Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
Oncogene. 2024 Sep;43(39):2951-2969. doi: 10.1038/s41388-024-03126-w. Epub 2024 Aug 22.
High invasive capacity and acquired tyrosine kinase inhibitors (TKI) resistance of kidney renal clear cell carcinoma (KIRC) cells remain obstacles to prolonging the survival time of patients with advanced KIRC. In the present study, we reported that sine oculis homeobox 1 (SIX1) was upregulated in sunitinib-resistant KIRC cells and metastatic KIRC tissues. Subsequently, we found that SIX1 mediated metastasis and sunitinib resistance via Focal adhesion (FA) signaling, and knockdown of SIX1 enhanced the antitumor efficiency of sunitinib in KIRC. Mechanistically, Integrin subunit beta 1 (ITGB1), an upstream gene of FA signaling, was a direct transcriptional target of SIX1. In addition, we showed that DExH-box helicase 9 (DHX9) was an important mediator for SIX1-induced ITGB1 transcription, and silencing the subunits of SIX1/DHX9 complex significantly reduced transcription of ITGB1. Downregulation of SIX1 attenuated nuclear translocation of DHX9 and abrogated the binding of DHX9 to ITGB1 promoter. Collectively, our results unveiled a new signal axis SIX1/ITGB1/FAK in KIRC and identified a novel therapeutic strategy for metastatic KIRC patients.
高侵袭性和获得性酪氨酸激酶抑制剂（TKI）耐药性仍是延长晚期肾透明细胞癌（KIRC）患者生存时间的障碍。在本研究中，我们报道 sine oculis homeobox 1（SIX1）在舒尼替尼耐药的 KIRC 细胞和转移性 KIRC 组织中上调。随后，我们发现 SIX1 通过粘着斑（FA）信号转导介导转移和舒尼替尼耐药，敲低 SIX1 增强了舒尼替尼对 KIRC 的抗肿瘤作用。在机制上，粘着斑信号转导的上游基因整合素亚基β 1（ITGB1）是 SIX1 的直接转录靶标。此外，我们表明 DExH-box 解旋酶 9（DHX9）是 SIX1 诱导的 ITGB1 转录的重要介质，沉默 SIX1/DHX9 复合物的亚基可显著降低 ITGB1 的转录。下调 SIX1 可减弱 DHX9 的核易位，并阻止 DHX9 与 ITGB1 启动子结合。总之，我们的研究结果揭示了 KIRC 中的一个新的信号轴 SIX1/ITGB1/FAK，并为转移性 KIRC 患者确定了一种新的治疗策略。
