Impact of homeobox genes in gastrointestinal cancer

Table 1 Aberrant expression of HOX and non-HOX genes in esophageal cancer

Homeobox gene	Change	Underlying mechanism	Ref.
BE/EAC
CDX2	↑ in BE/EAC	Concomitant decrease of PITX1	[12,13]
	No difference between BE and EAC	Association with β-catenin
HOXB5, B6, B7	↑ in BE/dysplasia/EAC	Induction of intestinal markers such as KRT20, Muc2 and villin	[15]
ESCC
CDX2	↓ in a ESCC cell line and tissues	Promoter hypermethylation	[18]
MEIS	↓ in ESCC, inversely related with nodal status and high tumor stage	Concomitant increase of SOX2	[24]
HOXA7, A9, C6	↑ in ESCC	Not presented	[16]
HOXA5, A10, B13, C6, C10, C13, D3	↑ in BE/EAC, highest in T2 stage	Not presented	[17]
HOXA13	↑ in ESCC, associated with OS and DFS	Targeting annexinA2, MnSOD, ERAB	[19-21]
HOXB7	↑ in ESCC, associated with T/N stage and DFS	Not presented	[23]

BE: Barrett’s esophagus; EAC: Esophageal adenocarcinoma; ESCC: Esophageal squamous cell carcinoma; MnSOD: Manganese superoxide dismutase; OS: Overall survival; DFS: Disease free survival.

Table 2 Aberrant expression of HOX and non-HOX genes in gastric cancer

Homeobox gene	Change	Underlying mechanism	Ref.
CDX2	↑ in complete IM > incomplete IM > dysplasia > GC	Promoter hypermethylation in GC	[27-29]
	Associated with differentiated type GC	Decreased intake of green tea or cruciferous vegetables
ISX	↑ in IM and GC	Increase of cyclin D1 and CD44	[31]
	Upregulated in undifferentiated type GC
PROX1	↑ in GC	Inhibition of apoptosis, promoting lymphangiogenesis and angiogenesis	[32]
	Associated with undifferentiated type, advanced stage and poor OS
PRRX1	↑ in GC	Induction of Wnt/β-catenin	[33]
	Associated with advanced stage and distant metastasis
IRX1	↓ in GC	Promoter hypermethylation	[35]
PDX1	↓ in GC	Promoter hypermethylation, histone hypoacetylation	[34,36,37]
	↑ in pseudopyloric gland IM
	Inversely related with advanced T/ N stage and undifferentiated type GC
HOXA13	↑ in GC	Not presented	[38]
	Associated with advanced TNM stage, undifferentiated type and poor response to chemotherapy
HOXB5	↑ in GC	Upregulation of β-catenin	[39]
HOXB7	↑ in primary or metastatic cancer than chronic gastritis or IM	Modulation of PI3K/Akt/PTEN axis	[41,42]
	Associated with advanced TNM stage and undifferentiated type GC
HOXD10	↓ in GC	Promoter hypermethylation	[40]
		Induction of IGFBP3

Note: PROX1, PRRX1, HOXA13 and HOXB7 are associated with advanced TNM stage, while PDX1 is inversely associated; ISX, PROX1, HOXA13 and HOXB7 are associated with undifferentiated type GC. IM: Intestinal metaplasia; GC: Gastric cancer; OS: Overall survival; PI3K: Phosphatidylinositol-3 kinase; IGFBP3: Insulin like growth factor binding protein 3.

Table 3 Aberrant expression of HOX and non-HOX genes in colorectal cancer

Homeobox gene	Change	Underlying mechanism	Ref.
CDX1	↑ in adenomatous polyp, ↓ in CRC	Regulation of cyclin D1 and β-catenin/TCF pathway	[55,56,58]
		Regulated by miR-215
CDX2	↓ in adenoma and CRC	Loss of Mucdhl	[50-55]
	Inversely associated with right side tumor, poorly differentiated type, advanced stage, poor prognosis, CIMP, MMR-deficient tumor	Induction of Wnt/β-catenin axis
ALX4	↓ in dysplasia and CRC	Promoter hypermethylation	[59]
PROX1	↑ in CRC	Induction of β-catenin/TCF axis	[60,61]
	Associated with advanced stage and lymph node metastasis	Inhibition of E-cadherin activity
HOXA4, D10	↑ in CRC	Stem cell overpopulation and crypt renewal	[63]
HOXA5, A9, A10, C6	Proximal colon tumor > distal colon tumor	Not presented	[64]
HOXB13	Distal colon tumor > proximal colon tumor	Not presented	[64]
HOXB7	↑ in CRC	Activation of PI3K/Akt and MAPK pathways	[67]
	Associated with advanced stage, T stage, distant metastasis and poor OS

CRC: Colorectal cancer; TCF: β-catenin/T-cell factor; CIMP: CpG island methylation phenotype; OS: Overall survival; PI3K: Phosphatidylinositol-3 kinase; MAPK: Mitogen-activated protein kinase.