Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China.
School of Life Sciences and Technology, ShanghaiTech University, China.
Carcinogenesis. 2018 Mar 8;39(3):439-446. doi: 10.1093/carcin/bgx143.
Progestin and adipoQ receptor 4 (PAQR4) is a member of the PAQR family, and the members within this family are involved in the regulation of a number of biological processes including metabolism and cancer development. The potential function of PAQR4 in human cancers is unknown. Analysis of ONCOMINE database reveals that PAQR4 is highly expressed in human breast cancers. We confirmed this finding by analyzing 82 human breast cancers samples. PAQR4 mRNA level was significantly upregulated in human breast cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The mRNA level of PAQR4 was negatively correlated with disease-free survival (P < 0.0001) and overall survival of the patients (P = 0.001). Knockdown of PAQR4 in human breast cancer cells SUM159 and MCF7 suppressed cell proliferation. In contrast, overexpression of PAQR4 in SUM159 cells enhanced cell proliferation and colony formation. In a tumor xenograft model, overexpression of PAQR4 promoted tumor growth of SUM159 cells in vivo, while PAQR4 knockdown suppressed the tumor growth. PAQR4 was able to negatively regulate cyclin-dependent kinases 4 (CDK4) protein level in the breast cancer cells. Knockdown of PAQR4 accelerated degradation of CDK4 together with upregulation of CDK4 polyubiquitination. On the other hand, overexpression of PAQR4 slowed down CDK4 protein degradation and reduced CDK4 polyubiquitination. Collectively, these data at the cellular, animal and human levels indicate that PAQR4 has a tumorigenic effect on human breast cancers, and such effect is associated with a modulatory activity of PAQR4 on protein degradation of CDK4.
孕激素和脂肪素受体 4（PAQR4）是 PAQR 家族的成员，该家族成员参与调节多种生物学过程，包括代谢和癌症发展。PAQR4 在人类癌症中的潜在功能尚不清楚。ONCOMINE 数据库分析显示，PAQR4 在人类乳腺癌中高度表达。我们通过分析 82 个人类乳腺癌样本证实了这一发现。与相应的癌旁组织正常组织相比，PAQR4 mRNA 水平在人类乳腺癌样本中显著上调（P < 0.0001）。PAQR4 的 mRNA 水平与无病生存率（P < 0.0001）和患者的总生存率呈负相关（P = 0.001）。PAQR4 在人乳腺癌细胞 SUM159 和 MCF7 中的敲低抑制了细胞增殖。相比之下，PAQR4 在 SUM159 细胞中的过表达增强了细胞增殖和集落形成。在肿瘤异种移植模型中，PAQR4 的过表达促进了 SUM159 细胞在体内的肿瘤生长，而 PAQR4 的敲低抑制了肿瘤生长。PAQR4 能够负调控乳腺癌细胞中的细胞周期蛋白依赖性激酶 4（CDK4）蛋白水平。PAQR4 的敲低加速了 CDK4 的降解，同时上调了 CDK4 的多泛素化。另一方面，PAQR4 的过表达减缓了 CDK4 蛋白的降解，并降低了 CDK4 的多泛素化。总之，这些细胞、动物和人类水平的数据表明，PAQR4 对人类乳腺癌具有致癌作用，这种作用与 PAQR4 对 CDK4 蛋白降解的调节活性有关。
