Journal
CANCER LETTERS
Volume 410, Issue -, Pages 212-227Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.09.035
Keywords
miR-148a-3p; AKAP1; RAB12; Cisplatin sensitivity; Gastric cancer
Categories
Funding
- National Natural Science Foundation Project of International Cooperation (NSFC-NIH) [81361120398]
- United States Department of Veterans affairs [1IK6BX003787]
- United States National Institutes of Health [R01CA177372, R01CA93999]
- National Natural Science Foundation of China [81572362, 81702369]
- Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) [JX10231801]
- 333 Project of Jiangsu Province [BRA2015474]
- Jiangsu Key Medical Discipline (General Surgery)
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University
- China Postdoctoral Science Foundation [2016M601868]
- Postdoctoral Science Foundation of Jiangsu Province [1701033B]
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Cisplatin (CDDP) resistance is a major clinical problem associated with poor prognosis in gastric cancer (GC) patients. In this study, we performed integrated analysis of TCGA data from microRNAs (miRNAs) expression matrix of GC patients who received CDDP-based chemotherapy with GEO dataset which contains differential miRNAs expression profiles in CDDP-resistant and -sensitive cell lines. We identified miR-148a-3p downregulation as a key step involved in CDDP resistance. Using a cohort consisting 105 GC patients who received CDDP-based therapy, we found that miR-148a-3p downregulation was associated with a decrease in patients' disease-free survival (DFS, P = 0.0077). A series of experiment data demonstrated that: 1) miR-148a-3p was downregulated in CDDP-resistant GC cell lines; 2) miR-148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AKAP1 expression level; 3) AKAP1 played a novel role in CDDP resistance by inhibiting P53-mediated DRP1 dephosphorylation; 4) miR-148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. Taken together, our study demonstrates that miR-148a-3p could be a promising prognostic marker or therapeutic candidate for overcoming CDDP resistance in GC. (C) 2017 The Authors. Published by Elsevier B.V.
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