期刊
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH
卷 12, 期 3, 页码 923-939出版社
E-CENTURY PUBLISHING CORP
关键词
Ovarian cancer; cisplatin-resistance; gene expression profile; differentially expressed genes; sanguinarine
资金
- Department of Science and Technology of Yunnan Province [2017FE467(-062)]
- Department of Public Health of Yunnan Province [D-201633]
- National Natural Science Foundation of China [81960469]
Ovarian cancer is refractory in response towards platinum-based chemotherapy, and resistance frequently develops. We attempted to identify the driving pathways in cisplatin-resistant ovarian cancer and develop targeted therapies to overcome this resistance. Using an integrated bioinformatics approach, a GSE15372 database from NCBI's Gene Expression Omnibus database was obtained for identifying differentially expressed genes (DEGs), in which 535 DEGs were found (407 up-regulated and 128 down-regulated) in association with ovarian cancer cisplatin-resistance. Gene ontology and pathway enrichment analyses further found that aberrant activation of EGFR/ErbB2 signaling was the driving event in resistant cells. A network of dysregulated genes was built based on these identified DEGs and protein-protein interaction network, which led to the identification of 7 potential inhibitors based on screening a 77 small molecule natural product library. Sanguinarine, alone and in combination with cisplatin, was found to significantly suppress the proliferation of wt/resistant ovarian cancer cells in vitro and the growth of parental and resistant ovarian xenograft tumors in vivo. Our study suggests that EGFR/ErbB2 activation is one of the driving pathways in developing cisplatin-resistance in ovarian cancer, and that sanguinarine has the potential to be developed as an effective therapy to overcome this therapeutic resistance.
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