Helicobacter pylori eradication to prevent gastric cancer: Underlying molecular and cellular mechanisms

Table 1 Molecular alteration in the process of gastric carcinogenesis

Molecules	Major alterations	Comments	Category
p53	Mutation, LOH	Reported in diffuse-type and intestinal-type adenocarcinomas, as well as some precancerous lesions.	Tumor suppressor
APC	Mutation, LOH	Reported in diffuse-type and intestinal-type adenocarcinomas, as well as some precancerous lesions.	Tumor suppressor
DCC	LOH	Reported in intestinal-type adenocarcinomas. Related to cell adhesion	Tumor suppressor
CDH1	Mutation	Reported in diffuse-type adenocarcinomas.	Tumor suppressor
β-catenin	Mutation	Reported in intestinal-type adenocarcinomas.	Tumor suppressor
Fhit	LOH or deletion at chr. 3p14.2	Reported in diffuse-type and, in less frequency, intestinal-type adenocarcinomas, as well as some precancerous lesions.	Tumor suppressor
RUNX3	Hypermethylation	Related to TGF-β/SMAD signaling.	Tumor suppressor
K-ras	Mutation	Reported in intestinal-type adenocarcinomas. An element in signal transduction regulating cell proliferation, etc..	Oncogene
bcl-2	LOH	Reported in intestinal-type adenocarcinomas. Anti-apoptotic factor.	Oncogene
c-met	Amplification	Reported in diffuse-type and intestinal-type adenocarcinomas. The HGF receptor / tyrosine-kinase. Upregulation without mutation is also reported after mucosal injury.	Oncogene / Growth stimulus
c-erbB2	Amplification	Reported in intestinal-type adenocarcinomas. One of receptor-tyrosine kinases for EGF-family proteins.	Oncogene / Growth stimulus
Cyclin E	Amplification	Reported in diffuse-type and intestinal type adenocarciomas.	Cell cycle regulator
K-sam	Amplification	Reported in diffuse-type adenocarcinomas. One of bFGF receptor family proteins, FGFR2.	Oncogene
Mismatch repair (MMR) genes	Silencing due to hypermethylation	Reported in diffuse-type and intestinal-type adenocarcinomas, as well as some precancerous lesions. A possible source of mutations of other genes involving gastric carcinogenesis.	Determinants of microsatelite instability (MSI)
MMR genes	Mutation	Reported in diffuse-type and intestinal-type adenocarcinomas. There are conflicting data suggesting that mucosa with intestinal metaplasia is prone to and resistant to MSI.	Determinants of MSI
EGFR	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas.	Growth stimulus
EGF	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas.	Growth stimulus
TGF-α	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas, as well as some precancerous lesions. Another EGF-family protein.	Growth stimulus
VEGF	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas.	Angiogenic factor
iNOS	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas, as well as some precancerous lesions and mucosa with H. pylori.	Enzyme
COX-2	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas, as well as some precancerous lesions and mucosa with H. pylori. Cytokines and growth factors are possible inducer of COX-2.	Enzyme
ODC	Overexpression	Reported earlier in gastritis.	Enzyme
Telomerase	Activated	Enlongs telomere and prevents cell senescence.	Enzyme
CDXs	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas, as well as precancerous lesions. Is involved in intestinal metaplasia.	Transcription factor
Ets1	Overexpression	A transcription factor involving angiogenesis.	Transcription factor
NF-κB	Overexpression	A transcription factor regulating expression of proinflammatory cytokines, chemokines, iNOS and COX-2.	Transcription factor
Sp-1	Overexpression	Reported in diffuse-type and intestinal-type adenocarcinomas.	Transcription factor
SC-1	Overexpression	Reported in diffuse-type adenocarcinomas.	Apoptosis receptor
Fas/CD95	Overexpression	Reported in diffuse-type adenocarcinomas.	Apoptosis receptor
E-cadherin	Mutation	Reported in diffuse-type and intestinal-type adenocarcinomas.	Cell adhesion
CD44	Splicing variant	Reported in diffuse-type and intestinal-type adenocarcinomas.	Cell adhesion
Gastrin	Elevation in serum	Elevation of amidated gastrin is reported. Transactivates EGF-family proteins.	Gut hormone

Table 2 "p53" mutation in gastric cancers of early stages and precancerous gastric lesions. In gastric cancers of early stages and precancerous gastric lesions, LOH and splicing are merely reported. Abbreviations for mutation: Del: deletion; Ins: insertion; F/S: frame shift. Abbreviations for lesion: EGC: early gastric cancer; AD: adenoma, CA/AD: carcinoma in adenoma; D: dysplasia; IM: intestinal metaplasia; N: mucosa without dysplasia, IM or carcinoma. Data are collected from references 104, 105, 113-118. (Modified from Tsuji et al[119,120])

First author	Year	Case	G:C→A:T	G:C→T:A	A:T→G:C	A:T→C:G	A:T→T:A	G or C	Del	Ins	F/S	Lesions
Yokozaki	1992	1			2	1	1	1				EGC
Tohdo	1993	5			3						1	AD or CA/AD
Uchino	1993	12	10			2		1				EGC
Correa	1994	8	4		3				1			D, IM, or N
Hongyo	1995	9	10					1	1	2		Cancer at stage I
Sakurai	1995	7	4									AD, CA/AD or EGC
Tamura	1995	1	1									AD
Tamura	1995	4	3	2								EGC
Ranzani	1995	18	13	1			1	1	1	2		EGC
Summary			45	3	8	3	2	3	4	4	1
(%)			62	4	11	4	3	4	5	5	1