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.

Abstract

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.

• Authors: Huihua Cai, Yong An, Xuemin Chen, Donglin Sun, Tongbing Chen, Yan Peng, Feng Zhu, Yong Jiang, Xiaozhou He
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 52 Pg. 86857-86870 (Dec 27 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27895308 (Publication Type: Journal Article)

Chemical References

• HOTAIR long untranslated RNA, human
• IGF2 protein, human
• MIRN663 microRNA, human
• MicroRNAs
• RNA, Long Noncoding
• Insulin-Like Growth Factor II

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Insulin-Like Growth Factor II (genetics)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Middle Aged
• Pancreatic Neoplasms (genetics, pathology)
• RNA, Long Noncoding (genetics)
• Up-Regulation
• Xenograft Model Antitumor Assays (methods)