Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
J Cell Mol Med. 2024 Apr;28(8):e18290. doi: 10.1111/jcmm.18290.
Growth hormone inducible transmembrane protein (GHITM), one member of Bax inhibitory protein-like family, has been rarely studied, and the clinical importance and biological functions of GHITM in kidney renal clear cell carcinoma (KIRC) still remain unknown. In the present study, we found that GHITM was downregulated in KIRC. Aberrant GHITM downregulation related to clinicopathological feature and unfavourable prognosis of KIRC patients. GHITM overexpression inhibited KIRC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, GHITM overexpression could induce the downregulation of Notch1, which acts as an oncogene in KIRC. Overexpression of Notch1 effectively rescued the inhibitory effect induced by GHITM upregulation. More importantly, GHITM could regulate PD-L1 protein abundance and ectopic overexpression of GHITM enhanced the antitumour efficiency of PD-1 blockade in KIRC, which provided new insights into antitumour therapy. Furthermore, we also showed that YY1 could decrease GHITM level via binding to its promoter. Taken together, our study revealed that GHITM was a promising therapeutic target for KIRC, which could modulate malignant phenotype and sensitivity to PD-1 blockade of renal cancer cells via Notch signalling pathway.
生长激素诱导跨膜蛋白 (GHITM) 是 Bax 抑制蛋白样家族的一员，其研究较少，GHITM 在肾透明细胞癌 (KIRC) 中的临床意义和生物学功能尚不清楚。在本研究中，我们发现 GHITM 在 KIRC 中下调。异常的 GHITM 下调与 KIRC 患者的临床病理特征和不良预后相关。GHITM 过表达抑制 KIRC 细胞在体外和体内的增殖、迁移和侵袭。机制上，GHITM 过表达可诱导 Notch1 的下调，Notch1 是 KIRC 中的致癌基因。Notch1 的过表达有效挽救了 GHITM 上调诱导的抑制作用。更重要的是，GHITM 可以调节 PD-L1 蛋白的丰度，GHITM 的异位过表达增强了 KIRC 中 PD-1 阻断的抗肿瘤作用，为抗肿瘤治疗提供了新的见解。此外，我们还表明，YY1 可以通过结合其启动子来降低 GHITM 水平。总之，我们的研究表明，GHITM 是 KIRC 有前途的治疗靶点，它可以通过 Notch 信号通路调节肾癌细胞的恶性表型和对 PD-1 阻断的敏感性。
