further revealed that CRCs with overexpression of miR-18a tended to have a poorer prognosis as compared with the tumors with lower expression of this miRNA.[23] miR-18a functions as a tumor suppressor miRNA by targeting the K-RAS oncogene.[24] Increased expression of cyclooxygenase-2 (COX-2) is a frequent event in CRC, and data indicate that downregulation of miR-101 is associated with overexpression of COX-2 in human CRC cells.[41]

Tumor Suppressor (tsmiRs) and Oncogenic (oncomiRs) MicroRNAs in Colorectal Cancer

Interrogation of the functional role of individual miRNAs has demonstrated that miR-135a and miR-135b directly target the 3′-untranslated region of the APC gene, suppress its expression and activate Wnt signaling.[25] Contrariwise, APC regulates expression of the tsmiR miR-122a and significantly downregulates miR-122a expression in gastrointestinal cell lines and tissues.[26] Inactivation of APC is considered a gatekeeper event for the initiation of CRC. These data reveal a miRNA-mediated mechanism for control of the APC gene and the activation of the Wnt signaling pathway.

Adenomatous polyps are precursors of most CRCs, and the progression of these lesions to cancer is a multistep process orchestrated through various genetic and epigenetic alterations. Increased expression of miR-21 has been linked to poor outcome and survival in CRC, so this functions as an oncomiR.[27] Moreover, recent reports of higher expression of miR-21 in adenomas and CRCs relative to normal surrounding tissue suggest that abnormal expression of this miRNA represents an early cellular event in the progression of CRC.[28,29] It has also been shown that miR-21 promotes cell migration and invasion by targeting the programmed cell death protein 4 (PDCD4) and phosphatase and tensin homolog (PTEN) tumor suppressor genes.[30]

Both miR-143 and miR-145 are downregulated in CRC, and the loci encoding these miRNAs are both located on 5q23.[31,32] Downregulation of insulin receptor substrate-1 (IRS-1) plays a significant role in the tumor suppressor activity of miR-145.[33] Upon further exploration of the functional role of these miRNAs, it was recently discovered that the tumor-suppressive role of miR-143 is achieved by targeting the DNA methyltransferase 3a (DNMT3A) gene.[42••] In further support of this, miR-143 was shown to inhibit translation of K-RAS.[34] Given the role of DNMTs and RAS/RAF signaling in the epigenetic regulation of gene expression, these data provide new directions for the possible development of miRNA-based targeted approaches to epigenetic therapy.

Molecular Regulation of MicroRNA Expression in Colorectal Cancer

The molecular mechanisms responsible for the deregulated expression of miRNAs in human cancer are poorly understood. A group of Japanese investigators[35••] elegantly demonstrated that the tumor suppressor gene p53 enhances the posttranscriptional maturation of several tsmiRs, including miR-16-1, miR-143 and miR-145, revealing a previously unrecognized function of p53 in miRNA processing. Additionally, it has been suggested that expression of tumor suppressive miRNAs can also be silenced via hypermethylation. In this regard, miR-34b, miR-34c, miR-9-1, miR-129-2 and miR-137, all of which are embedded in CpG islands, have been demonstrated to be targets of hypermethylation in CRC cell lines and tumor tissues.[36,37] MiR-9-1 methylation is also associated with the presence of lymph node metastases.[36] Taken together, there is a growing appreciation for the role of miRNAs in CRC and other cancers. The use of miRNAs as biomarkers is a newly emerging field, as is the potential exploitation of miRNAs as therapeutic targets.

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