HOX and MEINOX in cellular plasticity, fibrosis, and cancer

Table 1 HOX and MEINOX molecules in fibrosis related mechanisms and associated pathways

Mechanism	HOX-MEINOX molecule	Associated pathway(s)	Effect of molecule on pathway	Ref.
Myofibroblast differentiation	HOXA9	Wnt/β-catenin	Inhibition	[79]
	miR-196a/b	TGF-β	Inhibition	[117]
	miR-10a/b	TGF-β	Inhibition	[197]
	HOTTIP	TGF-β	Stimulation	[112]
ECM production	HOTTIP	TGF-β	Inhibition	[110]
	HOXA11	PDGF	Stimulation	[105]
	HOXA11	TGF-β	Stimulation	[106]
	HOXB7	Wnt/β-catenin	Stimulation	[108]
	HOXA9	Wnt/β-catenin	Stimulation	[79]
	HOXA11-AS	TGF-β	Stimulation	[107]
Fibroblast migration	HOXA11	PDGF	Stimulation	[106]
Fibroblast survival	MEIS1	TGF-β	Inhibition	[6]
	HOTTIP	TGF-β	Stimulation	[110,112]
Fibroblast activation	miR-10a/b	TGF-β	Stimulation	[114,197]
	HOXA11	TGF-β	Stimulation	[105,107]
	HOTAIR	Notch	Stimulation	[91]

TGF: Transforming growth factor; PDGF: Platelet derived growth factor; ECM: Extracellular matrix.

Table 2 The effects of protein-coding HOX genes in various fibrotic diseases

HOX genes	Disease	Mode of function in fibrosis	Proof of concept or mechanism of action	Ref.
HOXA2	Liver fibrosis	Anti-fibrotic	Gene silencing of HOXA2 via DNA hypermethylation correlates with advanced fibrosis in chronic hepatitis B	[198]
	Lung fibrosis	Pro-fibrotic	Expression is significantly upregulated in mesenchymal stromal cells from patients with progressive idiopathic pulmonary fibrosis	[199]
HOXA5	Lung fibrosis	Pro-fibrotic	HOXA5 drives DNM3OS transcription, which recruits EZH2 to suppress TSC2, promoting fibroblast proliferation, migration, and ECM gene expression	[169]
HOXA9	Skin fibrosis	Anti-fibrotic	In keloids, overexpression of HOXA9 reduces cell migration, increases MMP3 expression, regulates Wnt pathway inhibitors (reducing PRICKLE1, increasing DKK1 expression)	[79]
HOXB7	Lung fibrosis	Pro-fibrotic	Found to be upregulated in IPF patients’ lung tissues	[175]
HOXB13	Liver fibrosis	Pro-fibrotic	The number of HOXB13+ cells in fibrotic liver increases. HOXB13 expression is correlated with increased hepatic inflammatory activity, but not with fibrosis stages	[165]
HOXC8	Liver fibrosis	Pro-fibrotic	Inhibition of HOXC8 suppressed the hepatic stellate cell activation and the expression of fibrosis-associated genes (α-SMA and COL1A1)	[187]
HOXD10	Kidney fibrosis	Anti-fibrotic	In a mouse kidney fibrosis model, HOXD10 overexpression significantly reduced collagen deposition and renal dysfunction	[200]

DNM3OS: Dynamin 3 opposite strand; EZH2: Enhancer of zeste homolog 2; TSC2: Tuberous sclerosis complex subunit 2; ECM: Extracellular matrix; MMP: Matrix metalloproteinase; DKK1: Dickkopf-1; IPF: Idiopathic pulmonary fibrosis; α-SMA: Alpha-smooth muscle actin; COL1A1: Collagen type 1.

