Department of Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
School of Life Sciences, Zhengzhou University, Zhengzhou, China.
Cell Biol Int. 2021 Jun;45(6):1246-1259. doi: 10.1002/cbin.11568. Epub 2021 Feb 19.
Kidney renal clear cell carcinoma (KIRC) is a common malignant tumor in human genitourinary system. Previous studies have shown that the homeobox-D (HOXD) cluster genes, which belong to the homeobox (HOX) family, are involved in the progression of multiple types of cancer. However, the expression profile and prognostic values of the HOXD genes in KIRC remain largely unknown. Herein, we comprehensively analyzed the transcriptional levels and prognosis of HOXD genes in KIRC using four online The Cancer Genome Atlas analysis databases (GEPIA, UALCAN, starBase v3.0, and LinkedOmics). We found that several members of the HOXD gene family were abnormally expressed in KIRC and correlated with patient prognosis. The messenger RNA levels of HOXD1, HOXD8, and HOXD10 were significantly downregulated in KIRC tissues as compared with the normal tissues. Low expression of HOXD1 or HOXD8 predicted poor overall survival (OS) of KIRC patients, and downregulated HOXD1, HOXD3, or HOXD4 indicated unfavorable patient disease-free survival (DFS) in KIRC. Through integrated analysis, we found that HOXD1 was lowly expressed in KIRC and correlated with patient OS, DFS and advanced tumor stages. Moreover, gene set enrichment analysis showed that HOXD1 may be mainly implicated in cell cycle regulation, tumor growth factor-β (TGF-β) and Wnt signaling pathways in KIRC. Furthermore, both loss-of-function and gain-of-function experiments demonstrated that HOXD1 inhibited cell proliferation, cell cycle and the TGF-β signaling in KIRC. Taken together, our findings suggest that HOXD1 is a novel potential tumor suppressor in KIRC.
肾透明细胞癌（KIRC）是人类泌尿生殖系统常见的恶性肿瘤。既往研究表明，属于同源盒（HOX）家族的同源盒-D（HOXD）基因簇参与多种类型癌症的进展。然而，HOXD 基因在 KIRC 中的表达谱和预后价值仍知之甚少。在此，我们使用四个在线癌症基因组图谱分析数据库（GEPIA、UALCAN、starBase v3.0 和 LinkedOmics），全面分析了 HOXD 基因在 KIRC 中的转录水平和预后。我们发现 HOXD 基因家族的几个成员在 KIRC 中异常表达，并与患者的预后相关。与正常组织相比，KIRC 组织中 HOXD1、HOXD8 和 HOXD10 的信使 RNA 水平显著下调。HOXD1 或 HOXD8 低表达预示着 KIRC 患者总体生存率（OS）较差，下调的 HOXD1、HOXD3 或 HOXD4 表明 KIRC 患者无病生存率（DFS）不良。通过综合分析，我们发现 HOXD1 在 KIRC 中低表达，并与患者 OS、DFS 和晚期肿瘤分期相关。此外，基因集富集分析表明，HOXD1 可能主要参与 KIRC 中的细胞周期调控、肿瘤生长因子-β（TGF-β）和 Wnt 信号通路。进一步的功能丧失和获得性功能实验表明，HOXD1 抑制了 KIRC 中的细胞增殖、细胞周期和 TGF-β 信号。总之，我们的研究结果表明 HOXD1 是 KIRC 中的一种新型潜在肿瘤抑制因子。
