Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do, 25451, Republic of Korea.
Cancer Lett. 2018 Dec 1;438:219-231. doi: 10.1016/j.canlet.2018.09.009. Epub 2018 Sep 11.
CD133 is a surface marker of liver cancer stem cells. Transmembrane 4 L six family member 5 (TM4SF5) promotes sphere growth and circulation. However, it is unknown how CD133 and TM4SF5 cross-talk with each other for cancer stem cell properties. Here, we investigated the significance of inter-relationships between CD133, TM4SF5, CD44, and protein tyrosine phosphatase receptor type F (PTPRF) in a three-dimensional (3D) sphere growth system. We found that CD133 upregulated TM4SF5 and CD44, whereas TM4SF5 and CD44 did not affect CD133 expression. Signaling activity following CD133 phosphorylation caused TM4SF5 expression and sphere growth. TM4SF5 bound to CD133 and promoted c-Src activity for CD133 phosphorylation as a positive feedback loop, leading to CD133-mediated sphere growth that was inhibited by TM4SF5 inhibition or suppression. TM4SF5 also bound PTPRF and promoted paxillin phosphorylation. Decreased sphere growth upon CD133 suppression was recovered by TM4SF5 expression and partially by PTPRF suppression. TM4SF5 inhibition enhanced PTPRF levels and abolished PTPRF suppression-mediated sphere growth. Altogether, CD133-induced TM4SF5 expression and function were important for liver cancer sphere growth and may be a promising target to block metastasis.
CD133 是肝癌干细胞的表面标志物。跨膜 4L 六家族成员 5（TM4SF5）促进球体生长和循环。然而，CD133 和 TM4SF5 如何相互作用以维持癌症干细胞特性尚不清楚。在这里，我们在三维（3D）球体生长系统中研究了 CD133、TM4SF5、CD44 和蛋白酪氨酸磷酸酶受体 F（PTPRF）之间相互关系的意义。我们发现 CD133 上调 TM4SF5 和 CD44，而 TM4SF5 和 CD44 并不影响 CD133 的表达。CD133 磷酸化后的信号活性导致 TM4SF5 的表达和球体生长。TM4SF5 与 CD133 结合并促进 c-Src 活性以促进 CD133 磷酸化，形成正反馈环，导致 CD133 介导的球体生长，TM4SF5 的抑制或下调可抑制该生长。TM4SF5 还与 PTPRF 结合并促进桩蛋白磷酸化。CD133 抑制后球体生长的减少可通过 TM4SF5 的表达部分恢复，通过 PTPRF 的抑制部分恢复。TM4SF5 抑制增强了 PTPRF 水平，并消除了 PTPRF 抑制介导的球体生长。总之，CD133 诱导的 TM4SF5 表达和功能对肝癌球体生长很重要，可能是阻止转移的有前途的靶点。
