Original Articles Open Access
Copyright ©The Author(s) 2000. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 15, 2000; 6(6): 848-854
Published online Dec 15, 2000. doi: 10.3748/wjg.v6.i6.848
Multiple genetic alterations and behavior of cellular biology in gastric cancer and other gastric mucosal lesions: H. pylori infection, histological types and staging
Heng Jun Gao, Lian Zhen Yu, Kun Miu, Xiu Zhen Lü, Xiao Yong Zhang, Zhi Quan Zhao, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Jian Feng Bai, Gu Sun, Han Lin Zhao, Department of Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Yan Shen Peng, Renji Hospital, Shanghai Second Medical University, Shanghai Institute of Digestive Disease, Shanghai 200001, China
Heng Jun Gao, graduated from Yangzhou Medical College in 1986, worked in Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University as an assistant professor and a resident physician, now Ph.D. candidate in Renji Hospital, Shanghai Second Medical University, Shanghai Institute of Digestive Disease, majoring in the relationship between Helicobacter pylori and gastric cancer and gene therapy of gastrointestinal cancer, having 24 papers published, being the chief editor of two books and principal investigator for the study of two projects.
Author contributions: All authors contributed equally to the work.
Correspondence to: Heng Jun Gao, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China. Email: GaoHengJun@163.net
Telephone: 0086-21-63260930 Ext.2134
Received: April 3, 2000
Revised: April 12, 2000
Accepted: April 19, 2000
Published online: December 15, 2000


AIM: To investigate the expression of multiple genes and the behavior of cellular biology in gastric cancer (GC) and other gastric mucosal lesions and their relations to Helicobacter pylori (H. pylori) infection, tumor staging and histological subtypes.

METHODS: Three hundred and twenty-seven specimens of gastric mucosa obtained via endoscopy or surgical resection, and ABC immunohistochemical staining were used to detect the expression of p53, p16, Bcl-2 and COX-2 proteins. H. pylori was determined by rapid urea test combined with pathological staining or 14C urea breath test. Cellular image analysis was performed in 66 patients with intestinal metaplasia (IM) and/or dysplasia (Dys). In 30 of them, both cancer and the paracancerous tissues were obtained at the time of surgery. Histological pattern, tumor staging, lymph node metastasis, grading of differentiation and other clinical data were studied in the medical records.

RESULTS: p16 expression of IM or Dys was significantly lower in positive H. pylori chronic atrophic gastritis (CAG) than those with negative H. pylori (CAG: 54.8% vs 88.0%, IM:34.4% vs 69.6%, Dys: 23.8% vs 53.6%, all P < 0.05), Bcl-2 or COX-2 expression of IM or Dys in positive H. pylori cases was significantly higher than that without H. pylori (Bcl-2: 68.8% vs 23.9%, 90.5% vs 60.7%; COX-2: 50.0% vs 10.8%, 61.8% vs 17.8%; all P < 0.05). The mean number of most parameters of cellular image analysis in positive H. pylori group was significantly higher than that in negative H. pylori group (Ellipser: 53 ± 14, 40 ± 12 μm, Area 1: 748 ± 572, 302 ± 202 μm2, Area-2: 3050 ± 1661, 1681 ± 1990 μm2, all P < 0.05; Ellipseb: 79 ± 23, 58 ± 15 μm, Ratio 1: 22% ± 5%, 13% ± 4%, Ratio-2: 79% ± 17%, 53% ± 20%, all P < 0.01). There was significant correlation between Bcl-2 and histologic pattern of gas tric carcinoma, and between COX-2 and tumor staging or lymph node metastasis (Bcl-2: 75.0% vs 16.7%; COX-2: 76.0% vs 20.0%, 79.2% vs 16.7%; all P < 0.05).

CONCLUSION: p16, Bcl-2, and COX-2 but not p53 gene may play a role in the early genesis/progression of gastric carcinoma and are associated with H. pylori infection. p53 gene is relatively late event in gastric tumorigenesis and mainly relates to its progression. There is more cellular-biological behavior of malignant tumor in gastric mucosal lesions with H. pylori infection. Aberrant Bcl-2 protein expression appears to be preferentially associated with the intestinal type cancer. COX-2 seems to be related to tumor staging and lymph node metastasis.

