HOX and MEINOX in cellular plasticity, fibrosis, and cancer

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.