Department of Orthopedics, The Central Hospital of Linyi, Linyi, Shandong, China.
Department of Cosmetic Plastic Surgery, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, China.
Cancer Biomark. 2018;23(1):67-77. doi: 10.3233/CBM-181365.
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.
BRAF V600E 抑制剂维莫非尼治疗黑色素瘤提供了治疗益处，但常见的耐药性仍然是一个挑战。为了确定维莫非尼耐药的分子机制，我们生成了对维莫非尼耐药的 A375-R 和 WM35-R 细胞系，并证明这些细胞在体外和体内的磷酸化（p）-STAT3 被上调。特别是信号转导和转录激活因子 3（STAT3）通路的激活与维莫非尼耐药有关。用 STAT3 特异性 siRNA（shRNA）抑制该通路可使 A375-R、WM35-R 细胞对维莫非尼敏感，并在体外和体内诱导细胞凋亡。此外，靶向 STAT3 诱导 miR-579-3p 的表达并引发对维莫非尼的耐药性。然而，用抗 miR-579-3p 靶向 miR-579-3p 逆转了对维莫非尼的耐药性。总之，这些结果表明 STAT3 介导的 miR-579-3p 下调导致对维莫非尼的耐药性。我们的研究结果表明，通过将维莫非尼与 STAT3 沉默或 miR-579-3p 过表达相结合，可能为克服维莫非尼耐药提供新的方法。
