MiR-21 Upregulation Induced by Promoter Zone Histone Acetylation is Associated with Chemoresistance to Gemcitabine and Enhanced Malignancy of Pancreatic Cancer Cells

Song, Wei-Feng; Wang, Lei; Huang, Wei-Yi; Cai, Xun; Cui, Jiu-Jie; Wang, Li-Wei

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자료유형: 학술저널

저자정보: Song, Wei-Feng (Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University) Wang, Lei (Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University) Huang, Wei-Yi (Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University) Cai, Xun (Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University) Cui, Jiu-Jie (Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University) Wang, Li-Wei (Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University)

저널정보: 아시아태평양암예방학회 Asian Pacific journal of cancer prevention : APJCP Asian Pacific journal of cancer prevention : APJCP 제14권 제12호

발행연도: 2013.1

수록면: 7,529 - 7,536 (8page)

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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 ($IC_{50}s$). 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.

#Serum miR-21 #advanced pancreatic cancer #chemosensitivity #histone acetylation

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Song, Wei-Feng

소속기관 Department of Medical Oncology, Shanghai First People's Hospital, Shanghai Jiao Tong University