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Cell Death Dis. 2014 Apr 24;5:e1197. doi: 10.1038/cddis.2014.148.

MicroRNA-185 regulates chemotherapeutic sensitivity in gastric cancer by targeting apoptosis repressor with caspase recruitment domain.

Author information

1
National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
2
Department of Gastroenterology, Beijing Military General Hospital, Beijing 100700, China.
3
1] National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China [2] College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

Abstract

Gastric cancer remains the second leading cause of cancer deaths worldwide. Resistance to chemotherapy is a significant barrier for effective cancer treatment. Here, we identified miR-185 to be a contributor to chemosensitivity in gastric cancer. We observed low levels of miR-185 in gastric cancer cell lines and clinical tissues, compared with gastric epithelium cell line and noncancerous tissues. Furthermore, enforced expression of miR-185 increased the sensitivity of gastric cancer cells to low-dose chemotherapeutic agents, which alone cannot trigger significant apoptosis. Conversely, knockdown of endogenous miR-185 prevented high-dose chemotherapy-induced apoptosis. In elucidating the molecular mechanism by which miR-185 participated in the regulation of chemosensitivity in gastric cancer, we discovered that apoptosis repressor with caspase recruitment domain (ARC) is a direct target of miR-185. The role of miR-185 was confirmed in gastric tumor xenograft model. The growth of established tumors was suppressed by a combination therapy using enforced miR-185 expression and a low dose of anticancer drugs. Finally, we found that RUNX3 (Runt-related transcription factor) was involved in the activation of miR-185 at the transcriptional level. Taken together, our results reveal that RUNX3, miR-185 and ARC regulate the sensitivity of gastric cancer cells to chemotherapy.

PMID:
24763054
PMCID:
PMC4001303
DOI:
10.1038/cddis.2014.148
[Indexed for MEDLINE]
Free PMC Article

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