Table 3 The effects of non-coding HOX genes in various fibrotic diseases

HOX genes	Disease	Mode of function in fibrosis	Proof of concept or mechanism of action	Ref.
HOTAIR	Liver fibrosis	Pro-fibrotic	HOTAIR upregulation was found to be promoting liver fibrosis in mouse and cell line models. Arsenic exposure was found to induce hepatic fibrosis via T-cell expression of HOTAIR	[177,201,202]
	Lung fibrosis	Pro-fibrotic	Acts as a competing ceRNA to regulate MMP2 expression during paraquat-induced lung epithelial-mesenchymal transition, promoting fibrosis	[203]
	Kidney fibrosis	Pro-fibrotic	In a rat model with TGFβ-treated kidney cells, HOTAIR was elevated in renal fibrosis, driving epithelial-mesenchymal transition via the Notch pathway	[109]
	Cardiac fibrosis	Pro-fibrotic	Upregulated in atrial fibrillation and promotes pathological fibrosis in the atrium. In Ang II-treated atrial fibroblasts, HOTAIR and Wnt5a levels increased, and HOTAIR knockdown inhibited fibroblast proliferation, migration, and expression of collagen I/III and α-SMA	[12]
	Skin fibrosis	Pro-fibrotic	In systemic sclerosis dermal fibroblasts, HOTAIR is aberrantly upregulated and induces a pro-fibrotic gene program. Overexpression of HOTAIR in healthy skin fibroblasts caused epigenetic silencing of miR-34a via EZH2 (H3K27me3), which activated Notch signaling and secondarily upregulated the Hedgehog effector GLI2	[91,204]
HOTAIRM1	Lung fibrosis	Pro-fibrotic	Hypoxia-exposed alveolar epithelial cells secrete pro-fibrotic exosomes enriched in lncRNA HOTAIRM1	[205]
HOTTIP	Liver fibrosis	Pro-fibrotic	Promotes hepatic stellate cell activation through increased SRF expression by sponging miR-150	[206]
	Liver fibrosis	Pro-fibrotic	Highly upregulated in fibrotic livers and activated hepatic stellate cells. Increased HOTTIP acts as a sponge for miR-148a, relieving repression of TGFβ receptor genes. Consequently, TGFBR1/2 levels rise, driving HSC activation and collagen production	[112]
	Lung fibrosis	Pro-fibrotic	Enhances lung fibrosis by regulating the miR-744-5p/PTBP1 signaling axis	[110]
HOXA11-AS	Liver fibrosis	Pro-fibrotic	Upregulated in a mouse model of ischemia/reperfusion-induced liver fibrosis and exacerbates fibrosis via a PTBP1/HDAC4 mechanism	[167]
	Cardiac fibrosis	Pro-fibrotic	Drives TGFβ1-mediated cardiac fibroblast activation. Overexpression of HOXA11-AS in mouse cardiac fibroblasts significantly increased TGF-β1 expression and downstream Smad signaling, promoting fibroblast proliferation, colony formation, and invasion, whereas HOXA11-AS knockdown had opposite effects	[106]
	Skin fibrosis	Pro-fibrotic	Significantly overexpressed in keloid tissue and fibroblasts, promotes abnormal scar formation by acting as a ceRNA	[207]
miR-10a	Liver fibrosis	Pro-fibrotic	In a CCl4-induced mouse liver fibrosis model, miR-10a was found to exacerbate fibrosis. Overexpression of miR-10a increased TGF-β1/Smad3 signaling and collagen-I expression, whereas miR-10a inhibition ameliorated liver fibrosis	[197]
miR-10a/b	Kidney fibrosis	Pro-fibrotic	miR-10 family (miR-10a/10b, located in HOX clusters) is aberrantly expressed in chronic kidney disease. In fibrotic mouse kidneys, miR-10a/b levels are elevated and contribute to fibrosis by targeting VASH1, an anti-angiogenic factor that also inhibits TGF-β/Smad signaling	[114]
miR-196a	Lung fibrosis	Anti-fibrotic	In a bleomycin-induced fibrosis model, lncRNA H19 was upregulated and sponged miR-196a, thereby relieving suppression of COL1A1. Silencing H19 reduced fibroblast activation and collagen deposition, an effect reversed by miR-196a inhibition	[208]
miR-615-5p	Liver fibrosis	Pro-fibrotic	miR-615-5p expression is significantly upregulated in cirrhotic livers and in plasma of patients with advanced fibrosis compared to healthy controls	[209]

ceRNA: Competitive endogenous RNA; MMP: Matrix metalloproteinase; TGF: Transforming growth factor; α-SMA: Alpha-smooth muscle actin; EZH2: Enhancer of zeste homolog 2; GLI2: Glioma-associated oncogene homolog 2; SRF: Serum response factor; TGFBR1/2: Transforming growth factor-beta receptor 1/2; PTBP1: Polypyrimidine tract-binding protein 1; HDAC4: Histone deacetylation 4; VASH1: Vasohibin 1; lncRNA: Long non-coding RNA; COL1A1: Collagen type 1.

