Affiliations: [a] Department of Orthopedics, The Central Hospital of Linyi, Linyi, Shandong, China | [b] Department of Cosmetic Plastic Surgery, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, China | [c] Department of Cosmetic Plastic Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao, Shandong, China | [d] Department of Medcine, The People’s Hospital of Weifang, Weifang, Shandong, China
Correspondence:
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Corresponding author: Linxia Zhang, Department of Medcine, The people’s Hospital of Weifang, Weifang, Shandong, China. E-mail: tjykdx1806@126.com.
Note: [1] These authors contributed equally to the study.
Abstract: Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. To define molecular mechanisms of vemurafenib resistance, we generated A375-R, WM35-R cell lines resistant to vemurafenib and show that the phosphorylated (p)-STAT3 was upregulated in these cells in vitro and in vivo. In particular, activation of the Signal-transducer-and-activator-of-transcription 3 (STAT3) pathway was associated with vemurafenib resistance. Inhibition of this pathway with STAT3-specific siRNA (shRNA) sensitized A375-R, WM35-R cells to vemurafenib and induced apoptosis in vitro and in vivo. Moreover, targeting STAT3 induced expression of miR-579-3p and elicited resistance to vemurafenib. However, targeting microRNA (miR)-579-3p with anti-miR-579-3p reversed the resistance to vemurafenib. Together, these results indicated that STAT3-mediated downexpression of miR-579-3p caused resistance to vemurafenib. Our findings suggest novel approaches to overcome resistance to vemurafenib by combining vemurafenib with STAT3 sliencing or miR-579-3p overexpression.
