Ke Ning, Sundaram Roshni, Liu Guohong, Chionis John, Fan Wufang, Rogers Cheryl, Awad Tarif, Grifman Mirta, Yu Dehua, Wong-Staal Flossie, Li Qi-Xiang
Immusol, Inc., San Diego, CA 92121, USA.
Mol Cancer Ther. 2007 Jun;6(6):1840-50. doi: 10.1158/1535-7163.MCT-07-0066.
GPR56 is an orphan G protein - coupled receptor, mutations of which have recently been associated with bilateral frontoparietal polymicrogyria, a rare neurologic disease that has implications in brain development. However, no phenotype beyond central nervous system has yet been described for the GPR56-null mutations despite abundant GPR56 expression in many non - central nervous system adult tissues. In the present study, we show that higher GPR56 expression is correlated with the cellular transformation phenotypes of several cancer tissues compared with their normal counterparts, implying a potential oncogenic function. RNA interference-mediated GPR56 silencing results in apoptosis induction and reduced anchorage-independent growth of cancer cells via increased anoikis, whereas cDNA overexpression resulted in increased foci formation in mouse fibroblast NIH3T3 cell line. When GPR56 silencing was induced in vivo in several xenograft tumor models, significant tumor responses (including regression) were observed, suggesting the potential of targeting GPR56 in the development of tumor therapies. The expression profiling of GPR56-silenced A2058 melanoma cell line revealed several genes whose expression was affected by GPR56 silencing, particularly those in the integrin-mediated signaling and cell adhesion pathways. The potential role of GPR56 in cancer cell adhesion was further confirmed by the observation that GPR56 silencing also reduced cell adhesion to the extracellular matrix, which is consistent with the observed increase in anoikis and reduction in anchorage-independent growth phenotypes. The oncogenic potential and apparent absence of physiologic defects in adult human tissues lacking GPR56, as well as the targetable nature of G protein - coupled receptor by small molecule or antibody, make GPR56 an attractive drug target for the development of cancer therapies.
GPR56是一种孤儿G蛋白偶联受体，其突变最近与双侧额顶叶多小脑回畸形有关，这是一种罕见的神经系统疾病，对大脑发育有影响。然而，尽管GPR56在许多非中枢神经系统的成体组织中大量表达，但尚未发现GPR56基因敲除突变在中枢神经系统以外的表型。在本研究中，我们发现与正常组织相比，几种癌组织中较高的GPR56表达与细胞转化表型相关，这意味着它具有潜在的致癌功能。RNA干扰介导的GPR56沉默导致癌细胞凋亡，并通过增加失巢凋亡减少癌细胞的非锚定依赖性生长，而cDNA过表达则导致小鼠成纤维细胞NIH3T3细胞系中集落形成增加。当在几种异种移植肿瘤模型中体内诱导GPR56沉默时，观察到显著的肿瘤反应（包括消退），这表明在肿瘤治疗开发中靶向GPR56具有潜力。对GPR56沉默的A2058黑色素瘤细胞系进行表达谱分析，发现了几个其表达受GPR56沉默影响的基因，特别是那些参与整合素介导的信号传导和细胞粘附途径的基因。GPR56沉默也降低了细胞与细胞外基质的粘附，这一观察结果进一步证实了GPR56在癌细胞粘附中的潜在作用，这与观察到的失巢凋亡增加和非锚定依赖性生长表型减少一致。GPR56在缺乏GPR56的成人组织中具有致癌潜力且明显没有生理缺陷，以及G蛋白偶联受体可被小分子或抗体靶向的特性，使得GPR56成为癌症治疗开发中一个有吸引力的药物靶点。
