Zhao Weizhen, Qi Chenxiang, Mao Yixin, Ye Fengwen, Xia Tianxiang, Zhao Mingyu, Min Pengxiang, Zhang Yujie, Du Jun
Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167628. doi: 10.1016/j.bbadis.2024.167628. Epub 2024 Dec 15.
Targeted therapies persist as the conventional method of treatment of kidney clear cell carcinoma (KIRC). However, resistance to these drugs emerges as a significant impediment to the management of renal cancer. MICAL-L2 plays a pivotal role in cytoskeleton rearrangement. This study sought to elucidate the clinical relevance of MICAL-L2 in KIRC and its regulatory mechanism driving cancer progression and resistance to therapy. TCGA data mining was utilized to assess the expression of MICAL-L2 in samples from patients with KIRC. Kaplan-Meier analysis and immunohistochemistry were employed to explore the clinical significance of MICAL-L2. In vitro experiments, including assays for wound healing and Transwell migration, CCK-8, EDU staining, RT-PCR, flow cytometry, and co-immunoprecipitation analysis were conducted to investigate the effects of MICAL-L2 on the drug sensitivity of KIRC cells and to elucidate the molecular mechanisms involved. The results showed that MICAL-L2 was overexpressed in KIRC tissues. High levels of MICAL-L2 were associated with poor survival and a poor response to drug therapy among patients with KIRC. Overexpression of MICAL-L2 stimulated cell migration, proliferation, and rendered KIRC cells insensitive to sunitinib and everolimus, two traditional therapies for KIRC. Furthermore, MICAL-L2 overexpression accelerated cancer progression and resistance to therapy in KIRC cells by interacting with its downstream regulator α-actinin-4 (ACTN4) in a Rab13-dependent manner, which reduced the degradation of ACTN4, leading to increased Vimentin expression. All these findings indicate that MICAL-L2 plays a crucial role in the progression of KIRC and suggest that MICAL-L2 may serve as a potential therapeutic target for KIRC treatment.
靶向治疗仍然是肾透明细胞癌（KIRC）的传统治疗方法。然而，对这些药物的耐药性成为肾癌治疗的重大障碍。MICAL-L2在细胞骨架重排中起关键作用。本研究旨在阐明MICAL-L2在KIRC中的临床相关性及其驱动癌症进展和治疗耐药性的调控机制。利用TCGA数据挖掘评估KIRC患者样本中MICAL-L2的表达。采用Kaplan-Meier分析和免疫组织化学方法探讨MICAL-L2的临床意义。进行了体外实验，包括伤口愈合和Transwell迁移实验、CCK-8实验、EDU染色、RT-PCR、流式细胞术和免疫共沉淀分析，以研究MICAL-L2对KIRC细胞药物敏感性的影响，并阐明其中涉及的分子机制。结果表明，MICAL-L2在KIRC组织中过表达。KIRC患者中高水平的MICAL-L2与较差的生存率和对药物治疗的不良反应相关。MICAL-L2的过表达刺激细胞迁移、增殖，并使KIRC细胞对舒尼替尼和依维莫司这两种KIRC的传统治疗药物不敏感。此外，MICAL-L2的过表达通过以Rab13依赖的方式与其下游调节因子α-辅肌动蛋白-4（ACTN4）相互作用，加速了KIRC细胞的癌症进展和治疗耐药性，这减少了ACTN4的降解，导致波形蛋白表达增加。所有这些发现表明，MICAL-L2在KIRC的进展中起关键作用，并表明MICAL-L2可能作为KIRC治疗的潜在靶点。
