MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer

• Material Type: 博士論文
• Title: MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer
• Author/Editor: Okazaki, Jun; Tanahashi, Toshihito; Sato, Yasushi; Miyoshi, Jinsei; Nakagawa, Tadahiko; Kimura, Tetsuo; Miyamoto, Hiroshi; Fujino, Yasuteru; Nakamura, Fumika; Takehara, Masanori; Ma, Beibei; Bando, Masahiro; Kitamura, Shinji; Okamoto, Koichi; Muguruma, Naoki; Sogabe, Masahiro; Takayama, Tetsuji
• Author Heading: Okazaki, Jun; Tanahashi, Toshihito; Sato, Yasushi; Miyoshi, Jinsei; Nakagawa, Tadahiko; Kimura, Tetsuo; Miyamoto, Hiroshi; Fujino, Yasuteru; Nakamura, Fumika; Takehara, Masanori; Ma, Beibei; Bando, Masahiro; Kitamura, Shinji; Okamoto, Koichi; Muguruma, Naoki; Sogabe, Masahiro; Takayama, Tetsuji
• Publication, Distribution, etc.: Karger
• Publication Date: 2019-09-27
• Publication Date (W3CDTF): 2019-09-27
• Alternative Title: マイクロRNA296-5pはBcl2-Related Ovarian Killer遺伝子を介して細胞浸潤と薬剤耐性を促進し、膵癌の不良予後に寄与する; miRNA-296-5p and BOK in Pancreatic Cancer
• Periodical title: Digestion
• No. or year of volume/issue: 101 6
• Volume: 101
• Issue: 6
• Pages: 794-806
• ISSN (Periodical Title): ISSN : 0012-2823; ISSN : 1421-9867
• Degree grantor/type: 徳島大学
• Date Granted: 2019-12-26
• Dissertation Number: 甲第3341号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: Apoptosis; Biomarker; Epithelial-mesenchymal transition; MicroRNA; Pancreatic cancer
• Target Audience: 一般
• Note (General): Background/Aims: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive invasion, early metastasis, and resistance to chemotherapy, leading to a poor prognosis. To clarify the molecular mechanism of these malignant characteristics, we performed a genome-wide microRNA (miRNA) array analysis utilizing micro-cancer tissues from patients with unresectable PDAC (stage IV), obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA). Methods: The expression profiles of 2,042 miRNAs were determined using micro-cancer tissues from 13 patients with unresectable PDAC obtained by EUS-FNA. The relationship between individual miRNA levels and overall survival (OS) was analyzed. Possible target genes for miRNAs were bioinformatically analyzed using the online database miRDB. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and PK-8 were transfected with miRNA mimic or small interfering RNA, and cell invasion, epithelial-mesenchymal transition (EMT), and apoptosis markers were examined. miRNA and mRNA expressions were examined by quantitative polymerase chain reaction. Results: Of 2,042 miRNAs, the 10 that exhibited the lowest correlation coefficient (p ≤ 0.005) between miRNA expression level and OS among the patients were identified. The miRDB and expression analysis in cancer cell lines for the 10 miRNAs identified miR-296-5p and miR-1207-5p as biomarkers predictive of shorter survival (p < 0.0005). Bioinformative target gene analysis and transfection experiments with miRNA mimics showed that Bcl2-related ovarian killer (BOK), a pro-apoptotic gene, is a target for miR296-5p in pancreatic cancer cells; transfection of miR-296-5p mimic into PANC-1, MIA PaCa-2, and PK-8 cells resulted in significant suppression of BOK mRNA and protein expression. These transfectants showed significantly higher invasion capability compared with control cells, and knock down of BOK in pancreatic cancer cells similarly enhanced invasion capability. Transfectants of miR-296-5p mimic also exhibited aberrant expression of EMT markers, including vimentin and N-cadherin. Moreover, these transfectants showed a significantly lower apoptosis rate in response to 5-fluorouracil and gemcitabine with a decrease of BOK expression, suggesting a role of miR-296-5p in drug resistance. Conclusion: These results suggest that miR-296-5p is a useful biomarker for a poor prognosis in patients with PDAC, and that the miR-296-5p/BOK signaling axis plays an important role in cell invasion, drug resistance, and EMT in PDACs.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): © 2019 S. Karger AG, Basel
• Related Material (DOI): 10.1159/000503225
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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