Ahn Jun-Ho, Hwang Sung-Hee, Cho Hyun-Soo, Lee Michael
System Toxicology Research Center, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea.
Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea.
Biomol Ther (Seoul). 2019 May 1;27(3):302-310. doi: 10.4062/biomolther.2018.133.
Melanoma cells have been shown to respond to BRAF inhibitors; however, intrinsic and acquired resistance limits their clinical application. In this study, we performed RNA-Seq analysis with BRAF inhibitor-sensitive (A375P) and -resistant (A375P/Mdr with acquired resistance and SK-MEL-2 with intrinsic resistance) melanoma cell lines, to reveal the genes and pathways potentially involved in intrinsic and acquired resistance to BRAF inhibitors. A total of 546 differentially expressed genes (DEGs), including 239 up-regulated and 307 down-regulated genes, were identified in both intrinsic and acquired resistant cells. Gene ontology (GO) analysis revealed that the top 10 biological processes associated with these genes included angiogenesis, immune response, cell adhesion, antigen processing and presentation, extracellular matrix organization, osteoblast differentiation, collagen catabolic process, viral entry into host cell, cell migration, and positive regulation of protein kinase B signaling. In addition, using the PANTHER GO classification system, we showed that the highest enriched GOs targeted by the 546 DEGs were responses to cellular processes (ontology: biological process), binding (ontology: molecular function), and cell subcellular localization (ontology: cellular component). Ingenuity pathway analysis (IPA) network analysis showed a network that was common to two BRAF inhibitor-resistant cells. Taken together, the present study may provide a useful platform to further reveal biological processes associated with BRAF inhibitor resistance, and present areas for therapeutic tool development to overcome BRAF inhibitor resistance.
黑色素瘤细胞已被证明对BRAF抑制剂有反应；然而，内在抗性和获得性抗性限制了它们的临床应用。在本研究中，我们对BRAF抑制剂敏感（A375P）和抗性（获得性抗性的A375P/Mdr以及内在抗性的SK-MEL-2）的黑色素瘤细胞系进行了RNA测序分析，以揭示可能与对BRAF抑制剂的内在抗性和获得性抗性相关的基因和通路。在内在抗性和获得性抗性细胞中总共鉴定出546个差异表达基因（DEG），包括239个上调基因和307个下调基因。基因本体（GO）分析显示，与这些基因相关的前10个生物学过程包括血管生成、免疫反应、细胞粘附、抗原加工和呈递、细胞外基质组织、成骨细胞分化、胶原蛋白分解代谢过程、病毒进入宿主细胞、细胞迁移以及蛋白激酶B信号的正调控。此外，使用PANTHER GO分类系统，我们表明546个DEG靶向的最高度富集的GO是对细胞过程的反应（本体：生物学过程）、结合（本体：分子功能）和细胞亚细胞定位（本体：细胞成分）。 Ingenuity通路分析（IPA）网络分析显示了两个BRAF抑制剂抗性细胞共有的一个网络。综上所述，本研究可能提供一个有用的平台，以进一步揭示与BRAF抑制剂抗性相关的生物学过程，并提出克服BRAF抑制剂抗性的治疗工具开发领域。
