Inhibition of host immune response in colorectal cancer: Human leukocyte antigen-G and beyond

Table 1 List of associations found between single nucleotide polymorphisms/alleles in human leukocyte antigen-G untranslated regions and different pathologies; genotype-phenotype correlations were also reported

UTRs	SNP	Genotype and/or allele	Disease	Association with1	UTR SNP and sHLA-G correlation	sHLA-G level	Statistical significance2	Country	Ref.
3’	14 bp INDEL	14 bp I/I	PE	Increased disease risk	ND	ND	Yes	China	[36]
3’	14 bp INDEL	14 bp I/I	RSA3	Increased disease risk	ND	ND	No	Denmark	[112]
3’	+3142 C/G	+3142 GG and G allele	SLE	Increased disease risk	ND	ND	Yes	Brazil	[37]
3’	14 bp INDEL	14 bp I/I	SLE	Increased disease risk	ND	ND	No	Brazil	[37]
3’	14 bp INDEL	14 bp I/I	OvaC	Increased disease risk	ND	ND	Yes	Canada	[33]
3’	14 bp INDEL	14 bp D/D	EsophC	Increased disease risk	ND	ND	Yes	China	[34]
3’	14 bp INDEL	14 bp D/D and D allele	HCC	Increased disease risk	ND	ND	Yes	Brazil	[35]
3’	14 bp INDEL	14 bp I/I and D allele	HCC	Increased disease risk	ND	ND	No	South Korea	[137]
3’	14 bp INDEL	14 bp I/I	Allo-HSCT	Lower OS and DFS	ND	ND	Yes	Italy	[138]
3’	14 bp INDEL	14 bp D/D	RA	MTX therapy (responder group)	Yes	Higher	Yes4	Italy	[114]
3’	14 bp INDEL	14 bp I/I	RR-MS	sHLA-G	Yes	Lower	Yes4	Italy	[139]
3’	+3142 C/G	+3142 GG	RR-MS	sHLA-G	Yes	Lower	Yes4	Italy	[139]
3’	14 bp INDEL	14 bp I/I	IVF3	sHLA-G	Yes	Absent	Yes	Denmark	[141]
5’	-725C/G/T	-725C>G	IVF3	sHLA-G	Yes	Absent	ND	Denmark	[141]
3’	14 bp INDEL	14 bp I/I	Heart T	sHLA-G	Yes	Lower	Yes	Canada	[142]
3’	14 bp INDEL	14 bp I/I	HD	sHLA-G	Yes	Lower	Yes	China	[143]
3’	14 bp INDEL	14 bp D allele	ERA	Improved disease remission	Yes	Higher	Yes4	Italy	[144]
5’	-725C/G/T	-725Callele	RPL3	sHLA-G	Yes	Lower	Yes	Iraq	[148]
3’	14 bp INDEL	14 bp I/I	PTC	Increased disease risk not found	No	Higher	Yes5	Italy	[31]

¹Data reported in this column are related to the association with SNPs in UTRs; the increased disease risk was compared with a HD control group;

²Statistical significance is referred to HLA-G SNP and disease status analysis;

³The disease status is related to infertility problems;

⁴A statistical significance was found also between HLA-G SNP and sHLA-G levels;

⁵A statistical significance was found between sHLA-G levels and the disease risk. UTR: Untranslated region; SNP: Single nucleotide polymorphism; sHLA-G: Soluble human leukocyte antigen-G; INDEL: Insertion/deletion polymorphism; I: Insertion; D: Deletion; PE: Pre-eclampsia; RSA: Recurrent spontaneous abortions; SLE: Systemic lupus erythematous; OvaC: Ovarian cancer; EsophC: Esophageal cancer; HCC: Hepatocellular carcinoma; Allo-HSCT: Allogeneic hematopoietic stem cell transplantation; RA: Rheumatoid arthritis; RR-MS: Relapsing-remitting multiple sclerosis; IVF: In vitro fertilization failure; Heart T: Heart transplantation; HD: Healthy blood donors; ERA: Early rheumatoid arthritis; RPL: Recurrent pregnancy loss; PTC: Papillary thyroid carcinoma; OS: Overall survival; DFS: Disease free survival; MTX: Methotrexate; ND: Not determined.

Table 2 Summary of human leukocyte antigen-G evaluations in colorectal cancer and related colonic diseases of the gastrointestinal tract

Sample type	HLA-Gs	Methods	Disease, n	Relevances	Ref.
Tumor DNA	HLA-G	RT-PCR	CRC, n = 39	HLA-G mRNA was significantly more expressed in CRC (87.2%) than in the extra neoplastic tissue	[24]
Tumor tissue	HLA-G	IHC	CRC, n = 201	HLA-G is over-expressed in primary CRC sites (64.6%), but not in the normal CRC tissues or benign adenomas	[25]
Tumor tissue	HLA-G	IHC	UC, n = 24; CD, n = 19	HLA-G and IL-10 are highly expressed in UC but not in CD tissue biopsies	[154]
Tumor tissue	HLA-G	IHC	CRC, n = 60; DA, n = 67; BC, n = 37; AC, n = 52	HLA-G is over-expressed in 52 % of CRC lesions and also in 79% of PDAs, 76% in BC and 75% AC	[26]
Tumor tissue	HLA-G	IHC	CRC, n = 415	HLA-G is expressed in > 30% of CRC lesions (data summarize published data collected until 2008)	[16]
Tumor tissue	HLA-G	IHC	CRC, n = 154	HLA-G is expressed in > 30% of CRC lesions (data summarize published data collected until 2005)	[17]
Serum	sHLA-G	ELISA	CRC, n = 144	Higher sHLA-G levels in CRC (median 124.3 U/mL) compared to benign colorectal diseases (cut off value 88.6 U/mL). CEA showed less sensitivity e specificity	[27]
Plasma	sHLA-G	ELISA	CRC, n = 37	sHLA-G as a diagnostic biomarker for the detection of early CRC (median 84 U/mL) with respect to BD (median 34 U/mL)	[28]
PBMC	sHLA-G	ELISA	HD, n = 30; CD, n = 10; UC, n = 18	Spontaneous secretion of sHLA-G from cultured PBMCs of CD but not in UC and BD	[161]
				Secretion of sHLA-G in CD patient cultures and BD but no in UC, after LPS stimulation
Plasma and PBMC	HLA-G	ELISA	UC, n = 27; CD, n = 22	Immunosuppressive therapy decreases sHLA-G hyperproduction in CD and induces its release in UD, in both plasma and in PBMC culture supernatants	[162]

HLA-G: Human leukocyte antigen-G; sHLA-G: Soluble HLA-G; CRC: Colorectal cancer; UC: Ulcerative colitis; CD: Crohn’s disease; PDA: Pancreatic ductal adenocarcinoma; BC: Biliary cancer; AC: Ampullary cancer; HD: Healthy blood donors; PBMC: Peripheral blood mononuclear cells; IHC: Immunohistochemistry; LPS: Lipopolysaccharide; CEA: Carcinoembryonic antigen; IL: Interleukin; ELISA: Enzyme-linked immunosorbent assay.