Figure 2

Carcinogenesis of colorectal cancer cells and role of different miRNAs in cancer pathways. In the carcinogenesis of CRC, higher levels of miR-135a & miR-135b are associated with low levels of Adenomatous Polyposis Coli (APC) , which in turn leads to activation of the Wnt signalling pathway. Activation of the Wnt signalling pathway is a major tumour initiating event in the colonic epithelium. The low level of APC associated β-catenin degradation complex results in the formation of free cytoplasmic β-catenin that enters the nucleus and activates Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators (Survivin, c-Myc and Cyclin D1). As a consequence, there is a lack of apoptosis and increase proliferation of abnormal cells that results in autonomous growth and formation of adenoma. During the course of carcinogenesis, cells in adenoma accumulate few other genetic alterations leading to activation of other signalling pathways e.g. mitogen activated protein kinase (MAPK), Phosphatidylinositol 3-kinases (PI3K) and transforming growth factor-beta (TGFβ) pathways. The let-7 miRNA family, miR-18a* and miR-143 are adept at inhibiting the KRAS translation hence switching “off” the MAPK phosphorylation and inactivation of downstream transcription factors c-Myc, c-Fos and c-Jun. Furthermore, a targeted degradation of PTEN and p85β by miR-21 and miR-126 respectively , blocks the PI3K-Akt pathway. These changes drive the early adenoma to a large advanced adenoma. The loss of p53 function is associated with low expression levels of miR-34a family, indicating the role of this miRNA family in the transformation of adenoma to the carcinoma.