Key Words: stomach neoplasms, gastric mucosa/injuries, precancerous conditions, gene expression, Helicobacter pylori, gastroscopy, immunohistochemistry, neoplasm staging


Gastric cancer (GC) is a worldwide disease with a dismal prognosis. A better understanding of its pathogenesis and biological features is crucial in improving the diagnosis and treatment[1]. Tumorigenesis of GC is attributable to the interaction of environmental and genetic factors[2-12]. In addition to dietary factors, Helicobacter pylori (H. pylori) infection has been regarded recently as a presumed environmental factor contributing to the tumorigenesis of the disease based on the theory that H. pylori infection may enhance cellular proliferation and therefore lead to somatic mutations of critical genes[13-24]. However, the increase of H. pylori in the gene alterations as p53, p16, Bcl-2, and COX-2 remain unclear[25-30].

GC consists of two distinct histological types: intestinal and diffuse types[31]. They differ not only in morphology but also in their clinical and epidemiological characteristics. A different spectrum of genetic changes is believed to be involved in the intestinal type rather than in the diffuse type[32]. Whether such genes as p53, p16, Bcl-2, and COX-2 play different roles in these two different types is not known[33-38].

Little is known about the sequential genetic changes associated with the progression of GC as compared with colon cancer. In terms of its natural history, GC may be divided into early and advanced stages according to the invasiveness of tumor cells. Many reports have described genetic alterations in GC, but few have compared these alterations between the early and advanced stages[35-37,39,40].

It is necessary to shed further light on gastric tumorigenesis, the loss of p16 and the overexpression of mutant p53, Bcl-2, and COX-2 were investigated in patients with GC and other gastric mucosal lesions. The status of H. pylori infection, tumor staging, and histological types were correlated with alterations of these four genes and behavior of cell biology.

Patients and samples

A total of 327 patients with histologically confirmed GC (60 cases) and other gastric mucosal lesions (chronic superficial gastritis, CSG; chronic atrophic gastritis, CAG; intestinal metaplasia, IM; dysplasia, Dys; 84, 56, 78, and 49 cases, respectively) were enrolled in the study. Those cancers were resected in the first affiliated hospital of Nanjing Medical University between 1996 and 1998. Both cancer and the neighboring nontumorous tissue of 30 patients were obtained at the time of surgery. The histological slides were independently reviewed by one pathologist, who was unaware of the parameters to be investigated. Tumors were classified as intestinal or diffuse types according to the Lauren’s criteria. The extent of tumor invasion was further divided into early or advanced GC according to the criteria proposed by the Japanese Research Society for Gastric Cancer. It is defined as an early GC if the tumor is limited in the mucosa and submucosa, and advanced GC if the tumor invades the muscularis propria. Lymph node metastasis, grading of differentiation and other clinical data were obtained from medical records, and the status of H. pylori infection was determined by a rapid urease test and a histological examination (Giemsa stain)/14C urea breath test.


