School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai, China.
State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai, China.
Cell Death Dis. 2021 Oct 1;12(10):899. doi: 10.1038/s41419-021-04192-8.
The occurrence of metastasis is a serious risk for renal cell carcinoma (RCC) patients. In order to develop novel therapeutic approaches to control the progression of metastatic RCC, it is of urgent need to understand the molecular mechanisms underlying RCC metastasis and identify prognostic markers of metastatic risk. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been known to be closely associated with extracellular matrix (ECM) turnover, which plays a highly active role in tumor metastasis. Recent studies have shown that immunophilin FK-506-binding protein 51 (FKBP51) may be important for the regulation of ECM function, and exert effects on the invasion and migration of tumor cells. However, the mechanisms underlying these activities remain unclear. The present study detected the role of FKBP51 in clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC, and found that FKBP51 significantly promotes ccRCC invasion and migration by binding with the TIMP3, connecting TIMP3 with Beclin1 complex and increasing autophagic degradation of TIMP3. Given the important roles that TIMPs/MMPs play in ECM regulation and remodeling, our findings will provide new perspective for future investigation of the regulation of metastasis of kidney cancer and other types of cancer.
转移的发生是肾细胞癌（RCC）患者面临的严重风险。为了开发控制转移性 RCC 进展的新治疗方法，迫切需要了解 RCC 转移的分子机制，并确定转移风险的预后标志物。众所周知，基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制剂（TIMPs）与细胞外基质（ECM）的转化密切相关，而 ECM 的转化在肿瘤转移中起着高度活跃的作用。最近的研究表明，免疫亲和素 FK-506 结合蛋白 51（FKBP51）可能对 ECM 功能的调节很重要，并对肿瘤细胞的侵袭和迁移产生影响。然而，这些活性的机制尚不清楚。本研究检测了 FKBP51 在肾透明细胞癌（ccRCC）中的作用，ccRCC 是 RCC 最常见的亚型，结果发现 FKBP51 通过与 TIMP3 结合，将 TIMP3 与 Beclin1 复合物连接，并增加 TIMP3 的自噬降解，从而显著促进 ccRCC 的侵袭和迁移。鉴于 TIMPs/MMPs 在 ECM 调节和重塑中发挥的重要作用，我们的研究结果将为未来研究肾癌和其他类型癌症的转移调控提供新的视角。