Table 4 The effects of MEINOX genes in various fibrotic diseases

MEINOX genes	Disease	Mode of function in fibrosis	Proof of concept or mechanism of action	Ref.
MEIS1	Kidney fibrosis	Pro-fibrotic	MEIS1 is strongly induced in PDGFRβ+ pericytes as they transition into myofibroblasts during acute and chronic kidney injury	[210]
	Kidney fibrosis	Anti-fibrotic	In mice, fibroblast-specific MEIS1 overexpression inhibited myofibroblast activation and attenuated renal fibrosis, whereas MEIS1 knockout in fibroblasts worsened fibrosis	[6]
PKNOX2	Kidney fibrosis	Pro-fibrotic	TGF-β1 treatment induces PKNOX2 in fibroblasts, and PKNOX2 appears to support fibrogenesis by enhancing fibroblast survival	[93]
	Cardiac fibrosis	Anti-fibrotic	In healthy human heart, PKNOX2 is associated with normal fibroblast activation, but in failing heart, its expression drops during fibroblast-to-myofibroblast transition	[11]
	Myelofibrosis	Anti-fibrotic	PKNOX2 expression is significantly downregulated in Fanconi anemia patients’ bone marrow MSCs compared to healthy controls	[43]

PDGFRβ: Platelet-derived growth factor receptor beta; TGF: Transforming growth factor; MSC: Mesenchymal stem cell.

Table 5 HOX and MEINOX molecules in cancer hallmark mechanisms and associated pathways

Mechanism	HOX-MEINOX molecule	Associated pathway(s)	Effect of molecule on pathway	Ref.
Invasion	miR-10a/b	TGF-β	Inhibition	[113,143]
	HOXA10	TGF-β	Stimulation	[136]
	HOXA13	Wnt/β-catenin, TGF-β	Stimulation	[211]
	MEIS2D	Hippo	Inhibition	[141]
	MEIS2C, HAGLR, HOTAIR	Wnt/β-catenin	Stimulation	[139-141]
	HOXA5	Wnt/β-catenin	Inhibition	[212]
	miR-196a/b	MAPK	Stimulation	[151]
Chemoresistance	PKNOX2	PI3K	Inhibition	[42]
	MEIS2C, HAGLR, HOTAIR, HOXA13	Wnt/β-catenin	Stimulation	[139-141,211]
	HOXA5	Wnt/β-catenin	Inhibition	[212]
Proliferation	PKNOX2, HOXA5	p53	Stimulation	[152,153,174,212]
	MEIS2C, HAGLR, HOTAIR	Wnt/β-catenin	Stimulation	[139-141]
	HOXA13	Wnt/β-catenin, TGF-β	Stimulation	[211]
	miR-196a/b	JAK/STAT	Stimulation	[150]
	HOXA11-AS	β-catenin/c-Myc	Stimulation	[145]
	MEIS2D	Hippo	Inhibition	[141]
Transformation	HOXA10	TGF-β	Stimulation	[136]
Evading apoptosis	miR-196a/b	JAK/STAT, MAPK	Stimulation	[150,151]
	HOXA11-AS	β-catenin/c-Myc	Stimulation	[145]
	PKNOX2	PI3K	Inhibition	[42]
	PKNOX2	p53	Stimulation	[153]
	HOXA5	p53	Stimulation	[152,212]
Immune evasion	HOXA11-AS	β-catenin/c-Myc	Stimulation	[145]

TGF: Transforming growth factor; MAPK: Mitogen-activated protein kinases; PI3K: Phosphatidylinositol 3-kinase; JAK: Janus kinase; STAT: Signal transducer and activator of the transcription.

