MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN

Abstract

BackgroundMicroRNAs (miRNAs) can function as either oncogenes or tumor suppressor genes via regulation of cell proliferation and/or apoptosis. MiR-221 and miR-222 were discovered to induce cell growth and cell cycle progression via direct targeting of p27 and p57 in various human malignancies. However, the roles of miR-221 and miR-222 have not been reported in human gastric cancer. In this study, we examined the impact of miR-221 and miR-222 on human gastric cancer cells, and identified target genes for miR-221 and miR-222 that might mediate their biology.MethodsThe human gastric cancer cell line SGC7901 was transfected with AS-miR-221/222 or transduced with pMSCV-miR-221/222 to knockdown or restore expression of miR-221 and miR-222, respectively. The effects of miR-221 and miR-222 were then assessed by cell viability, cell cycle analysis, apoptosis, transwell, and clonogenic assay. Potential target genes were identified by Western blot and luciferase reporter assay.ResultsUpregulation of miR-221 and miR-222 induced the malignant phenotype of SGC7901 cells, whereas knockdown of miR-221 and miR-222 reversed this phenotype via induction of PTEN expression. In addition, knockdonwn of miR-221 and miR-222 inhibited cell growth and invasion and increased the radiosensitivity of SGC7901 cells. Notably, the seed sequence of miR-221 and miR-222 matched the 3'UTR of PTEN, and introducing a PTEN cDNA without the 3'UTR into SGC7901 cells abrogated the miR-221 and miR-222-induced malignant phenotype. PTEN-3'UTR luciferase reporter assay confirmed PTEN as a direct target of miR-221 and miR-222.ConclusionThese results demonstrate that miR-221 and miR-222 regulate radiosensitivity, and cell growth and invasion of SGC7901 cells, possibly via direct modulation of PTEN expression. Our study suggests that inhibition of miR-221 and miR-222 might form a novel therapeutic strategy for human gastric cancer.

Anti-microRNA-222 (Anti-miR-222) and -181B Suppress Growth of Tamoxifen-resistant Xenografts in Mouse by Targeting TIMP3 Protein and Modulating Mitogenic Signal

“…Subsequently, up-regulation of miR-221 and -222 has been implicated in resistance to drugs such as fulvestrant (30) and cisplatin (31) in breast cancer, castration-resistant prostate cancer (32), TNF-related apoptosis-inducing ligand (TRAIL)-resistant non-small cell lung cancer cells (33), and radiation-resistant gastric carcinoma cells (34). The ability of miR-221/222 to confer resistance has, however, been attributed mostly to targeting p27/Kip1 in breast cancer (9,10) and non-small cell lung cancer, ER␣ in breast cancer (10), and phosphatase and tensin homolog (PTEN) in gastric cancer (34). Here, we have shown for the first time that miR-221 and -222 can confer resistance to tamoxifen in breast cancers by regulating TIMP3 levels.…”

MicroRNAs and Their Impact on Radiotherapy for Cancer

“…Knockout of these miRNAs results in increased PTEN levels, which in turn lead to suppressed Akt activity and increased apoptosis, and most importantly, to enhanced radiosensitivity in various cancer cell lines (57). These results are in agreement with observations by other authors reporting studies using gastric (58) and colorectal cancer cell lines (54). Furthermore, PTEN is a known target of miR-21.…”

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

“…Therefore, the antitumor effect of gemcitabine might be associated with miR-1260b inhibition. miR-222 was also recognized as oncogenic miRNA (39)(40)(41)(42)(43). The cell cycle-dependent kinase inhibitor, p27Kip1 is the target gene of miR-222 (39,40,43).…”