HOX and MEINOX in cellular plasticity, fibrosis, and cancer

Table 7 The effects of non-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.
HAGLR	Breast cancer	Upregulated	Oncogenic	HAGLR is highly expressed in triple-negative breast cancer. HAGLR sponges miR-335-3p, leading to upregulation of Wnt2 and activation of Wnt signaling to promote TNBC cell proliferation, invasion, and tumor growth	[139]
HOTAIR	Glioblastoma (brain cancer)	Upregulated	Oncogenic	The lncRNA HOTAIR is highly upregulated in temozolomide-resistant glioblastoma. HOTAIR overexpression in GBM cells activates Wnt/β-catenin signaling and increases MGMT levels (via a HOTAIR/miR-214/β-catenin network), conferring chemoresistance. Silencing HOTAIR restores TMZ sensitivity, indicating HOTAIR drives drug resistance and tumor progression	[140]
	HCC	Upregulated	Oncogenic	The HOXC-derived lncRNA HOTAIR is overexpressed in HCC tissues and is strongly linked to cancer progression. High HOTAIR levels associate with advanced TNM stage, vascular invasion, poor differentiation, and shorter overall and relapse-free survival. HOTAIR is higher in tumors than normal liver and correlates with aggressive phenotypes	[226]
HOTAIRM1	AML	Upregulated	Oncogenic	HOTAIRM1 is significantly overexpressed in AML with NPM1 mutation and promotes leukemic cell proliferation. High HOTAIRM1 is associated with poorer outcomes in intermediate-risk AML	[227]
HOTTIP	HCC	Upregulated	Oncogenic	HOTTIP is highly expressed in HCC tumors. HOTTIP expression strongly correlates with HOXA13 Levels, forming a positive feedback loop. High HOTTIP is associated with increased metastasis. Silencing HOTTIP in HCC cells reduces HOXA13 and inhibits cell proliferation	[142]
	SCLC	Upregulated	Oncogenic	HOTTIP is focally amplified and overexpressed in SCLC, correlating with advanced stage and poor prognosis. HOTTIP acts as an oncogene by sponging miR-574-5p and upregulating EZH1, thereby promoting SCLC cell proliferation and cell-cycle progression. Knocking down HOTTIP in SCLC models impairs tumor growth	[228]
HOXA11-AS	Glioma (high-grade)	Upregulated	Oncogenic	HOXA11-AS is significantly overexpressed in high-grade gliomas and correlates with poor prognosis. It acts as a ceRNA, sponging tumor-suppressive let-7b-5p to upregulate CTHRC1/c-Myc, also scaffolds with c-Jun to activate the TPL2-MEK1/2-ERK1/2 pathway	[145]
	HCC	Upregulated	Oncogenic	HOXA11-AS is significantly upregulated in HCC tumors and cell lines. It acts as a ceRNA, sponging miR-506-3p, thereby de-repressing the EMT transcription factor Slug. Through this miR-506/Slug axis, HOXA11-AS promotes HCC cell proliferation, invasion and epithelial-mesenchymal transition. Knockdown of HOXA11-AS inhibits these malignant behaviors	[168]
HOXB-AS1	HCC	Upregulated	Oncogenic	HOXB-AS1 is highly upregulated in HCC tissues and patient serum. Silencing HOXB-AS1 in HCC cell lines (Hep3B, Huh7) markedly reduces proliferation, migration, and invasion. Clinically, high HOXB-AS1 is associated with lower survival	[229]
miR-10a	PDAC	Upregulated	Oncogenic	miR-10a is overexpressed in a subset of pancreatic cancers and promotes an invasive, metastatic phenotype. In PDAC cells, miR-10a-5p enhances migration and invasion and its inhibition reduces metastasis. Notably, retinoic acid receptor antagonists can repress miR-10a, leading to reduced invasion. miR-10a likely exerts its pro-metastatic effect by suppressing HOX genes (e.g., HOXB1/B3) that restrain motility	[230]
	HCC	Downregulated	Tumor suppressor	miR-10a plays a context-dependent role in HCC. It is significantly downregulated in HCC tissues and cell lines, especially in metastatic tumors. miR-10a-5p acts as a tumor-suppressor miR: Restoring miR-10a-5p inhibits HCC cell migration, invasion, and EMT, both in vitro and in vivo. It directly targets spindle and kinetochore-associated protein 1 (SKA1), leading to its mRNA degradation and suppression of pro-metastatic signaling. Thus, loss of miR-10a in HCC unleashes metastasis, whereas its presence restrains tumor spread	[143]
miR-10b	Breast cancer	Upregulated	Oncogenic	miR-10b is significantly overexpressed in metastatic breast cancer cells and was shown to initiate tumor invasion and metastasis. Overexpression of miR-10b drives cell migration/invasion, whereas silencing miR-10b in mouse models inhibits metastasis	[113,182,184,231]
	HCC	Upregulated	Oncogenic	miR-10b is markedly overexpressed in HCC tumor samples and cell lines. Higher miR-10b levels associate with metastatic potential. Overexpression of miR-10b enhances HCC cell proliferation, migration and invasion, whereas inhibition of miR-10b reduces invasiveness. Mechanistically, miR-10b targets and downregulates HOXD10, which in turn upregulates pro-migratory genes RhoC, uPAR, MMP2/9	[232]
miR-196a/b	OSCC	Upregulated	Oncogenic	miR-196a and miR-196b are significantly overexpressed in OSCCs. High miR-196 levels promote cancer cell migration and invasion, contributing to an invasive tumor phenotype. Clinically, elevated miR-196a/b in oral tumors correlates with advanced tumor stage and nodal metastasis. These “metastamiRs” target multiple genes (including HOX genes) to drive tumor progression	[151]
	HCC	Upregulated	Oncogenic	The miR-196a and miR-196b are upregulated in HCC tissues and cell lines. High miR-196a/b levels are linked to aggressive tumor features. miR-196a/b act as oncogenic miRNAs by targeting negative regulators of growth. miR-196a/b directly suppresses SOCS2, a tumor suppressor that normally inhibits the JAK/STAT pathway. Consequently, miR-196 overactivity leads to unchecked JAK/STAT signaling and tumor progression. Experimental downregulation of miR-196a or miR-196b was shown to inhibit HCC proliferation and metastasis by de-repressing SOCS2 and dampening JAK/STAT signaling. Clinically, elevated miR-196a is associated with HCC metastasis and poor prognosis	[150]

TNBC: Triple negative breast cancer; lncRNA: Long non-coding RNA; GBM: Glioblastoma; MGMT: O6-methylguanine-methyltransferase; TMZ: Temozolomide; HCC: Hepatocellular carcinoma; TNM: Tumor-node-metastasis; AML: Acute myeloid leukemia; NPM1: Nucleophosmin 1; SCLC: Small cell lung cancer; EZH1: Enhancer of zeste homolog 1; ceRNA: Competitive endogenous RNA; CTHRC1: Collagen triple helix repeat containing-1; TPL2: Tumor progression locus 2; MEK1/2: Mitogen-activated protein kinase kinase1/2; ERK1/2: Extracellular signal-regulated kinase1/2; EMT: Epithelial-mesenchymal transition; PDAC: Pancreatic ductal adenocarcinoma; uPAR: Urokinase plasminogen activator receptor; MMP: Matrix metalloproteinase; OSCC: Oral squamous cell carcinoma; miRNA: MicroRNA; SOCS2: Suppressors of cytokine signaling 2; JAK: Janus kinase; STAT: Signal transducer and activator of the transcription.