Gururajan Murali, Cavassani Karen A, Sievert Margarit, Duan Peng, Lichterman Jake, Huang Jen-Ming, Smith Bethany, You Sungyong, Nandana Srinivas, Chu Gina Chia-Yi, Mink Sheldon, Josson Sajni, Liu Chunyan, Morello Matteo, Jones Lawrence W M, Kim Jayoung, Freeman Michael R, Bhowmick Neil, Zhau Haiyen E, Chung Leland W K, Posadas Edwin M
Urologic Oncology Program/Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Oncotarget. 2015 Dec 29;6(42):44072-83. doi: 10.18632/oncotarget.6398.
FYN is a SRC family kinase (SFK) that has been shown to be up-regulated in human prostate cancer (PCa) tissues and cell lines. In this study, we observed that FYN is strongly up-regulated in human neuroendocrine PCa (NEPC) tissues and xenografts, as well as cells derived from a NEPC transgenic mouse model. In silico analysis of FYN expression in prostate cancer cell line databases revealed an association with the expression of neuroendocrine (NE) markers such as CHGA, CD44, CD56, and SYP. The loss of FYN abrogated the invasion of PC3 and ARCaPM cells in response to MET receptor ligand HGF. FYN also contributed to the metastatic potential of NEPC cells in two mouse models of visceral metastasis with two different cell lines (PC3 and TRAMPC2-RANKL). The activation of MET appeared to regulate neuroendocrine (NE) features as evidenced by increased expression of NE markers in PC3 cells with HGF. Importantly, the overexpression of FYN protein in DU145 cells was directly correlated with the increase of CHGA. Thus, our data demonstrated that the neuroendocrine differentiation that occurs in PCa cells is, at least in part, regulated by FYN kinase. Understanding the role of FYN in the regulation of NE markers will provide further support for ongoing clinical trials of SFK and MET inhibitors in castration-resistant PCa patients.
FYN是一种Src家族激酶（SFK），已证实在人类前列腺癌（PCa）组织和细胞系中上调。在本研究中，我们观察到FYN在人类神经内分泌PCa（NEPC）组织、异种移植瘤以及源自NEPC转基因小鼠模型的细胞中强烈上调。对前列腺癌细胞系数据库中FYN表达的电子分析显示，其与神经内分泌（NE）标志物如CHGA、CD44、CD56和SYP的表达相关。FYN的缺失消除了PC3和ARCaPM细胞对MET受体配体HGF的侵袭反应。FYN还在两种不同细胞系（PC3和TRAMPC2-RANKL）的内脏转移小鼠模型中促进了NEPC细胞的转移潜能。MET的激活似乎调节了神经内分泌（NE）特征，这在HGF处理的PC3细胞中NE标志物表达增加得到证明。重要的是，DU145细胞中FYN蛋白的过表达与CHGA的增加直接相关。因此，我们的数据表明，PCa细胞中发生的神经内分泌分化至少部分受FYN激酶调节。了解FYN在调节NE标志物中的作用将为去势抵抗性PCa患者正在进行的SFK和MET抑制剂临床试验提供进一步支持。
