Song Wei-Feng, Wang Lei, Huang Wei-Yi, Cai Xun, Cui Jiu-Jie, Wang Li-Wei
Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China E-mail :
Asian Pac J Cancer Prev. 2013;14(12):7529-36. doi: 10.7314/apjcp.2013.14.12.7529.
BACKGROUND AND AIMS: MicroRNA-21 (miR-21) is reported to be overexpressed and to contribute to proliferation, apoptosis and gemcitabine resistance in pancreatic ductal adenocarcinomas (PDACs). The aims of this study were to explore regulation of miR-21 expression by epigenetic change and its impact on chemoresistance and malignant properties of of pancreatic cancer. MATERIALS AND METHODS: We retrospectively collected 41 cases of advanced pancreatic cancer patients who were sensitive or resistant to gemcitabine and assessed levels of serum circulating miR-21 for correlation with cytotoxic activity. Histone acetylation in the miR-21 promoter was also studied in gemcitabine-sensitive and gemcitabine-resistant PDAC cells. Gemcitabine-resistant HPAC and PANC-1 cells were transfected with pre-miR-21 precursors (pre-miR-21) and antisense oligonucleotides (anti-miR-21), and were treated with TSA. Finally, invasion and metastasis assays were performed and alteration in mir-21, PTEN, AKT and pAKT level was evaluated in these cells. RESULTS: Serum miR-21 levels were increased in gemcitabine- resistant PDAC patients compared with gemcitabine-sensitive subjects. The miR-21 levels were increased in 6 PDAC cells treated with gemcitabine significantly, associated with 50% inhibitory concentrations (IC50s). Histone acetylation levels at miR-21 promoter were increased in PDAC cells after treatment with gemcitabine. Enhanced invasion and metastasis, increased miR-21 expression, decreased PTEN, elevated pAKT level were demonstrated in gemcitabine-resistant HPAC and PANC-1 cells. Pre-miR-21 transfection or TSA treatment further increased invasion and metastasis ability, decreased PTEN, and elevated pAKT levels in these two lines. In contrast, anti-miR-21 transfection could reverse invasion and metastasis, and PTEN and pAKT expressions induced by gemcitabine. CONCLUSIONS: MiR-21 upregulation induced by histone acetylation in the promoter zone is associated with chemoresistance to gemcitabine and enhanced malignant potential in pancreatic cancer cells.
背景与目的：据报道，微小RNA-21（miR-21）在胰腺导管腺癌（PDAC）中过表达，并促进其增殖、凋亡及吉西他滨耐药。本研究旨在探讨表观遗传变化对miR-21表达的调控及其对胰腺癌化疗耐药性和恶性生物学行为的影响。 材料与方法：我们回顾性收集了41例对吉西他滨敏感或耐药的晚期胰腺癌患者，检测血清循环miR-21水平，并分析其与细胞毒性活性的相关性。同时研究吉西他滨敏感和耐药的PDAC细胞中miR-21启动子区的组蛋白乙酰化情况。对吉西他滨耐药的HPAC和PANC-1细胞转染pre-miR-21前体（pre-miR-21）和反义寡核苷酸（anti-miR-21），并进行曲古抑菌素A（TSA）处理。最后进行侵袭和转移实验，并评估这些细胞中miR-21、PTEN、AKT和磷酸化AKT（pAKT）水平的变化。 结果：与吉西他滨敏感的患者相比，吉西他滨耐药的PDAC患者血清miR-21水平升高。6种经吉西他滨处理的PDAC细胞中miR-21水平显著升高，且与半数抑制浓度（IC50）相关。吉西他滨处理后，PDAC细胞中miR-21启动子区的组蛋白乙酰化水平升高。在吉西他滨耐药的HPAC和PANC-1细胞中，侵袭和转移能力增强，miR-21表达增加，PTEN表达降低，pAKT水平升高。pre-miR-21转染或TSA处理进一步增强了这两种细胞系的侵袭和转移能力，降低了PTEN表达，升高了pAKT水平。相反，anti-miR-21转染可逆转吉西他滨诱导的侵袭和转移以及PTEN和pAKT表达。 结论：启动子区组蛋白乙酰化诱导的miR-21上调与胰腺癌细胞对吉西他滨的化疗耐药及恶性潜能增强有关。
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