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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. [ABSTRACT FROM AUTHOR]

Objectives: Kidney renal clear cell carcinoma (KIRC) is one of the most common lethal cancers in the human urogenital system. As members of the Homeobox (HOX) family, Homeobox-A (HOXA) cluster genes have been reported to be involved in the development of many cancer types. However, the expression and clinical significance of HOXA genes in KIRC remain largely unknown. Materials and methods: In this study, we comprehensively analyzed the mRNA expression and prognostic values of HOXA genes in KIRC using The Cancer Genome Atlas (TCGA) analysis databases online. Colony formation assay, flow cytometry and Western blot were used to detect cell proliferation, apoptosis, cell cycle, and protein level of the indicated gene. Results: We found that the HOXA genes were differentially expressed in KIRC tissues when compared with normal tissues. The expression of HOXA4 and HOXA13 were significantly up-regulated, while HOXA7 and HOXA11 were down-regulated in KIRC. High mRNA levels of HOXA2, HOXA3 and HOXA13, and low level of HOXA7 predicted poor overall survival (OS) of KIRC patients. High mRNA level of HOXA13 further indicated a poor disease-free survival (DFS) of KIRC patients. Functionally, knockdown of HOXA13 significantly suppressed cell proliferation of KIRC in vitro, increased the protein level of p53 and decreased the protein level of cyclin D1 in KIRC cells. Over-expression of HOXA13 had the opposite effects on KIRC cells. Conclusion: Collectively, our findings suggest that HOXA13 functions as a novel oncogene in KIRC and may be a potential biomarker for this malignancy. [ABSTRACT FROM AUTHOR]

Accumulating evidence has confirmed the involvement of the homeobox (HOX) gene family in carcinogenesis. HOXC11, belongs to the homeobox-C (HOXC) gene cluster, has been reported to play important roles in the development of several cancers. However, its expression and clinical value in pan-cancer remain elusive. Bioinformatics analysis, CCK-8 assay, Flow cytometry and Western blot were used to analyze gene expression and patient survival, cell proliferation, cell apoptosis and protein level, respectively. In this study, we comprehensively analyzed the expression profile and prognostic value of HOXC11 in human pan-cancer using online The Cancer Genome Atlas (TCGA) databases. HOXC11 was widely up-regulated in tumor tissues when compared with the normal tissues in pan-cancer across nine cancer types. In addition, high mRNA level of HOXC11 predicted poor overall survival (OS) of patients with adrenocortical carcinoma (ACC), colon adenocarcinoma (COAD), kidney renal clear cell carcinoma (KIRC), mesothelioma (MESO) and pancreatic adenocarcinoma (PAAD), respectively. By comparative analysis, we found that HOXC11 was up-regulated and closely correlated patient OS in COAD and KIRC. Functionally, down-regulation of HOXC11 inhibited cell proliferation but promoted apoptosis of COAD and KIRC in vitro. Mechanistically, HOXC11 promoted cell proliferation of COAD and KIRC might by inactivating the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. Our findings suggest that HOXC11 may act as a tumor driving gene in COAD and KIRC. [ABSTRACT FROM AUTHOR]