The specimens in paraffin blocks were sectioned into 4 μm in thickness. The first section was routinely stained with HE for histological diagnosis, and additional sequential sections were retained for immunohistochemistry. Immunosta ining for p53, p16, Bcl-2, and COX-2 was performed by a standard avidin-biotin-peroxidase complex detection system. Mouse monoclonal antihuman p53 (diluted with PBS to 1∶50; Oncogene Science, Inc, USA), rabbit polyclonal anti-p16 (diluted with PBS to 1∶80, Dako, USA), mouse monoclonal antihuman Bcl-2 (diluted with PBS to 1∶100; Dako, USA), and rabbit polyclonal anti-COX-2 (diluted with PBS to 1∶50; Gene Company Limited) were used as the primary antibodies. Tissue sections were dewaxed, microwaved, and rehydrated. The sections were boiled for 30 min in 10 mmol/L citrate buffer solution (pH6.0) using a microwave heater for antigen retrieval. Endogenous peroxidase activity and nonspecific binding were blocked by incubation with 30 mL/L hydrogen peroxide (H2O2) and nonimmune serum, respectively. The slides were then incubated sequentially with primary mouse monoclonal or polyclonal antibodies overnight at 4 °C, with a biotinylated goat anti-mouse secondary antibody (diluted with PBS to 1∶200) for 30 min, with peroxidase-conjugated asreptavidin for 10 min, and finally, with 3,3’-diaminobenzidine-tetr-achloride (0.25 mg dissolved in 1 mL 0.2 mL/L hydrogen peroxide) chromogen substrate for 10 min so that demonstration of binding sites with peroxidase reaction was obtained. Negative control sections were prepared by substituted primary antibody with buffered saline, and positive control sections were obtained from known positive sections. The percentage of positively stained cells was evaluated for each tissue section after counting 1000 cells at high power field. Tissues were classified as being immunohistochemically positive if ≥ 5% of cells stained and showed distinct nuclear staining for p53 dominant nuclear staining and a little cytoplasmic staining for p16, nuclear membrane or cytoplasmic staining for Bcl-2 and cytoplasmic staining for COX-2. The staining intensity was expressed as weakly positive (+), moderately positive (++) and strongly positive (+++).

Cellular image analysis (CIA)

CIA was performed in 66 patients (H. pylori positive 33, H. pylori negative 33) with intestinal metaplasia (IM) and/or dysplasia (Dys). CIA (Vidas, Opton, Germany) supported by the Department of Cellular and Molecular Biology, Shanghai Second Medical University, which was used to study the following parameters: Fshape (shape factor), Fllipser (long axle, μm), Fllipseb (short axle, μm), Ratio-1 (nucleus to cytoplasm ratio, %), Ratio-2 (structure atypical index, %), Area-1 (area of nuclear, μm2), Area-2 (area of cytoplasm, μm2), taking the mean value of the parameters for analysis.

Statistical analysis

Statistical analysis system (SAS) software package for t test, χ² test, and Wilcoxon Scores (Rank Sums) test. A value of P < 0.05 was considered statistically significant.

Expressions of p53, p16, Bcl-2, and COX-2 proteins

The positive rates of p53, p16, Bcl-2, and COX-2 in GC were 46.7%, 38.3%, 68.3%, and 75.0% respectively. The positive rate of p53 gene in GC was significantly higher than that in DYS (P < 0.05); p16 gene expression in CSG or CAG was significantly higher than that in GC (P < 0.01) or Dys (P < 0.05). As to Bcl-2 expression, there was no significant difference between Dys and GC (P > 0.05), the positive rate of Bcl-2 expression in DYS or GC was significantly higher than that in CSG, CAG or IM (P < 0.01, P < 0.05). In addition, COX-2 expression in GC was also significantly higher than that in Dys or IM (P < 0.05, Table 1).

Table 1 Expressions of p53, p16, Bcl-2, and COX-2 proteins in gastric mucosal lesions (n, %).
GC6028 (46.7)a23 (38.3)41 (68.3)ba45 (75.0)a
Dys4910 (20.4)20 (40.8)36 (73.5)ba18 (36.7)
IM781 (1.3)43 (55.1)33 (42.3)21 (26.9)
CAG560 (0)39 (69.6)a9 (16.1)5 (8.9)
CSG840 (0)67 (79.8)b7 (8.3)0 (0)
The expression of p53, p16, Bcl-2 and COX-2 proteins in gastric mucosal lesions with H. pylori infection

No significant difference for the positive rate in p53 expression of GC or Dys between positive H. pylori and negative H. pylori group (P > 0.05). There was also no significant difference for p16, Bcl-2, or COX-2 expression in GC between positive H. pylori and negative H. pylori group (P > 0.05). However, the positive rate and staining intensity of p16 expressions of CAG, IM or Dys with H. pylori infection were significantly lower than those without H. pylori infection (P < 0.05, P < 0.01). On the contrary, Bcl-2 and COX-2 expressions of IM or Dys with positive H. pylori were significantly higher than those with H. pylori (P < 0.05, Table 2, Table 3).

