Mechanisms and role of microRNA deregulation in cancer onset and progression

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5' end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms.

Epigenetic Alterations and Loss of Imprinting in Colorectal Cancer

Two forms of genomic instability have been described in colorectal cancer: chromosomal (CIN) and microsatellite instability (MIN). Colorectal cancer has been considered to progress through one of these two major pathways. However, recently a CpG island methylator pathway (CIMP) has been established among sporadic MIN cancers. Aberrant methylation of a promoter CpG island is associated with inactivation of tumor suppressor genes and is one of the epigenetic alterations identified to be involved in tumorigenesis. Now, several types of epigenetic alterations appear to play roles complementary to genetic mutations in colorectal carcinogenesis and seem to contribute to the progression of cancer. Epigenetic alterations also increase the probability that genetic changes will lead to cancer initiation. So far, major epigenetic alterations have been categorized into four groups of dysregulations: 1) hypomethylation with oncogene activation and chromosomal instability, 2) hypermethylation with tumor suppressor gene silencing, 3) chromatin modifications, and 4) loss of imprinting (LOI). Especially, LOI is a common epigenetic variant and should have a field effect on the colon, making it more vulnerable to genetic insults. Genomic imprinting is parental-origin-specific allele silencing, a form of gene silencing that is epigenetic in origin and does not involving alterations in the DNA sequence but does involve methylation and other modifications that are heritable during cell division. LOI is the loss of parental-origin-specific marks, leading either to aberrant activation of a normally silent allele of a growth promoter gene or to silencing of the growth inhibitor allele. Most of the attention has been focused on LOI of the IGF2 (insulin-like growth factor II) gene in a Wilms' tumor and colorectal cancer. LOI of IGF2 involves abnormal activation of a normally silent maternally inherited allele and has been associated with personal and family history of colorectal cancer, supporting a role for LOI in carcinogenesis. LOI may be a valuable predictive marker of an individual's risk for colorectal cancer. Now, epigenetics and imprinting are emerging areas in the study of human-cancer genetics.

Mechanism of Genomic Instability and Its Clinical Applications

Multiple genetic alterations are common prerequisite for carcinogenesis including colorectal cancers (CRCs). Recently, mutations within microsatellites have been described as a result of defective DNA mismatch repair (MMR) mechanisms, resulting in the phenomenon of microsatellite instability (MSI). This has been implicated in the etiology of hereditary non-polyposis colorectal cancer (HNPCC) and significant portions of sporadic colorectal cancers. However, the mechanisms underlying the MSI are different from hereditary CRCs and sporadic CRCs. While the germline mutation of MMR genes is responsible for HNPCC, the hypermethylation of MLH1 gene promoter regions, an epigenetic, not inherited alteration is responsible for most sporadic CRCs showing MSI. MSI tumors exhibit characteristic clinco- pathologic features, i.e, tumors are preferentially located to proximal to splenic flexure, poorly differentiated, mucinous cell type, frequently showing peritumoral lymphocytic infiltration, and, of importance, showing better survival in stage- matched cases. In this article, the results of recent investigations about MSI and its clinical applications are comprehensively reviewed. Knowledge of these biochemical mechanisms are likely to lead to more effective diagnosis and therapy of CRCs in the future