Let-7 microRNA as a Genetic Regulator of Colorectal Carcinogenesis Process: Principles and Queries - Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide, whose mortality remains high, despite the huge amount of knowledge accumulated and the development of preventive strategies. Recent advances have demonstrated that small, non-coding RNA molecules (microRNAs), which inhibit or abrogate the translation of their mRNA-targets, are critical regulators across the full spectrum of stages of colorectal tumorigenesis process. The prototypical microRNA is let-7, with highly conserved sequence through species. Let-7 is found in ten mature isoforms, characterized by remarkable redundancy and abundance in colorectal epithelium. Let-7 is widely considered a tumor-suppressor, with scarce reports implying a concurrent oncogenic activity as well. K-ras oncogene, one of the most crucial genetic alterations in colorectal tumorigenesis, is a major target of let 7. The intact let-7 complementary sites (LCSs) in the 3’ UTR of mRNA of K-ras are indispensable for the complete action of let-7 upon K-ras expression. LCS6 is viewed as the most important of these LCSs, and a SNP variant (T to G) inside this locus exerts more prognostic and predictive role in CRC, when combined with K-ras status and let-7 levels. Mature let-7 is down regulated in colorectal cancer tissue compared with its paired normal mucosa; nonetheless it is gradually up regulated through the successive stages of colorectal tumorigenesis process, playing a central role in all the accomplishment of all these intermediate stages. Its high levels are considered a favorable prognostic and predictive biomarker, whereas its low levels may confer to early diagnosis of colorectal cancer. As let-7 collaborates with other miRNAs, regulates crucial oncogenes (as K-ras and c-myc) and tumor-suppressing pathways (as Wnt/APC and p53) and is regulated by a plethora of its effectors, it might serve as an in vivo manipulator of patients suffering from colorectal cancer in the future.