Functional promoter polymorphisms of NFKB1 influence susceptibility to the diffuse type of gastric cancer

  • Authors:
    • Tomiyasu Arisawa
    • Tomomitsu Tahara
    • Hisakazu Shiroeda
    • Kaho Yamada
    • Tomoe Nomura
    • Hideto Yamada
    • Ranji Hayashi
    • Kazuhiro Matsunaga
    • Toshimi Otsuka
    • Masakatsu Nakamura
    • Takeo Shimasaki
    • Nobuyuki Toshikuni
    • Natsuko Kawada
    • Tomoyuki Shibata
  • View Affiliations

  • Published online on: October 1, 2013     https://doi.org/10.3892/or.2013.2768
  • Pages: 3013-3019
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

In the present study, we report an association between gastric cancer and polymorphisms in NFKB1 (rs28362941 and rs78696119). We employed the PCR-SSCP method to detect gene polymorphisms in 479 gastric cancer cases and 880 controls. The rs28362941 del/del homozygote was significantly associated with gastric cancer development; in particular it was closely associated with diffuse type gastric cancer. The rs78696119 GG homozygote was also associated with the diffuse type of gastric cancer. In young subjects, both polymorphisms were significantly associated with the development of gastric cancer. In addition, both polymorphisms were related to tumor progression such as tumor invasion and lymph node metastasis. The inflammatory cell infiltration into non-cancerous gastric mucosa was greater in the subjects with the rs28362491 del/del or rs78696119 GG genotype when compared to those with the other genotypes. In conclusion, functional polymorphisms of NFKB1 are associated with an increased risk of gastric cancer; in particular they are closely associated with the development of diffuse type of gastric cancer via severe gastric inflammation. These polymorphisms also appear to be associated with gastric cancer progression.

Introduction

Gastric cancer (GC) is one of the most common and lethal malignancies in Japanese and East Asian populations, and the second most common cause of cancer-related death in the world (1). Although the incidence and mortality rate of GC located outside the cardia have decreased over the last few decades, a considerable percentage of patients still have advanced disease at diagnosis. Helicobacter pylori (H. pylori) infection is now accepted as a crucial event in the development of atrophic gastritis and is implicated in the development of gastric carcinoma, particularly those not located in the cardia (24). However, there is marked variation in the extent of gastric inflammation among H. pylori-infected patients, and only a small percentage of them actually develop GC. That is, the occurrence and development of GC is a process involving genetic and environmental factors, for example H. pylori infection and other environmental factors. This suggests that genetic factors play an important role in the long-term outcome of H. pylori infection (59).

Lipopolysaccharide (LPS), which is a component of the outer membrane of Gram-negative bacteria including H. pylori, is a signaling molecule for the innate immune system and is one of the main sources of inflammation (10). LPS binding to TLR4 activates signal transduction through MyD88, IRAK and TRAF6 to activate the nuclear factor (NF)-κB (11). Activation of NF-κB by H. pylori induces nuclear translocation, which causes an increase in IL-8 messenger RNA and protein levels (12). In addition, the NF-κB pathway is responsible for the generation of several cell adhesion molecules including ICAM-1 (13). Thus, H. pylori is a potent activator of NF-κB in gastric epithelial cells, and NF-κB is a major molecule in H. pylori-induced inflammation (14). On the other hand, NF-κB activation is known to regulate cellular growth responses, including apoptosis, and is required for the induction of inflammatory and tissue-repair genes (15). These facts suggest that NF-κB plays an important role in inflammation-associated carcinogenesis. NFKB1 which is a gene encoding 2 subunits (p50 and p105) of NF-κB is located on 4q24 (16). Recently, many studies have reported the association between polymorphism rs28362491 (−94 ins/del ATTG of NFKB1) and cancer risk in various organs (17). However, these results do not always lead to the same conclusions, and there has been no report concerning the risk of this polymorphism in the development of GC in Japan. Furthermore, certain genetic variation in rs72696119 (−449 C>G in 5′-UTR of NFKB1) has been identified. We previously reported a closely association between NFKB1 polymorphisms (rs28362491 and rs72696119) and aberrant gene methylation in gastric mucosa, which is considered to be a pre-malignant condition (18).

In the present study, we attempted to clarify the association between −94 ins/del ATTG polymorphism (rs28362491) of NFKB1 and GC development in Japanese subjects. In addition, the −449 C>G polymorphism (rs72696119) in 5′-UTR of NFKB1 was also investigated.

