The Adiponectin-AdipoR1 Axis Mediates Tumor Progression and Tyrosine Kinase Inhibitor Resistance in Metastatic Renal Cell Carcinoma
The Adiponectin-AdipoR1 Axis Mediates Tumor Progression and Tyrosine Kinase Inhibitor Resistance in Metastatic Renal Cell Carcinoma
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脂联素-AdipoR1 轴介导转移性肾细胞癌的肿瘤进展和酪氨酸激酶抑制剂耐药性
DOI：
10.1016/j.neo.2019.07.004
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发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Zeng, Hao
中科院分区：
文献类型：
--
作者：
Sun, Guangxi;Zhang, Xingming;Zeng, Hao
诊断为转移性肾细胞癌（RCC）的患者的生存率仍然有限，目前的靶向治疗仅部分有效。本文旨在探讨脂联素受体（AdipoR 1和AdipoR 2）在接受酪氨酸激酶抑制剂（TKI）治疗的转移性肾细胞癌（RCC）患者中的临床价值和功能。共收集了2008年至2017年期间在一家机构接受一线TKI治疗的127例mRCC患者。AdipoR 1和AdipoR 2的表达通过免疫组织化学进行评估。AdipoR 1在87.4%（111/127）的肿瘤组织中呈阳性表达，尤其在肺和骨病变中呈高表达。原发性肿瘤组织中AdipoR 1表达低的患者在TKI治疗期间更有可能发生疾病进展（40.0% vs. 11.1%，P = 0.02），无进展生存期降低（PFS：19.5 vs. 37.8 mo，P = 0.001）和总生存期（OS：62.3 vs. 101.1 mo，P = 0.004）。此外，转移组织中的低AdipoR 1表达也与PFS（P = .006）和OS（P = .037）差相关。相反，AdipoR 2表达与舒尼替尼反应和患者生存率均不相关。在体外实验中，我们发现脂联素通过与AdipoR 1相互作用而不是与AdipoR 2相互作用来抑制RCC细胞的迁移、侵袭和对舒尼替尼的致敏。此外，我们证明脂联素-AdipoR 1轴通过阻断GSK 3 β/β-Catenin通路抑制肿瘤细胞的迁移和侵袭，并通过消除PI 3 K/AKT/NF-κ B信号通路增强舒尼替尼的敏感性。我们的研究结果表明，脂联素-AdipoR 1轴可能作为TKI反应的预测因子，并可能成为未来转移性RCC治疗的潜在靶点。
The survival of patients diagnosed with metastatic renal cell carcinoma (RCC) is still limited and the current targeted therapies are only partially effective. Herein, we investigated the clinical value and functions of adiponectin receptors (AdipoR1 and AdipoR2) in metastatic renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKIs). A total of 127 mRCC patients treated with first-line TKIs between 2008 and 2017 at a single institution were collected. AdipoR1 and AdipoR2 expression was assessed by immunohistochemistry. AdipoR1 was positively expressed in 87.4% (111/127) of tumors, especially, highly expressed in pulmonary and bone lesions. Patients with low AdipoR1 expression in primary tumor tissues were more likely to suffer from progressive disease during TKIs treatment (40.0% vs. 11.1%, P = 0.02), and with decreased progression-free survival (PFS: 19.5 vs. 37.8 mo, P = .001) and overall survival (OS: 62.3 vs 101.1 mo, P = .004) compared to those with high-AdipoR1 expression. Moreover, low-AdipoR1 expression in metastatic tissues was also associated with poor PFS (P = .006) and OS (P = .037). In contrast AdipoR2 expression was neither associated with sunitinib response nor patient survival. In vitro, we found that adiponectin inhibited migration, invasion and sensitized RCC cells to sunitinib though interacting with AdipoR1, but not AdipoR2. Furthermore, we demonstrated that adiponentin-AdipoR1 axis inhibits tumor cells migration and invasion by blocking the GSK3 beta/beta-Catenin pathway and enhances sunitinib sensitivity via abrogating PI3K/AKT/NF-kappa B signaling. Our results suggest that adiponentin-AdipoR1 axis may serve as a predictor of TKIs response and could be a potential therapeutic target in the future treatment for metastatic RCC.