HOX and MEINOX in cellular plasticity, fibrosis, and cancer

Table 6 The effects of protein-coding HOX genes in various cancers

HOX genes	Disease	Mode of expression	Mode of function in cancer	Proof of concept or mechanism of action	Ref.
HOXA1	Breast cancer	Upregulated	Oncogenic	HOXA1 is overexpressed in breast tumors and correlates with advanced disease and poor patient survival. HOXA1 knockdown in breast cancer cells induces cell cycle arrest and apoptosis, suggesting it promotes tumor growth	[213]
	Cervical cancer	Upregulated	Oncogenic	HOXA1 is highly expressed in cervical carcinoma. HOXA1 directly transactivates glycolytic enzymes ENO1 and PGK1, enhancing aerobic glycolysis and promoting cervical cancer cell growth and metastasis. HOXA1 knockdown impairs tumor growth and increases chemosensitivity	[147]
HOXA2	Breast cancer	Downregulated	Tumor suppressor	HOXA2 is frequently silenced by promoter hypermethylation in breast tumors. Restoring HOXA2 inhibits breast cancer cell proliferation and motility	[198]
HOXA3	OSCC	Dysregulated	Context-dependent	HOXA3 shows stage-specific expression changes in oral tumorigenesis; upregulated in dysplastic lesions but then downregulated in advanced OSCC. Hypermethylation of the HOXA3 3’UTR in OSCC was linked to worse overall survival	[214]
HOXA5	Colorectal cancer	Downregulated	Tumor suppressor	HOXA5 is frequently hypermethylated and silenced in colorectal cancers. Loss of HOXA5 correlates with poor differentiation; demethylation can restore HOXA5 expression, supporting a tumor-suppressor role	[193]
	NSCLC	Downregulated	Tumor suppressor	HOXA5 exhibits reduced expression in NSCLC. A meta-analysis found that high HOXA5 is associated with increased overall survival in NSCLC, consistent with a tumor-suppressor function	[146,152]
	HCC	Downregulated	Tumor suppressor	HOXA5 is significantly downregulated in HCC tissues. Low HOXA5 levels associate with larger tumor size, high AFP, and predict worse overall and recurrence-free survival. HOXA5 acts as a tumor suppressor: Restoring HOXA5 (or inhibiting its upstream repressor miR-130b-3p) restrains HCC angiogenesis and growth. In HCC cells, loss of HOXA5 Leads to increased VEGF and microvessel formation, whereas HOXA5 overexpression inhibits these pro-tumorigenic processes	[215]
HOXA7	ESCC	Upregulated	Oncogenic	HOXA7 is one of several HOX genes significantly overexpressed in ESCC tumor tissue (vs normal esophagus). High HOXA7 Levels are associated with worse overall survival in ESCC patients	[216]
HOXA9	AML	Upregulated	Oncogenic	Overexpressed in > 50% of AML cases; drives leukemogenesis and correlates with poor prognosis. HOXA9 forms a complex with SAFB to repress differentiation genes, and its disruption induces differentiation and apoptosis	[217]
	NSCLC	Downregulated	Oncogenic	Transient transfection of HOXA9 into H23 Lung cancer cells resulted in the inhibition of cell migration but not proliferation	[218]
	HCC	Upregulated	Oncogenic	HOXA9 is dramatically upregulated in HCC and its high expression predicts poor patient survival. HOXA9 may be controlled by RPL38 and is involved in epigenetic and immune-regulatory networks in HCC. Targeting HOXA9 (e.g., via siRNA) led to suppressed tumor growth and induced apoptosis in vitro	[188]
HOXA10	HCC	Upregulated	Oncogenic	HOXA10 is one of the most overexpressed HOX genes in HCC and liver tumor-initiating cells. A long noncoding RNA “lncHOXA10” drives HOXA10 transcription, which in turn promotes self-renewal of liver cancer stem cells and tumorigenesis. Knocking out HOXA10 impairs sphere formation and tumor propagation, confirming its tumor-promoting role	[219]
	PDAC	Upregulated	Oncogenic	HOXA10 is significantly overexpressed in PDAC and is associated with higher tumor stage and shorter survival. HOXA10 overactivity drives pancreatic cancer progression by directly activating the NF-κB signaling pathway, thereby promoting tumor cell proliferation and invasion. HOXA10 silencing can reduce PDAC cell aggressiveness	[220]