Materials and methods

Clinical samples

Our gastric cancer group included 479 patients (GC cases) enrolled at the Endoscopy Center of Fujita Health University Hospital or Kanazawa Medical University Hospital between July 2006 and August 2012. As a control group, 880 subjects without a malignant neoplasm, confirmed endoscopically and histologically, were selected at random from our DNA biobank, collected over the same period as that defined above (controls). Our final study cohort comprised 1,359 subjects for whom polymorphisms could be clearly analyzed.

All subjects underwent upper gastrointestinal endoscopy, and patients with severe systemic diseases, malignancies in other organs, and who had previously received non-steroidal anti-inflammatory drugs, antibiotics, and H. pylori eradication treatment were excluded. H. pylori infection status was assessed by serology, histological examination, or the urea breath test. Patients were diagnosed as having infection when at least one of the diagnostic tests was positive.

The Ethics Committees of Fujita Health University and Kanazawa Medical University approved the protocol, and written informed consent was obtained from all of the participating subjects.

Histological evaluation

In 778 of the 1,359 subjects (592 controls and 186 GC cases), the severity of chronic gastritis in non-cancerous mucosa was classified according to the updated Sydney system (19) by a pathologist who had no access to any clinical information.

Genotyping of polymorphisms

DNA was isolated from biopsy specimens or peripheral blood and genotyped using the PCR-SSCP method as reported previously (18,20). We had previously confirmed that each genotype was clearly determined by this method. To detect NFKB1 rs28362491 (−94 ins/del ATTG) using the primer pairs (94F, 5′-gctatggaccgcatgactctatcag-3′ and 94R, 5′-ggggctctggcttcctagcag-3′), PCR was carried out in a volume of 20 μl containing 0.1 μg of genomic DNA. The DNA was denatured at 95°C for 3 min, followed by 35 cycles at 96°C for 15 sec, 58°C for 40 sec, and 72°C for 30 sec, with final extension at 72°C for 5 min. Thereafter, 2 μl of the PCR product was denatured with 10 μl of formamide (Sigma-Aldrich Co., St. Louis, MO, USA) at 90°C for 5 min. SSCP was carried out at 6°C using a GenePhor DNA separation system with GeneGel Excel 12.5/24 (Amersham Biosciences Corp., USA), after which the denatured single-strand DNA bands were detected using a DNA Silver Staining kit (Amersham Biosciences Corp.).

To detect NFKB1 −449 C>G, using the primer pairs (449F, 5′-cgtgtgtccgtctgtctgtatgctc-3′ and 449R, 5′-cgctggtgcacttctctctctttct-3′), PCR was carried out in a volume of 20 μl containing 0.1 μg of genomic DNA. The DNA was denatured at 95°C for 3 min, followed by 35 cycles at 95°C for 30 sec, 57°C for 40 sec, and 72°C for 45 sec, with a final extension at 72°C for 5 min. Thereafter, SSCP was carried out in the same manner as described above.

Statistical analysis

Data are expressed as means ± SD. Mean ages between GC cases and controls were compared using the Student’s t-test. The ratios of male/female and H. pylori infection were compared between 2 groups using a 2×2 table and the Fisher’s exact test. Allele and genotype frequencies were calculated by direct counting. The allele counts and genotype distribution were also compared by the Fisher’s exact test. Furthermore, the strength of association between genotype frequencies and the disease was assessed by calculating the odds ratio (OR) at 95% confidence intervals (CI). Adjusted ORs were calculated with the use of logistical multivariate regression analysis. The association of genotypes with the progression of gastric cancer was assessed by ANCOVA using the number of alleles as a covariate. Each updated Sydney system was compared using Mann-Whitney U test. For all analyses, the level of significance was set at p<0.05.

Results

Subject characteristics and genotype frequencies

In the controls, rs72696119 was in Hardy-Weinberg equilibrium (p=0.091), whereas rs28362491 was not (p=0.0495). The mean age, male/female ratio and frequency of H. pylori positivity of the controls were significantly lower than these value in the GC cases (Table I). The minor allele frequency and genotype distribution were not significantly different between the controls and GC cases.

Table I

Subject characteristics and genotype frequencies.

Table I

Subject characteristics and genotype frequencies.