Table 2 Expression rates of p53, p16, Bcl-2, and COX-2 proteins in gastric mucosal lesions with H. pylori infection (n, %).
ProteinCSG (84)
CAG (56)
IM (78)
Dys (49)
GC (60)
Hp+ (49)Hp-(35)Hp+ (31)Hp-(25)Hp+ (32)Hp-(46)Hp+ (21)Hp-(28)Hp+ (33)Hp-(27)
p530000106 (28.6)4 (14.3)17 (515)11 (40.7)
p1636 (73.5)31 (88.6)17 (54.8)22 (88.0)a11 (34.4)32 (69.6)a5 (23.8)15 (53.6)a11 (33.3)12 (44.4)
Bcl-24 (8.2)3 (8.6)6 (19.4)3 (12.0)22 (68.8)a11 (23.9)19 (90.5)a17 (60.7)25 (75.6)16 (59.3)
COX-2003 (9.7)2 (8.0)16 (50.0)a5 (10.8)13 (61.8)a5 (17.8)26 (78.7)19 (70.4)
Table 3 The expression intensity of p53, p16, Bcl-2, and COX-2 proteins in gastric mucosal lesions with H. pylori infection (n).
Cellular image analysis of gastric mucosal lesions with H. pylori infection

Cellular image analysis (CIA) was performed in 66 patients with IM and/or Dys, the mean value of most parameters of CIA in the positive H. pylori group was significantly higher than that in the negative H. pylori group (P < 0.05, P < 0.01, Table 4).

Table 4 Comparisons of each parameter of CIA between H. pylori positive and H. pylori negative.
parametersHp+ (33)Hp-(33)
Ellipser (μm)79 ± 2358 ± 15b
Ellipseb (μm)53 ± 1440 ± 12a
Ratio1 (%)22 ± 513 ± 4b
Ratio2 (%)79 ± 1753 ± 20b
Area1 (μm2)748 ± 572301 ± 202a
Area2 (μm2)3050 ± 16611681 ± 1990a
Fshape0.67 ± 0.090.71 ± 1.10
Expressions of p53, p16, Bcl-2, and COX-2 proteins in GC related to tumor staging and histological types

No correlation between p53, p16, or Bcl-2 expression and pathologic staging; grading of differentiation, or status of lymph node metastasis was observed (P > 0.05), there was significant correlation between Bcl-2 and types of GC (P < 0.05). However, there was significant correlation between COX-2 and pathologic staging or lymph node metastasis (all P < 0.05), no correlation between COX-2 expression and type or grading of differentiation (all P > 0.05, Table 5).

Table 5 Expressions of p53, p16, Bcl-2, and COX-2 proteins in GC related to tumor staging and histological types (n, %).
Intestinal2414 (58.3)9 (37.5)18 (75.0)a16 (66.7)
Diffuse63 (30.0)2 (33.3)1 (16.7)4 (66.7)
Stage of GC
Early52 (40.0)2 (40.0)4 (80.0)1 (20.0)
Advanced2515 (60.0)9 (36.0)15 (60.0)19 (76.0)a
Grade of differentiation
High or middle146 (42.9)6 (42.9)12 (85.7)8 (57.1)
Low or not108 (80.0)3 (30.0)7 (70.0)8 (80.0)
Lymph node metastasis
No42 (50.0)2 (50.0)3 (75.0)1 (16.7)
Yes2615 (57.7)9 (34.6)16 (61.5)19 (79.2)a

GC remains a common disease with a dismal prognosis in China and other Asian countries. Both genetic and environmental factors, such as H. pylori infection and dietary carcinogens, are crucial in cancer development and progression. The role of genetic changes in the pathogenesis of GC has recently received considerable attention[26-28]. The development of GC is a multistep process with accumulation of multiple oncogene activations and inactivation of tumor suppressor gene.

