Inflammatory response in gastrointestinal cancers: Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications

Table 1 Functions/mechanisms of six transmembrane epithelial antigens of the prostate involved in gastrointestinal cancers

Protein	Organ	Function/mechanism	Ref.
STEAP1	Stomach	Promoting peritoneal metastasis of GC	[113]
		Regulated at the level of cap-dependent translation initiation by phosphorylated eIF4E in GC	[114]
		Increasing cell proliferation, migration, and invasion of GC, via the activation of AKT/FoxO1 pathway and epithelial-mesenchymal transition	[72]
	Colon/rectum	Inducing cytotoxic T lymphocytes to recognize colon cancer with STEAP1 by specific STEAP1 peptide	[81]
		Reducing ROS and preventing apoptosis of CRC cells via NRF2 pathway	[115]
	Liver	Increased hepatic uptake of STEAP1 antibody-drug conjugates	[116]
		Accelerating cell proliferation by targeting c-Myc in liver cancer cells	[100]
STEAP3	Colon/rectum	Increased in CRC, along with CTR1 to induce copper accumulation	[84]
		Facilitating iron uptake and resistance to iron deprivation-induced apoptosis under hypoferric condition	[86]
		Time-dependent change of STEAP3 during inflammatory activation, along with specific accumulation of Fe (II) in inflammatory-activated macrophages	[85]
		Increasing exosome secretion in CRC, which can be cleaved by RHBDD1 in a dose/activity dependent manner	[87]
		Protected by hypoxia-induced lncRNA STEAP3-AS1 by preventing m6A-mediated degradation of STEAP3 mRNA	[89]
	Liver	Decreased expression in liver, associated with the transition from cirrhosis to HCC	[117]
		Increased in HCC cell nucleus, promoting proliferation via RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling axes	[102]
		Ferroptosis-related differential gene in HCV-infected cirrhotic HCC, impaired by matrix stiffness	[105]
STEAP4	Stomach	Highly expressed in GC, associated with infiltration of immune cells	[73]
	Colon/rectum	Decreased in CRC and positively correlated with immune-related biomarkers	[118]
		Highly induced in mouse models of colitis and inflammatory bowel disease patients, increasing ROS production in a hypoxia-dependent manner	[91]
		Induced by the inflammatory cytokine IL-17 to drive copper uptake, critical for colon tumor formation	[119]
	Liver	Lowly expressed in HCC, controlled by hypermethylation in STEAP4 promoter region	[109]
		Inhibiting proliferation and metastasis of HCC through PI3K/AKT/mTOR pathway inhibition	[111]
		Low level in HCC, associated with advanced HCC stage, poor survival, and immunosuppressive microenvironment	[112]
		Stimulated by the inflammatory cytokine IL-6, through STAT3 and CCAAT/enhancer-binding protein alpha in liver	[106]
		Hepatic STEAP4 antagonizes HBx-mediated hepatocyte dysfunction by interacting with and decreasing the stability of HBx	[107]
		Therapeutic effect of recombinant FGF21 on NAFLD is performed by increasing hepatic STEAP4 to protect hepatocytes	[108]

STEAP: Six transmembrane epithelial antigen of the prostate; GICs: Gastrointestinal cancers; GC: Gastric cancer; eIF4E: Eukaryotic initiation factor 4E; ROS: Reactive oxygen species; CRC: Colorectal cancer; NRF2: Nuclear erythroid 2-related factor; CTR1: Copper transporter 1; RHBDD1: Rhomboid domain containing 1; HCV: Hepatitis C virus; IL-17: Interleukin-17; HCC: Hepatocellular carcinoma; STAT3: Signal transducer and activator of transcription 3; PI3K: Phosphoinositide 3-kinase; mTOR: Mammalian target of rapamycin; JNK: c-Jun N-terminal kinase; ERK: Extracellular signal-regulated kinase; IL-6: Interleukin-6; HBx: Hepatitis B virus x protein; FGF21: Fibroblast growth factor 21; NAFLD: Non-alcoholic fatty liver disease.