HCaRG/COMMD5 inhibits ErbB receptor-driven renal cell carcinoma.
HCaRG/COMMD5 inhibits ErbB receptor-driven renal cell carcinoma.
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DOI：
10.18632/oncotarget.18012
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发表时间：
2017-09-19
期刊：
影响因子：
--
通讯作者：
Tremblay J
中科院分区：
文献类型：
--
作者：
Matsuda H;Campion CG;Fujiwara K;Ikeda J;Cossette S;Verissimo T;Ogasawara M;Gaboury L;Saito K;Yamaguchi K;Takahashi S;Endo M;Fukuda N;Soma M;Hamet P;Tremblay J
高血压相关的钙调节基因（HCaRG/COMMD 5）在肾近端小管中高度表达，在那里它有助于控制细胞增殖和分化。HCaRG通过促进受损近端肾小管上皮细胞的再分化来加速肾小管修复，从而改善急性肾损伤后小鼠的存活率。持续的过度增殖和去分化是肿瘤进展的重要标志。在这里，我们证明了过表达HCaRG的癌细胞保持了更分化的表型，而其中一些发生自噬细胞死亡。其在小鼠肾细胞癌中的过表达导致在同种移植肿瘤模型中具有较少肿瘤血管化的较小肿瘤尺寸。机制上，HCaRG通过启动子甲基化促进原癌基因成红细胞增多症癌基因B（Erb B）2/HER2的去磷酸化和表皮生长因子受体和Erb B 3的表观遗传基因沉默。细胞外信号调节激酶、AKT和哺乳动物雷帕霉素靶标介导ErbB下游信号通路被HCaRG表达失活。此外，HCaRG在人肾细胞癌中表达不足，而在预后良好的肾细胞癌患者的邻近正常组织中表达更多。综上所述，我们的数据表明HCaRG作为癌症中ErbB信号的天然抑制剂和作为肾细胞癌的潜在预后标志物在抑制肿瘤进展中的作用。
Hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is highly expressed in renal proximal tubules, where it contributes to the control of cell proliferation and differentiation. HCaRG accelerates tubular repair by facilitating re-differentiation of injured proximal tubular epithelial cells, thus improving mouse survival after acute kidney injury. Sustained hyper-proliferation and de-differentiation are important hallmarks of tumor progression. Here, we demonstrate that cancer cells overexpressing HCaRG maintain a more differentiated phenotype, while several of them undergo autophagic cell death. Its overexpression in mouse renal cell carcinomas led to smaller tumor size with less tumor vascularization in a homograft tumor model. Mechanistically, HCaRG promotes de-phosphorylation of the proto-oncogene erythroblastosis oncogene B (ErbB)2/HER2 and epigenetic gene silencing of epidermal growth factor receptor and ErbB3 via promoter methylation. Extracellular signal-regulated kinase, AKT and mammalian target of rapamycin which mediate ErbB-dowstream signaling pathways are inactivated by HCaRG expression. In addition, HCaRG is underexpressed in human renal cell carcinomas and more expressed in normal tissue adjacent to renal cell carcinomas of patients with favorable prognosis. Taken together, our data suggest a role for HCaRG in the inhibition of tumor progression as a natural inhibitor of the ErbB signals in cancer and as a potential prognostic marker for renal cell carcinomas.
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