Georgia Cancer Center, Augusta University, Augusta, GA.
Research Service, Charlie Norwood VA Medical Center, Augusta, GA.
Mol Cancer Ther. 2019 Apr;18(4):801-811. doi: 10.1158/1535-7163.MCT-18-1167. Epub 2019 Feb 20.
β-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that β-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. β-Arrestin-1 (ARRB1) and β-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts ( = 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, disease-specific-mortality, and failure to Gemcitabine + Cisplatin (G+C) chemotherapy; ∼80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9-mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.
β- arrestins 是经典的 G 蛋白偶联受体信号转导抑制剂。然而，它们在细胞生理学中具有多种作用，包括致癌作用。这项工作首次表明，β-arrestins 对预测膀胱癌的转移和化疗反应具有预后意义。通过定量 RT-PCR 在两个临床标本队列（n = 63 和 43）中测量 β-arrestin-1（ARRB1）和 β-arrestin-2（ARRB2）mRNA 水平。研究了 ARRBs 在调节类似干细胞表型和对化疗治疗反应中的作用。使用裸鼠膀胱癌异种移植研究了强制表达 ARRBs 对肿瘤生长和吉西他滨反应的影响。与正常组织相比，癌症组织中 ARRB1 水平显著升高，ARRB2 水平下调。在多变量分析中，只有 ARRB2 是转移、疾病特异性死亡率和吉西他滨+顺铂（G+C）化疗失败的独立预测因子；预测临床结果的敏感性和特异性约为 80%。发现 ARRB 调节膀胱癌细胞中的干细胞特征。ARRB2 耗竭导致癌症干细胞标志物增加，但 ARRB2 过表达减少干细胞标志物（CD44、ALDH2 和 BMI-1）的表达，并增加对吉西他滨的敏感性。过表达 ARRB2 导致肿瘤异种移植中的肿瘤生长减少和对吉西他滨的反应增加。CRISPR-Cas9 介导的 ARRB1 基因敲除导致这种侵袭性表型的逆转。ARRBs 调节膀胱癌中的癌症干细胞样特性，是肿瘤进展和化疗反应的潜在预后指标。
