https://scholars.lib.ntu.edu.tw/handle/123456789/470374
標題: | KRAS Mutation Is a Predictor of Oxaliplatin Sensitivity in Colon Cancer Cells | 作者: | Lin Y.-L. JAU-YU LIAU SHAN-CHI YU DA-LIANG OU LIANG-IN LIN LI-HUI TSENG YIH-LEONG CHANG KUN-HUEI YEH ANN-LII CHENG |
公開日期: | 2012 | 卷: | 7 | 期: | 11 | 起(迄)頁: | e50701 | 來源出版物: | PLoS ONE | 摘要: | Molecular biomarkers to determine the effectiveness of targeted therapies in cancer treatment have been widely adopted in colorectal cancer (CRC), but those to predict chemotherapy sensitivity remain poorly defined. We tested our hypothesis that KRAS mutation may be a predictor of oxaliplatin sensitivity in CRC. KRAS was knocked-down in KRAS-mutant CRC cells (DLD-1G13D and SW480G12V) by small interfering RNAs (siRNA) and overexpressed in KRAS-wild-type CRC cells (COLO320DM) by KRAS-mutant vectors to generate paired CRC cells. These paired CRC cells were tested by oxaliplatin, irinotecan and 5FU to determine the change in drug sensitivity by MTT assay and flow cytometry. Reasons for sensitivity alteration were further determined by western blot and real-time quantitative reverse transcriptase polymerase chain reaction (qRT -PCR). In KRAS-wild-type CRC cells (COLO320DM), KRAS overexpression by mutant vectors caused excision repair cross-complementation group 1 (ERCC1) downregulation in protein and mRNA levels, and enhanced oxaliplatin sensitivity. In contrast, in KRAS-mutant CRC cells (DLD-1G13D and SW480G12V), KRAS knocked-down by KRAS-siRNA led to ERCC1 upregulation and increased oxaliplatin resistance. The sensitivity of irinotecan and 5FU had not changed in the paired CRC cells. To validate ERCC1 as a predictor of sensitivity for oxaliplatin, ERCC1 was knocked-down by siRNA in KRAS-wild-type CRC cells, which restored oxaliplatin sensitivity. In contrast, ERCC1 was overexpressed by ERCC1-expressing vectors in KRAS-mutant CRC cells, and caused oxaliplatin resistance. Overall, our findings suggest that KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells by the mechanism of ERCC1 downregulation. ? 2012 Lin et al. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84870376365&doi=10.1371%2fjournal.pone.0050701&partnerID=40&md5=90193f7ab104d0bcfcc74761012c6d0e https://scholars.lib.ntu.edu.tw/handle/123456789/470374 |
ISSN: | 1932-6203 | DOI: | 10.1371/journal.pone.0050701 | SDG/關鍵字: | biological marker; doxorubicin; excision repair cross complementing protein 1; fluorouracil; irinotecan; K ras protein; messenger RNA; oxaliplatin; small interfering RNA; apoptosis; article; cancer cell; cell level; cell viability; colon cancer; concentration response; controlled study; down regulation; drug mechanism; drug sensitivity; gene mutation; gene overexpression; gene silencing; gene vector; human; human cell; IC 50; KRAS gene; predictive value; protein function; protein localization; treatment response; tumor gene; upregulation; Antineoplastic Agents; Apoptosis; Camptothecin; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; DNA-Binding Proteins; Endonucleases; Fluorouracil; Humans; Mutation; Organoplatinum Compounds; Proto-Oncogene Proteins; ras Proteins |
顯示於: | 病理學科所 |
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