Research Paper Volume 15, Issue 19 pp 10746—10766

A pan-cancer analysis of the role of HOXD1, HOXD3, and HOXD4 and validation in renal cell carcinoma

Lumin Wang1, *, , Xiaofei Wang2, *, , Haifeng Sun3, , Wenjing Wang4, , Li Cao2, ,

  • 1 Department of Gastroenterology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710004, P.R. China
  • 2 Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, P.R. China
  • 3 The Third Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi 710065, P.R. China
  • 4 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China
* Co-first authors

Received: June 12, 2023       Accepted: September 26, 2023       Published: October 12, 2023
How to Cite

Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


HOXD1, HOXD3, and HOXD4 are members of the HOXD genes family and are related to tumorigenesis of the tumor. However, whether HOXDs (1, 3, 4) have a crucial role across pan-cancer is still unknown. HOXD1, HOXD3, and HOXD4 expressions were analyzed using public databases in 33 types of tumors. The UCSC Xena website was carried out to investigate the relationship between the expression of genes and the progress of cancers. The biological functions of HOXD3 were tested by colony forming, transwell, wound healing, and xenograft assay in vitro and in vivo. GSEA was used to identify the associated cancer hallmarks with HOXDs expression. Immune cell infiltration analysis was applied to verify the immune cell infiltrations related to genes. The results showed HOXD1, HOXD3, and HOXD4 co-low expressed in BRCA, COAD, KICH, KIRC, KIRP, READ, and TGCT. In the KIRC, all of HOXDs expression was connected with tumor stage and histological grade. Upregulation of HOXDs was associated with improved OS, DSS, and PFI. Down-expression of HOXD3 induced cell proliferation, migration, and invasion in vivo and in vitro. In addition, HOXDs were connected with immune-activated hallmarks and cancer immune cell infiltrations. These findings demonstrated that HOXDs may be indicative biomarkers for the prognosis and immunotherapy in pan-cancer.


ACC: Adenoid cystic carcinoma; BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: cholangiocarcinoma; COAD: colon adenocarcinoma; DFI: disease-free interval; DLBC: Lymphoid neoplasm diffuse Large B-cell Lymphoma; DSS: disease-specific survival; EMT: epithelial-mesenchymal transition; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; GSEA: Gene Set Enrichment Analysis; GTEx: The Genotype-Tissue Expression; HNSC: Head and neck squamous cell carcinoma; KICH: Kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; KM: Kaplan-Meier; LGG: Brain lower grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; OS: overall survival; OV: Ovarian serous cystadenocarcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and paraganglioma; PFI: progression-free interval; RCC: Renal cell carcinoma; READ: Rectum adenocarcinoma; SKCM: Skin cutaneous melanoma; STAD: Stomach adenocarcinoma; TCGA: The Cancer Genome Atlas; TGCT: Testicular germ cell tumors; THCA: Testicular germ cell tumors; THYM: Thymoma; TIMER: Tumor Immune Estimation Resource; TISCH: Tumor Immune Single-cell Hub; UCEC: Uterine corpus endometrial carcinoma; UCS: Uterine carcinosarcoma; UCSC: University of California Santa Cruz.