Honn Kenneth V, Guo Yande, Cai Yinlong, Lee Menq-Jer, Dyson Gregory, Zhang Wenliang, Tucker Stephanie C
Department of Pathology, Wayne State University, Detroit, Michigan, USA; Department of Chemistry, Wayne State University, Detroit, Michigan, USA Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan, USA;
Department of Pathology, Wayne State University, Detroit, Michigan, USA;
FASEB J. 2016 Jun;30(6):2360-9. doi: 10.1096/fj.201500076. Epub 2016 Mar 10.
Previously we identified and deorphaned G-protein-coupled receptor 31 (GPR31) as the high-affinity 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] receptor (12-HETER1). Here we have determined its distribution in prostate cancer tissue and its role in prostate tumorigenesis using in vitro and in vivo assays. Data-mining studies strongly suggest that 12-HETER1 expression positively correlates with the aggressiveness and progression of prostate tumors. This was corroborated with real-time PCR analysis of human prostate tumor tissue arrays that revealed the expression of 12-HETER1 positively correlates with the clinical stages of prostate cancers and Gleason scores. Immunohistochemistry analysis also proved that the expression of 12-HETER1 is positively correlated with the grades of prostate cancer. Knockdown of 12-HETER1 in prostate cancer cells markedly reduced colony formation and inhibited tumor growth in animals. To discover the regulatory factors, 5 candidate 12-HETER1 promoter cis elements were assayed as luciferase reporter fusions in Chinese hamster ovary (CHO) cells, where the putative cis element required for gene regulation was mapped 2 kb upstream of the 12-HETER1 transcriptional start site. The data implicate 12-HETER1 in a critical new role in the regulation of prostate cancer progression and offer a novel alternative target for therapeutic intervention.-Honn, K. V., Guo, Y., Cai, Y., Lee, M.-J., Dyson, G., Zhang, W., Tucker, S. C. 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression.
此前，我们鉴定并确定了G蛋白偶联受体31（GPR31）为高亲和力的12（S）-羟基二十碳四烯酸[12（S）-HETE]受体（12-HETER1）。在此，我们通过体外和体内试验确定了其在前列腺癌组织中的分布及其在前列腺肿瘤发生中的作用。数据挖掘研究强烈表明，12-HETER1的表达与前列腺肿瘤的侵袭性和进展呈正相关。对人类前列腺肿瘤组织阵列进行的实时PCR分析证实了这一点，该分析显示12-HETER1的表达与前列腺癌的临床分期和 Gleason评分呈正相关。免疫组织化学分析也证明，12-HETER1的表达与前列腺癌的分级呈正相关。在前列腺癌细胞中敲低12-HETER1可显著减少集落形成并抑制动物肿瘤生长。为了发现调控因子，我们在中国仓鼠卵巢（CHO）细胞中检测了5个候选的12-HETER1启动子顺式元件作为荧光素酶报告基因融合体，其中基因调控所需的假定顺式元件定位于12-HETER1转录起始位点上游2 kb处。这些数据表明12-HETER1在前列腺癌进展的调控中具有关键的新作用，并为治疗干预提供了一个新的替代靶点。-洪恩，K.V.，郭阳，蔡阳，李美珍，戴森，G.，张伟，塔克，S.C.12-HETER1/GPR31，一种高亲和力的12（S）-羟基二十碳四烯酸受体，在前列腺癌中显著上调并在前列腺癌进展中起关键作用。
