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.

LncRNA HOTAIR acts as competing endogenous RNA to control the expression of Notch3 via sponging miR-613 in pancreatic cancer

“…HOTAIR was found to play an important role in pancreatic cancer progression, which has been shown in our previous study [14], and we further examined whether miR-613 had an interaction with HOTAIR. The bioinformatics prediction using the starBase tool [17, 18] found that HOTAIR was also a target of miR-613, and HOTAIR may act as a sponge for miR-613.…”

“…Our previous study showed that HOTAIR regulated the expression of miR-663b via histone modification in pancreatic cancer [14]. Recently, HOTAIR was proposed to function as a competing endogenous RNA by sponging miRNAs to regulate miRNAs levels.…”

“…One of important mechanisms is that the lncRNA acts as a miRNA sponge to regulate the miRNA expression, which in turn regulates the expression of specific genes targeted by miRNA. Previously, our study has shown that the lncRNA, HOX transcript antisense RNA (HOTAIR) regulates the expression of miR-663b via the histone modification, which results in the regulation of pancreatic cancer progression [14]. In addition, HOTAIR was found to control the expression of Rab22a by sponging miR-373 in ovarian cancer [15]; Liu et al, showed that HOTAIR functions as a competing endogenous RNA to regulated human epidermal growth factor receptor 2 (HER2) expression by sponging miR-331-3p in gastric cancer [16].…”

Exosomal miR‐663b targets Ets2‐repressor factor to promote proliferation and the epithelial–mesenchymal transition of bladder cancer cells

“…The miR‐663b has been demonstrated to promote cell proliferation, migration, invasion, and EMT in nasopharyngeal carcinoma (Liang et al, ; Wang et al, ). Blockade of miR‐663b inhibited cell proliferation and induced apoptosis in osteosarcoma (Shu et al, ), whereas miR‐663b was shown to exert tumor‐suppressive functions in pancreatic cancer (Cai et al, ). Here, we found that exosomal miR‐663b promoted cell proliferation and the EMT in BC cells, implying it functioned as tumor promoter in BC.…”

Long non‐coding RNAs in cancer: Another layer of complexity

“…Another mechanism of proliferation regulation via HOTAIR was reported in pancreatic cancer cells. HOTAIR induces histone modifications on the miR‐663b promoter, resulting in repression of this microRNA and, indirectly, up‐regulation of IGF2 . In retinoblastoma and cervical cancer, the NOTCH signaling pathway was abnormally activated as a consequence of HOTAIR up‐regulation …”