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.

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.

Table 8 The effects of MEINOX genes in various cancers

HOX genes	Disease	Mode of expression	Mode of function in cancer	Proof of concept or mechanism of action	Ref.
MEIS1	AML	Upregulated	Oncogenic	MEIS1 is highly expressed in AML and promotes a stem cell-like program. High MEIS1 Levels predict shorter survival and chemo-resistance. Targeting MEIS1/PBX interaction is explored as therapy	[233]
	HCC	Downregulated	Tumor suppressor	MEIS1 is often decreased in HCC. Patients with higher MEIS1 experienced significantly longer time-to-progression after ablation. In a rodent HCC model, adding MEIS1 enhanced the tumor-killing effect of radioablation. MEIS1 acts as a negative regulator of HCC, and low MEIS1 permits aggressive tumor behavior, while high MEIS1 is favorable for prognosis	[234]
MEIS2	Breast cancer	Downregulated	Tumor suppressor	MEIS2 acts as a tumor suppressor in breast cancer. Its expression is reduced in breast tumors, and MEIS2 loss correlates with tumor progression. In cell-line and xenograft models, restoring MEIS2 suppresses proliferation and invasion through downregulation of IL10	[235]
MEIS2C/D	HCC	Upregulated	Oncogenic	The MEIS2 isoforms C and D are overexpressed in HCC tumors vs adjacent liver. Elevated MEIS2C/D correlates with worse prognosis in HCC patients. MEIS2C/D knockdown markedly inhibits HCC cell proliferation, migration, and invasion (in vitro and in mice), whereas MEIS2 overexpression accelerates tumor growth. MEIS2C activates Wnt/β-catenin signaling (with CDC73), and MEIS2D activates YAP by suppressing Hippo signaling - together promoting HCC progression	[141]
MEIS3	CRC	Upregulated	Oncogenic	MEIS3 is overexpressed at the invasive front of CRC tumors and in tumor buds. Higher MEIS3 correlates with advanced stage and worse 5-year disease-free survival. Functional assays showed MEIS3 promotes CRC cell migration and invasion	[148]
	HCC	Upregulated	Oncogenic	MEIS3 is aberrantly expressed in HCC and has been implicated as a pro-metastatic factor. High MEIS3 expression promotes HCC cell migration and invasion and is associated with higher recurrence rates in postoperative patients	[236]
PKNOX1	Melanoma (cutaneous)	Downregulated	Tumor suppressor	PKNOX1 is absent or strongly downregulated in about 70% of diverse human cancers. In mouse models, PKNOX1 deficiency leads to spontaneous development of lymphomas and carcinomas, confirming a tumor-suppressor role. In melanoma, a specific lncRNA (lnc-PKNOX1-1), encoded from PKNOX1 gene locus shown to inhibit melanoma progression	[155]
PKNOX2	AML	Downregulated	Tumor suppressor	In a mouse AML model, PKNOX2 was downregulated in KRAS-mutant model	[171]
	NSCLC	Downregulated	Tumor suppressor	PKNOX2 is frequently downregulated in lung cancer via promoter methylation. Restoring PKNOX2 suppresses NSCLC cell proliferation by inhibiting the PI3K/AKT/mTOR pathway. Low PKNOX2 is associated with poorer prognosis in lung cancer, and PKNOX2 is proposed as a tumor suppressor in both lung and gastric cancers	[42]
	GC	Downregulated	Tumor suppressor	PKNOX2 expression is often silenced via hypermethylation in GC. In vivo, PKNOX2 activates the transcription of IGFBP5 and stabilizes p53, thereby inhibiting gastric tumor growth. Low PKNOX2 in GC is linked to increased proliferation and poor prognosis	[153]

AML: Acute myeloid leukemia; HCC: Hepatocellular carcinoma; IL: Interleukin; CDC37: Cell division cycle 37; YAP: Yes-associated protein; CRC: Colorectal cancer; lncRNA: Long non-coding RNA; NSCLC: Non small cell lung cancer; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; GC: Gastric cancer; IGFBP5: Insulin-like growth factor-binding protein 5.