Shin Sang Hun, Kwon Yang Woo, Heo Soon Chul, Jeong Geun Ok, Kim Ba Reun, Seo Eun Jin, Kim Jae Ho
1] Medical Research Center for Ischemic Tissue Regeneration, School of Medicine, Pusan National University, Yangsan, Republic of Korea [2] Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
1] Medical Research Center for Ischemic Tissue Regeneration, School of Medicine, Pusan National University, Yangsan, Republic of Korea [2] Department of Physiology, School of Medicine, Pusan National University, Yangsan, Republic of Korea [3] Medical Research Institute, Pusan National University, Yangsan, Republic of Korea [4] Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea.
Exp Mol Med. 2014 Jul 4;46(7):e104. doi: 10.1038/emm.2014.34.
Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer mortality among men in the United States. Accumulating evidence suggests that lysophosphatidic acid (LPA) serves as an autocrine/paracrine mediator to affect initiation, progression and metastasis of prostate cancer. In the current study, we demonstrate that LPA stimulates migration and proliferation of highly metastatic human prostate cancer, PC-3M-luc-C6 cells. LPA-induced migration of PC-3M-luc-C6 cells was abrogated by pretreatment of PC-3M-luc-C6 cells with the LPA receptor 1/3 inhibitor Ki16425 or small interfering RNA (siRNA)-mediated silencing of endogenous LPA receptor 1, implicating a key role of the LPA-LPA receptor 1 signaling axis in migration of PC-3M-luc-C6 cells. In addition, LPA treatment resulted in augmented expression levels of Krüppel-like factor 4 (KLF4), and siRNA or short-hairpin RNA (shRNA)-mediated silencing of KLF4 expression resulted in the abolishment of LPA-stimulated migration and proliferation of PC-3M-luc-C6 cells. shRNA-mediated silencing of KLF4 expression resulted in the inhibition of in vivo growth of PC-3M-luc-C6 cells in a xenograft transplantation animal model. Taken together, these results suggest a key role of LPA-induced KLF4 expression in cell migration and proliferation of prostate cancer cells in vitro and in vivo.
前列腺癌是美国男性中最常被诊断出的恶性肿瘤，也是癌症死亡的第二大主要原因。越来越多的证据表明，溶血磷脂酸（LPA）作为一种自分泌/旁分泌介质，影响前列腺癌的发生、发展和转移。在本研究中，我们证明LPA能刺激高转移性人前列腺癌PC-3M-luc-C6细胞的迁移和增殖。用LPA受体1/3抑制剂Ki16425预处理PC-3M-luc-C6细胞，或通过小干扰RNA（siRNA）介导沉默内源性LPA受体1，可消除LPA诱导的PC-3M-luc-C6细胞迁移，这表明LPA-LPA受体1信号轴在PC-3M-luc-C6细胞迁移中起关键作用。此外，LPA处理导致Krüppel样因子4（KLF4）表达水平升高，而siRNA或短发夹RNA（shRNA）介导的KLF4表达沉默导致LPA刺激的PC-3M-luc-C6细胞迁移和增殖被消除。在异种移植动物模型中，shRNA介导的KLF4表达沉默导致PC-3M-luc-C6细胞的体内生长受到抑制。综上所述，这些结果表明LPA诱导的KLF4表达在体外和体内前列腺癌细胞的细胞迁移和增殖中起关键作用。