HOXA11	NSCLC	Upregulated	Oncogenic	HOXA11 is overexpressed in some NSCLC cohorts and has been linked to worse outcomes. HOXA11 was identified as an independent predictor of poor overall survival in NSCLC	[146]
HOXA13	HCC	Upregulated	Oncogenic	HOXA13 is significantly overexpressed in HCC. High HOXA13 correlates with advanced disease and poor outcome - patients with elevated HOXA13 had more metastases and shorter survival	[142]
HOXB5	HCC	Upregulated	Oncogenic	HOXB5 is aberrantly elevated in HCC. Its high expression correlates with poor differentiation, higher stage, and worse prognosis. HOXB5 acts as a metastasis promoter: It transactivates FGFR4 and CXCL1 to drive HCC cell invasion and myeloid suppressor cell recruitment. Knockdown of HOXB5 or its targets suppresses lung and liver metastases in mice, confirming HOXB5 as a pro-metastatic oncogene in HCC	[189]
HOXB7	HCC	Upregulated	Oncogenic	HOXB7 is highly overexpressed in HCC tumors compared to normal liver. HOXB7 overexpression correlates with poor patient survival and aggressive disease. HOXB7 enhances proliferation, sphere formation (stemness), migration and invasion of HCC cells, while HOXB7 knockdown has the opposite effect. Mechanistically, HOXB7 activates the AKT pathway; it upregulates c-Myc and Slug to promote EMT and cancer stem cell traits	[190]
HOXB13	HCC	Upregulated	Oncogenic	HOXB13 is overexpressed in a subset of HCC cases. High HOXB13 has been shown to enhance HCC cell proliferation, metastasis, and chemoresistance	[166]
	PCa	Downregulated	Tumor suppressor	HOXB13 plays a complex role in prostate cancer; In early, androgen-dependent disease it is an important AR cofactor, but in castration-resistant PCa, loss of HOXB13 drives metastasis. HOXB13 recruits HDAC3 to suppress lipid biosynthesis; loss of HOXB13 (or the germline G84E mutant) causes abnormal lipid accumulation, which increases cell motility and metastasis	[149,191]
HOXC4/HOXC6	PCa	Upregulated	Oncogenic	HOXC4 is overexpressed in prostate tumors, especially in high-grade disease. Genomic analyses identified HOXC4 (and HOXC6) as part of a gene signature associated with aggressive prostate cancer. HOXC4 overexpression has been linked to increased proliferation of prostate cancer cells, and HOXC4/HOXC6 mRNA in urine has been tested as a biomarker to predict high-risk prostate cancer	[191]
HOXC13	ESCC	Upregulated	Oncogenic	HOXC13 is significantly overexpressed in ESCC tumors relative to normal tissue	[221]
HOXD10 (through miR-10b)	Gastric cancer	Downregulated	Tumor suppressor	HOXD10 expression is reduced through miR-10b in gastric cancer, and its low expression correlates with better outcomes. Restoration of HOXD10 can inhibit tumor cell migration	[222,223]
HOXD10/HOXC9	PTC	Downregulated	Tumor suppressor	HOXD10 and HOXC9 are significantly downregulated in PTC compared to normal thyroids. Lower HOXD10 and HOXC9 expression in PTC is associated with greater invasiveness - including higher incidence of lymph node metastasis and extrathyroid extension	[224]
Multiple HOX genes (HOXA6, HOXC6, HOXD9/HOXD10/HOXD13)	HCC	Upregulated	Oncogenic	A systematic analysis found widespread upregulation of HOX family genes in HCC. Notably, HOXA6, HOXC6, HOXD9, HOXD10, and HOXD13 were among the most overexpressed and each was an independent risk factor for poor overall survival. HCC tissues show higher total HOX mRNA levels than normal liver, reflecting a global reactivation of HOX clusters in liver carcinogenesis	[225]

OSCC: Oral squamous cell carcinoma; UTR: Untranslated region; NSCLC: Non small cell lung cancer; HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein; VEGF: Vascular endothelial growth factor; ESCC: Esophageal squamous cell carcinoma; AML: Acute myeloid leukemia; SAFB: Scaffold attachment factor B; siRNA: Small interfering RNA; PDAC: Pancreatic ductal adenocarcinoma; NF-κB: Nuclear factor-kappa B; FGFR4: Fibroblast growth factor-4 receptor; CXCL1: C-X-C motif ligand 1; AKT: Protein kinase B; EMT: Epithelial-mesenchymal transition; PCa: Prostate cancer; PTC: Papillary thyroid cancer.