National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China.
Department of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China.
Eur J Clin Invest. 2023 Jul;53(7):e13986. doi: 10.1111/eci.13986. Epub 2023 Mar 23.
Renal cell carcinoma (RCC) accounts for approximately 4% of all adult malignancies with high mortality worldwide. Although conventional chemotherapy and radiotherapy treatment has been applied for RCC in clinic, the mortality rate of patients is increasing each year, and patients with metastatic RCC are still suffering from poor prognosis. Thus, further investigation of the molecular mechanisms responsible for the development and progression of RCC is of particular importance.
Total of 10 pairs of RCC tissues and adjacent nontumor tissues were collected for examination of ALKBH1 and GPR137 expression. The correlations between ALKBH1 and GPR137 expression in RCC patient were assessed by GEPIA online tool and were analyzed using auto best cutoff. The human RCC cell lines Caki-1, 786-O, ACHN, Osrc2, A498, and 769-P, were used for mechanistic investigation.
Here, we report that the expression of AlkB homologue 1 (ALKBH1) is upregulated in RCC tissues, which is correlated with G-protein-coupled receptor 137 (GPR137) expression. The elevated expression of ALKBH1 is associated with RCC cell malignant characteristics, including cell proliferation and movement (migration and invasion). Mechanistic investigation further reveals that ALKBH1 reduces m A levels of GPR137 mRNA in RCC cells, which upregulates GPR137 mRNA levels, resulting in the increased GPR137 protein expression subsequently and the enhanced RCC cell biological actions consequently. In contrast, the suppression of GPR137 effectively alleviates the ALKBH1-induced malignancies of RCC cells.
Our results indicate that ALKBH1-GPR137 axis might be used as a potential therapeutic target in RCC, contributing to finding new prognostic biomarkers for RCC at an early stage.
肾细胞癌（RCC）约占全球所有成人恶性肿瘤的 4%，死亡率较高。虽然传统的化疗和放疗已应用于临床治疗 RCC，但患者的死亡率仍在逐年上升，转移性 RCC 患者的预后仍较差。因此，进一步研究 RCC 发生发展的分子机制尤为重要。
收集了 10 对 RCC 组织及其相邻非肿瘤组织，检测 ALKBH1 和 GPR137 的表达。利用 GEPIA 在线工具评估 RCC 患者中 ALKBH1 和 GPR137 表达的相关性，并采用自动最佳截断值进行分析。采用人 RCC 细胞系 Caki-1、786-O、ACHN、Osrc2、A498 和 769-P 进行机制研究。
我们报道了 AlkB 同源物 1（ALKBH1）在 RCC 组织中的表达上调，与 G 蛋白偶联受体 137（GPR137）的表达相关。ALKBH1 的高表达与 RCC 细胞的恶性特征有关，包括细胞增殖和运动（迁移和侵袭）。机制研究进一步表明，ALKBH1 降低了 RCC 细胞中 GPR137 mRNA 的 mA 水平，上调了 GPR137 mRNA 水平，随后导致 GPR137 蛋白表达增加，进而增强了 RCC 细胞的生物学作用。相反，抑制 GPR137 可有效减轻 ALKBH1 诱导的 RCC 细胞恶性作用。
我们的研究结果表明，ALKBH1-GPR137 轴可能作为 RCC 的潜在治疗靶点，有助于寻找早期 RCC 的新预后生物标志物。
