miR-372 Regulates Cell Cycle and Apoptosis of AGS Human Gastric Cancer Cell Line through Direct Regulation of LATS2

Abstract

Previously, we have reported tissue- and stage-specific expression of miR-372 in human embryonic stem cells and so far, not many reports speculate the function of this microRNA (miRNA). In this study, we screened various human cancer cell lines including gastric cancer cell lines and found first time that miR-372 is expressed only in AGS human gastric adenocarcinoma cell line. Inhibition of miR-372 using antisense miR-372 oligonucleotide (AS-miR-372) suppressed proliferation, arrested the cell cycle at G2/M phase, and increased apoptosis of AGS cells. Furthermore, AS-miR-372 treatment increased expression of LATS2, while over-expression of miR-372 decreased luciferase reporter activity driven by the 3' untranslated region (3' UTR) of LATS2 mRNA. Over-expression of LATS2 induced changes in AGS cells similar to those in AGS cells treated with AS-miR-372. Taken together, these findings demonstrate an oncogenic role for miR-372 in controlling cell growth, cell cycle, and apoptosis through down-regulation of a tumor suppressor gene, LATS2.

Involvement of parental imprinting in the antisense regulation of onco-miR-372-373

“…5b). These findings are in agreement with a previous report 21 , by which specific inhibition of miR-372-3 in human gastric cancer cell lines results in cell cycle arrest in the G2/M stage, along with increased levels of cellular apoptosis. To test the ability of anti-miR-371-3 to inhibit tumour formation in vivo, Tera1 cells were infected with lentiviruses carrying either antimiR-371-3 or an empty control vector.…”

“…An accumulating body of work links the overexpression of miR-372-3 with cell proliferation in different types of tumours 9,21,22 . Particularly, an oncogenic role for miR-372-3 was previously recognized in TGCTs where these miRs were shown to contribute to proliferation and cellular transformation 9 .…”

“…Therefore, we suggest that anti-miR-371-3 has a tumour suppressive role in TGCTs, as its overexpression in cancer cells prevents tumour formation in vivo. A well-established target of miR-372-3 is the large tumour suppressor homologue 2 (LATS2) 9,21 , whose deletion in mice was previously shown to increase cell proliferation and tumour development 26 . We thus inferred that overexpression of anti-miR-371-3 in Tera1 cells should remove LATS2 inhibition by miR-372-3 and result in cell growth arrest.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Similar to YAP overexpression, ablation of the Hippo pathway components Mer and Sav and double knockout of Mst1/2 in mice result in liver enlargement and tumor formation characteristic of HCC and cholangiocarcinoma (CC) (Zhou et al, 2009;Benhamouche et al, 2010;Lee et al, 2010;Lu et al, 2010;Song et al, 2010;. Aberrant Mst1/2 and Lats1/2 expression is observed in human cancers (Hisaoka et al, 2002;Jimé-nez-Velasco et al, 2005;Takahashi et al, 2005;Jiang et al, 2006;Minoo et al, 2007;Seidel et al, 2007;Cho et al, 2009;Zhou et al, 2009). Lats2 is also found mutated in human mesothelioma cell lines and non-small cell lung cancer (Strazisar et al, 2009;Murakami et al, 2011).…”

Resveratrol Alters microRNA Expression Profiles in A549 Human Non-Small Cell Lung Cancer Cells

“…Base pairing between miRNAs and complementary sites located in the 3′-untranslated regions of target mRNAs results in either the degradation or inhibition of mRNA translation, which subsequently reduces target gene protein levels (Ambros and Chen, 2007;Rana, 2007). miRNAs have been found to play roles in diverse biological processes, including development, differentiation, proliferation, and apoptosis (Chen et al, 2006;Cheng et al, 2005;Cho et al, 2009). Furthermore, human miRNAs exhibit aberrant expression patterns in several cancers, including lung cancer; additionally, miRNA genes are commonly found in cancer-associated genomic regions (Calin et al, 2005;He et al, 2005;Johnson et al, 2005).…”