A number of molecular events are being recognized as implicating a part in the gastric carcinogenesis[41]. Among these, mutation of the tumor suppressor gene p53 is well described in gastric adenocarcinomas[42] as is loss of heterozygosity on chromosome 17p, the locus of p53[43]. The wild type acts functionally as a tumor suppressor gene[44] and may also have a role in preventing replication of the damaged DNA[45] while failure of this function in mutant p53 may lead to instability of the genome and predisposed to the development of aneuploidy[46]. The missense mutations of p53 genes have frequently been associated with the progression of GC[34,47].

Progression of cells through the different phases of the cell cycle is closely regulated by phase-specific activators and inhibitors. A novel cell cycle control gene, the p16 gene, also referred to as CDKN2, MTS1, or INK4A, which encodes components of cell cycle checkpoints, has been cloned and characterized. p16 gene is located on chromosome 9p21 and has been described as one of the principal negative regulators of the early G1 phase. Changes in this gene could thus lead to uncontrolled cell growth and contribute to tumorigenesis[35,48]. Recent studies have shown that the p16 gene is indeed inactivated in a wide range of cancer cell lines and primary tumors[48,49]. p16 gene may correlate with tumorigenesis and tumor expansion due to decrease or loss of gene products in gastric cancer[50,51]. However, studies on changes in p16 genes in GC remain scanty[38].

Recently, emphasis has been placed on the role of apoptosis and its regulation in carcinogenesis. In the gastrointestinal tract, apoptosis has been demonstrated to play an active role in the maintenance of the mucosa. Apoptosis may play a role in selection of clonal subpopulations with high growth potential resulting in malignant transformation[52]. The Bcl-2 protooncogene, located on chromosome 18, codes for a 26 Kd protein involved in inhibiting apoptosis[53]. Bcl-2 protein is believed to play a role in the gastric carcinogenic sequence where it has been demonstrated in dysplastic epithelium[54]. Aberrant Bcl-2 protein expression has been noted in gastric epithelial Dys and in CAG[36].

In addition, there was no expression of a novel isoenzyme of cyclooxygenase, cyclooxygenase-2 (COX-2) in normal tissue, however, large expression occurred in inflammatory sites. Recently, some researches show that there is an increasing expression of COX-2 in gastrointestinal tumors[37,55]. Although the potential role of the four genes’ protein expression have been recognized to be related to the carcinogenic sequence, that the role of H. pylori infection may promote changes of gene remains unclear[26,27,29,56]. Moreover, the relationship between these gene alterations and histological types, tumor staging, lymph node metastasis, grading of differentiation remains controversial[34,35,37,40]. Hence, we undertook the present study to investigate the effect of H. pylori infection on changes in the four genes and to further study their relation to types of GC and tumor progression.

H. pylori infection has been documented as an important risk factor for GC[57]. Chronic inflammation due to persistent H. pylori infection would be expected to cause repetitive degeneration and regeneration of the mucosal epithelium that could facilitate malignant transformation. While epithelial cell proliferation is not carcinogenic in itself, it is likely to promote neoplastic transformation in combination with additional factors, such as genetic alterations and oncoprotein overexpression. In the current study, we noted that the positive rate of p53, p16, Bcl-2, and COX-2 in GC was 46.7%,38.3%, 68.3%, and 75.0% respectively and four genetic changes were not different between positive H. pylori and negative H. pylori GC. However, the positive rate and staining intensity of p16 expression of CAG, IM or Dys with positive H. pylori were significantly lower than those with negative H. pylori. On the contrary, Bcl-2 expression of IM or DYS with positive H. pylori was significantly higher than that with negative H. pylori. p16 or Bcl-2 gene expression alteration might play a role in the early development/promotion of gastric carcinoma and was associated with H. pylori infection[50,51,58]. It seemed that H. pylori infection was not related to p53 gene alteration[30,59,60] because p53 gene overexpression was closely associated with the potential for advancement of tumor and a poorer prognosis in patients with GC[25,41,58,59,61,62] (Table 1, Table 2, Table 3). The result was different from that reported by Chang et al[63]. In the early stage of H. pylori infection, it not induces apoptosis in the gastric epithelium, at least in part due to downregulation of antiapoptotic Bcl-2[26] but promotes proliferation due to activation of oncogene[14]. However, persistent H. pylori infection would cause deletion of p16 gene and overexpression of Bcl-2[27], leading to overproliferation of gastric epithelium. In addition, inducible COX-2 is an important regulator of mucosal inflammation and epithelial cell growth. The expression of COX-2 gene is the result of direct response to H. pylori infection[28,29]. Our study found that COX-2 expression of IM or Dys with positive H. pylori was significantly higher than that with negative H. pylori. It is possible that the induced COX-2 in positive H. pylori gastric mucosal lesions plays a role in gastric carcinogenesis. Moreover, we found that the mean number of parameters of CIA except Fshape in the positive H. pylori group was significantly higher than that in the negative H. pylori group. It confirms that there are more cellular-biological behaviors of malignant tumor in gastric mucosal lesions with H. pylori infection.

