Somatic mutations and losses of expression of microRNA regulation‐related genes AGO2 and TNRC6A in gastric and colorectal cancers

Abstract

Mounting evidence indicates that deregulation of microRNAs (miRNAs) are involved in development of many human diseases, including cancers. Regulation of miRNA is a complicated process and some components in the regulation are known to be altered in human cancers. Among the miRNA regulation-related genes, we found that AGO1, AGO2, TNRC6A, TNRC6C, TARBP2 and EXPORTIN5 genes have mononucleotide repeats in their coding sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analysed the mononucleotide repeats in 27 gastric cancers (GCs) with high MSI (MSI-H), 18 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 41 colorectal cancers (CRCs) with MSI-H, 14 CRCs with MSI-L and 45 CRCs with stable MSI (MSS) by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. We found AGO2, TNRC6A, TARBP2, TNRC6C and EXPORTIN5 mutations in 10, six, one, one and one cancer(s), respectively. They were detected in MSI-H but not in MSI-L or MSS cancers. The GCs and CRCs with MSI-H harboured one or more mutations of the genes in 22% and 27%, respectively. We also analysed Ago2 and TNRC6A protein expressions in GCs and CRCs with MSI-H. In cancers with MSI-H, loss of Ago2 expression was observed in 40% of GCs and 35% of CRCs, while loss of TNRC6A was observed in 52% of the GCs and 54% of the CRCs. Our data indicate that frameshift mutations in AGO2 and TNRC6A and their losses of expression are common in GCs and CRCs with MSI-H, and suggest that these alterations may contribute to the cancer development by deregulating miRNA regulation.

The Multiple Functions of TRBP, at the Hub of Cell Responses to Viruses, Stress, and Cancer

“…For example, increased expression levels of miRNAs, Dicer, TRBP, and Ago2 have been shown for prostate cancer cells compared to normal tissue (45). A mutation in the tarbp2 gene was also found in a gastric carcinoma, a cancer with microsatellite instability and a deregulation of miRNA expression (77). Further studies are needed to confirm the relevance and the role of these mutations in cancer development and to determine if TRBP deregulations contribute to additional cancers.…”

MicroRNA dysregulation in gastric cancer: a new player enters the game

“…In gastric cancer, the mRNA and protein expression of Dicer1 are significantly reduced during disease progression (Zheng et al, 2007). In a subset of gastric cancer with high microsatellite instability, Ago2 and TNRC6A, both of which are related to the execution of the gene-silencing function of miRNA, are also mutated and downregulated (Kim et al, 2010). Ago2 is a major component of RNAinduced silencing complex, whereas TNRC6A associates with Ago proteins and the target mRNA to induce gene silencing (Lazzaretti et al, 2009).…”

Functional Roles of microRNAs in Cancer: microRNomes and oncomiRs Connection

“…In addition, other reports showed that low expression levels of Drosha were significantly associated with advanced tumor stage in ovarian cancer [41]. Other components of the microRNA machinery that have been implicated in cancer include Argonaute family members Ago1, Ago3, and Ago4 which cluster on the 1p34-35 chromosomal region, that is often lost in in human cancers such as Wilms tumors, neuroblastoma and breast, liver and colon carcinomas [42]. In summary, emerging evidence suggests that oncomiRs play important roles in human cancers.…”