Epigenetic inhibition of miR-663b by long non-coding RNA HOTAIR promotes pancreatic cancer cell proliferation via up-regulation of insulin-like growth factor 2
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Huihua Cai1,*, Yong An1,*, Xuemin Chen1, Donglin Sun1, Tongbing Chen3, Yan Peng3, Feng Zhu1, Yong Jiang1, Xiaozhou He2
1Department of Hepatobiliary Surgery, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, China
2Department of Urology, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, China
3Department of Pathology, The First People's Hospital of Changzhou, The Third Hospital Affiliated to Soochow University, Changzhou, Jiangsu, China
*Both authors have contributed equally to this work
Xiaozhou He, email: [email protected]
Keywords: pancreatic cancer, miR-663b, IGF2, HOTAIR, tumor growth
Received: July 07, 2016 Accepted: September 06, 2016 Published: November 22, 2016
Pancreatic cancer is one of the most deadly cancers with a poor prognosis. Although microRNAs are involving in the carcinogenesis and development of pancreatic cancer, little information is known regarding the role of miR-663b in pancreatic cancer. In this study, the expression of miR-663b in pancreatic cancer cells was down-regulated by hypermethylation in its putative promoter region, and overexpression of miR-663b repressed cell proliferation, invasion and migration, and induced apoptosis in pancreatic cancer cells. Bioinformatics analysis, luciferase report assay and rescue experiments showed that insulin-like growth factor 2 (IGF2) was a direct target of miR-663b. Results from clinical samples showed that the expression level of miR-663b correlated with the pathological grading, and the expression of miR-663b was down-regulated and was inversely correlated with IGF2 expression level in pancreatic cancer tissues. More importantly, the long non-coding RNA, HOX transcript antisense RNA (HOTAIR), was up-regulated in both pancreatic cancer cells and tissues, and HOTAIR suppressed the expression of miR-663b in pancreatic cancer by histone modification on H3K4me3 and H3K27me3 on miR-663b promoter. Further in vivo studies demonstrated that the stable overexpression of miR-663b or knock-down of HOTAIR inhibited tumor growth and was associated with IGF2 expression. In summary, our studies demonstrated that miR-663b is epigenetically repressed by HOTAIR and exerts its tumor-suppressive function via targeting IGF2 in pancreatic cancer.
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