Histologically, GC can be classified into intestinal and diffuse types based on the differences between precancerous lesions and glandular formation[31]. The intestinal type GC predominates in the elderly and has a similar histological appearance to colonic cancer, while the diffuse type GC occurs more commonly in younger patients with scattered tumor cells. The possible alterations of p53 suppressor gene were even in samples of gastric cancer and non tumoral mucosa. Mutation of p53 suppressor gene was frequent in gastric carcinoma[64]. Overexpression of p53 was more frequent in early intestinal than early diffuse GC[59]. In the current study, p53 was not different between the two types[33,65]. Although not statistically significant[65], differences in p53 immunopositivity between the various growth patterns were observed, with tumors invading the submucosa tending to show a higher frequency of staining than mucosal tumors (60.0% vs 40.0%). Tumors with lymph node metastases showed higher frequency of p53 staining (57.7%). We also found immunopositivity for p53 in 80.0% GC of low and undifferentiated tumor cells. These observations support the suggestion that over expression of p53 is associated with tumor progression in gastric carcinogenesis and may be related to prognosis[34,39,40,47]. Although the Bcl-2 proto-oncogene is important in determining tumor cell susceptibility to apoptosis, data about its clinical importance in GC are not available[66]. A significantly higher expression of Bcl-2 protein was found in the intestinal type than in the diffuse type of GC (75.0% vs 16.7%, P < 0.05) in our studies[36,67]. No correlation was also found between Bcl-2 expression and the prognostic parameters, depth of invasion, differentiation, and lymphnode invasion. Although not statistically significant, well and moderately differentiated tumors were more often Bcl-2-positive than poorly differentiated tumors, and lymph node negative tumors were more often Bcl-2-positive than nodal positive tumors. Bcl-2 expression has no prognostic impact on GC[36], which was different from the report of Inada et al[66]. Little is known about the role of p16 gene alterations in the genesis of GC[68,69]. This result suggested that no correlation between p16 expression and grade of pathologic staging, grading of differentiation, or lymph node status was observed. p16 gene played a limited role in tumor progression[25,68], which was discordant with some other reports[38]. Finally, no correlation was present between COX-2 expression and type or grading of differentiation (all P > 0.05), however, there was significant correlation between COX-2 and pathologic staging or lymph node metastasis (all P < 0.05). It was proposed that COX-2 played an important role in the development of GC[37,55,70].

In conclusion, prolonged and persistent H. pylori infection may promote Bcl-2 and COX-2 protein overexpression, but suppress p16 protein expression in gastric precancerous lesions. It seems that H. pylori infection is not related to p53 gene alteration because the p53 gene overexpression is relatively a late event in gastric tumorigenesis and is mainly relates to progression. However, p16, Bcl-2, and COX-2 gene expression alterations might play a role in the early development/promotion of gastric carcinoma but not in tumor progression and aberrant Bcl-2 protein expression appears to be preferentially associated with the intestinal type tumors. Moreover, there is significant correlation between COX-2 and pathologic staging or lymph node metastasis. p53, p16, Bcl-2, and COX-2 not only play independant but also synergistic role in the development and progression of gastric cancer[25,71].


Edited by You DY

Verified by Ma JY

Project supported by the Natural Science Foundation of the Educational Committee of Jiangsu Province, No.125FA9608.

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