Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Cell Biol Int. 2022 Apr;46(4):554-567. doi: 10.1002/cbin.11750. Epub 2021 Dec 30.
Clear cell renal cell carcinoma (ccRCC) is one frequent form of urologic malignancy characterized by deregulated hypoxia-inducible factor signaling, genetic and epigenetic alterations. Metastasis is the leading cause of mortality from ccRCC, and understanding the underlying mechanism of this event will provide better strategies for its management. Here, we identify tripartite motif containing 7 (TRIM7) as a tumor suppressor in ccRCC cells, which negatively regulates hypoxia-inducible factor 1α (HIF-1α) signaling through targeting the proto-oncogene Src. We observed the downregulated expression of TRIM7 in clinical ccRCC tissues and its correlation with the poor prognosis. In Caki-1 cells, depletion of TRIM7 increased cell migration and invasion under normoxic and hypoxic conditions. TRIM7 markedly reduced the abundance of Src protein via the ubiquitin-proteasome pathway. Further study showed that TRIM7 affected HIF-1α accumulation through targeting either the Src-triggered PI3K/AKT/mTOR signaling pathway or reactive oxygen species production. Overall, our findings highlight a novel mechanism for negative regulation of HIF-1 signaling pathway by TRIM7 and define a promising therapeutic strategy for ccRCC by modulating TRIM7.
透明细胞肾细胞癌（ccRCC）是一种常见的泌尿系统恶性肿瘤，其特征是缺氧诱导因子信号失调、遗传和表观遗传改变。转移是 ccRCC 患者死亡的主要原因，了解这一事件的潜在机制将为其治疗提供更好的策略。在这里，我们发现三结构域蛋白 7（TRIM7）是 ccRCC 细胞中的肿瘤抑制因子，通过靶向原癌基因Src 来负调控缺氧诱导因子 1α（HIF-1α）信号。我们观察到 TRIM7 在临床 ccRCC 组织中的表达下调，其表达水平与预后不良相关。在 Caki-1 细胞中，TRIM7 的缺失会增加常氧和缺氧条件下细胞的迁移和侵袭。TRIM7 通过泛素-蛋白酶体途径显著降低Src 蛋白的丰度。进一步的研究表明，TRIM7 通过靶向 Src 触发的 PI3K/AKT/mTOR 信号通路或活性氧的产生来影响 HIF-1α的积累。总的来说，我们的研究结果强调了 TRIM7 负调控 HIF-1 信号通路的新机制，并通过调节 TRIM7 为 ccRCC 提供了一种有前途的治疗策略。
