MicroRNA-203 impacts on the growth, aggressiveness and prognosis of hepatocellular carcinoma by targeting MAT2A and MAT2B genes

Abstract

Hepatocellular carcinoma (HCC) is characterized by the down-regulation of the liver-specific methyladenosyltransferase 1A ( MAT1A ) gene, encoding the S-adenosylmethionine synthesizing isozymes MATI/III, and the up-regulation of the widely expressed methyladenosyltransferase 2A ( MAT2A ), encoding MATII isozyme, and methyladenosyltransferase 2B ( MAT2B ), encoding a β-subunit without catalytic action that regulates MATII enzymatic activity. Different observations showed hepatocarcinogenesis inhibition by miR-203. We found that miR-203 expression in HCCs is inversely correlated with HCC proliferation and aggressiveness markers, and with MAT2A and MAT2B levels. MiR-203 transfection in HepG2 and Huh7 liver cancer cells targeted the 3’-UTR of MAT2A and MAT2B , inhibiting MAT2A and MAT2B mRNA levels and MATα2 and MATβ2 protein expression. These molecular events were paralleled by an increase in SAM content and were associated with growth restraint and apoptosis, inhibition of cell migration and invasiveness, and suppression of the expression of CD133 and LIN28B stemness markers. In contrast, MAT2B transfection in the same cell lines led to a rise of both MATβ2 and MATα2 expression, associated with increases in cell growth, migration, invasion and overexpression of stemness markers and p-AKT. Altogether, our results indicate that the miR-203 oncosuppressor activity may at least partially depend on its inhibition of MAT2A and MAT2B and show, for the first time, an oncogenic activity of MAT2B linked to AKT activation.

Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma

“…Recent research indeed showed that miR-21-3p lessens MAT2A and MAT2B expression in HepG2 cells by targeting their 3’-primer untraslated regions (3′-UTRs); it also inhibits cell growth [169]. Furthermore, we found that miR-203 expression is inversely correlated with MAT2A and MAT2B expression and the expression of HCC proliferation and aggressiveness markers [168]. MiR-203 expression is genetically regulated and contributes to determining patients’ outcomes [168].…”

“…Additionally, MAT2A cross-talks with polyamine synthesis in colon and liver carcinoma [166], and the sumoylated Matα2 protein protects human colon and liver cancer cells from apoptosis by regulating BCL2 expression [167]. Furthermore, we recently demonstrated an oncogenic activity of both MAT2A and MAT2B genes [168]. These finding suggest that these genes could be targets of anticancer therapies.…”

“…Furthermore, we found that miR-203 expression is inversely correlated with MAT2A and MAT2B expression and the expression of HCC proliferation and aggressiveness markers [168]. MiR-203 expression is genetically regulated and contributes to determining patients’ outcomes [168]. MiR-203 transfection of HepG2 and Huh7 liver cancer cells targets the 3′-UTR of MAT2A and MAT2B and strongly inhibits the expression of MAT2A and MAT2B mRNAs and MATα2 and MATβ2 proteins.…”

Luteolin exhibits anti-breast cancer property through up-regulating miR-203

“…Herein, we for the first time illustrated miR-203 as another anti-tumour executor of luteolin. miR-203 has been widely identified as an anti-tumour miRNA [17][18][19][20], but its exact function in breast cancer is confusing. Two of the previous studies reported miR-203 as an oncogene, as silence of its expression inhibited breast cancer cells colony formation, transformation, stemness and migration [21,37].…”

“…miR-203 is one of such oncogenic miRNA that locates at chromosome 14q32.33. The antitumour role of miR-203 has been found in various kinds of cancers, such as colorectal cancer [17], hepatocellular carcinoma [18], gastric cancer [19], prostate cancer [20] and so forth. However, miR-203 exerted contradictory roles in breast cancer.…”