Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo, Japan.
AMED-CREST, Japan Agency for Medical Research and Development, Hachioji-shi, Tokyo, Japan.
Cancer Res. 2017 Jan 15;77(2):366-377. doi: 10.1158/0008-5472.CAN-16-0991. Epub 2016 Sep 26.
Insights into mechanisms of drug resistance could extend the efficacy of cancer therapy. To probe mechanisms in melanoma, we performed siRNA screening of genes that mediate the development of neural crest cells, from which melanocytes are derived. Here, we report the identification of ZIC5 as a mediator of melanoma drug resistance. ZIC5 is a transcriptional suppressor of E-cadherin expressed highly in human melanoma. ZIC5 enhanced melanoma cell proliferation, survival, drug resistance, in vivo growth and metastasis. Microarray analysis revealed that ZIC5 downstream signaling included PDGFD and FAK activation, which contributes to drug resistance by enhancing STAT3 activation. Silencing of ZIC5 or PDGFD enhanced the apoptotic effects of BRAF inhibition and blocked survival of melanoma cells resistant to BRAF inhibitors. Furthermore, inhibition of FAK or STAT3 suppressed expression of ZIC5, which was positively regulated by PDGFD, FAK, and STAT3 in a positive feedback loop. Taken together, our results identify ZIC5 and PDGFD as candidate therapeutic targets to overcome drug resistance in melanoma. Cancer Res; 77(2); 366-77. ©2016 AACR.
深入了解耐药机制可以延长癌症治疗的效果。为了探究黑色素瘤的机制，我们对神经嵴细胞（黑素细胞来源于此）发育过程中起介导作用的基因进行了 siRNA 筛选。在这里，我们报告了 ZIC5 作为黑色素瘤耐药性介质的鉴定。ZIC5 是 E-钙黏蛋白的转录抑制剂，在人黑色素瘤中高表达。ZIC5 增强了黑素瘤细胞的增殖、存活、耐药性、体内生长和转移。微阵列分析显示，ZIC5 的下游信号包括 PDGFD 和 FAK 的激活，通过增强 STAT3 的激活促进了耐药性。沉默 ZIC5 或 PDGFD 增强了 BRAF 抑制剂的促凋亡作用，并阻断了对 BRAF 抑制剂耐药的黑素瘤细胞的存活。此外，抑制 FAK 或 STAT3 抑制了 ZIC5 的表达，ZIC5 受 PDGFD、FAK 和 STAT3 的正向调节，形成正反馈回路。总之，我们的研究结果确定 ZIC5 和 PDGFD 是克服黑色素瘤耐药性的候选治疗靶点。Cancer Res; 77(2); 366-77. ©2016 AACR.