CharacteristicsControlsGC casesp-value
No. of subjects880479
Mean age ± SD61.4±13.565.2±11.6<0.0001a
Male:female506:373336:143<0.0001b
HP-positive rate61.8%86.0%<0.0001b
NFKB1 rs28362491
 ins/ins342172
 ins/del435239
 del/del10368
 del. allele frequency36.4%39.1%NS
NFKB1 rs72696119
 CC352189
 CG428226
 GG10064
 G allele frequency35.7%37.0%NS

a Student’s t-test;

b Fisher’s exact test.

{ label (or @symbol) needed for fn[@id='tfn3-or-30-06-3013'] } NS, not significant. GC, gastric cancer.

Association between gene polymorphisms and gastric carcinogenesis

The rs28362491 del/del homozygote was significantly but weakly associated with susceptibility to gastric carcinogenesis (OR, 1.43; 95% CI, 1.01–2.02; p=0.045). This homozygote was strongly associated with diffuse type of GC (OR, 1.85; 95% CI, 1.21–2.84; p=0.0049), whereas it was not significantly associated with intestinal type of GC (Table II). The rs72696119 GG homozygote appeared to be associated with gastric carcinogenesis (p=0.089). This homozygote was also strongly associated with diffuse type of GC (OR, 1.81; 95% CI, 1.17–2.78; p=0.0073).

Table II

Association between genetic polymorphisms and gastric cancer.

Table II

Association between genetic polymorphisms and gastric cancer.

NFKB1 rs28362491ins/insins/deldel/deldel/del vs. others; OR (95% CI)p-value
Controls (880)a342435103Reference
Overall GC cases (479)b172239681.43 (1.01–2.02)0.045
 Intestinal (283)101150321.14 (0.724–1.78)0.58
 Diffuse (191)6986361.85 (1.21–2.84)0.0049

NFKB1 rs72696119CCCGGGGG vs. others; OR (95% CI)p-value

Controls (880)352428100Reference
Overall GC cases (479)b189226641.36 (0.955–1.94)0.089
 Intestinal (283)116138291.05 (0.656–1.67)0.85
 Diffuse (191)7185351.81 (1.17–2.78)0.0073

{ label (or @symbol) needed for fn[@id='tfn4-or-30-06-3013'] } By logistical regression analysis after adjustment for age, gender and H. pylori infection status.

a (Number) of subjects.

b The type of GC in 5 cases was unknown.

{ label (or @symbol) needed for fn[@id='tfn7-or-30-06-3013'] } GC, gastric cancer. OR, odds ratio; CI, confidence intervals.

In subjects younger than or 60 years of age, both rs28362491 del/del and rs72696119 GG homozygotes conferred an increased risk for the development of gastric cancer (OR, 2.24; 95% CI, 1.33–3.75; p=0.0023 and OR, 1.95; 95% CI, 1.16–3.28; p=0.012, respectively) (Table III). In subjects older than 60 years of age, however, no significant association was found between polymorphisms and gastric carcinogenesis.

Table III

Risk of gastric carcinogenesis with genotype in young and old subjects.

Table III

Risk of gastric carcinogenesis with genotype in young and old subjects.

NFKB1 rs28362491ins/insins/deldel/deldel/del vs. others; OR (95% CI)p-value
≤60 years of age
 Controls (359)a14417144Reference
 GC cases (167)5773372.24 (1.33–3.75)0.0023

NFKB1 rs72696119CCCGGGGG vs. others; OR (95% CI)p-value

≤60 years of age
 Controls (359)14217245Reference
 GC cases (167)6072351.95 (1.16–3.28)0.012

NFKB1 rs28362491ins/insins/deldel/deldel/del vs. others; OR (95% CI)p-value

>60 years of age
 Controls (521)19826459Reference
 GC cases (312)115166310.938 (0.583–1.51)0.79

NFKB1 rs72696119CCCGGGGG vs. others; OR (95% CI)p-value

>60 years of age
 Controls (521)21025655Reference
 GC cases (312)129154290.913 (0.559–1.49)0.71

{ label (or @symbol) needed for fn[@id='tfn8-or-30-06-3013'] } By logistical regression analysis after adjustment for gender and H. pylori infection status.

a (Number) of subjects.

{ label (or @symbol) needed for fn[@id='tfn10-or-30-06-3013'] } GC, gastric cancer; OR, odds ratio; CI, confidence intervals.

Association between genetic polymorphisms and the progression of gastric cancer

We further investigated the influence of genetic polymorphisms on the progression of GC. According to the UICC (Unio Internationalis Contra Cancrum) classification v. 7, gastric cancer cases at stage 0–I are classified as early GC cases and those at stage II–IV are classified as advanced GC cases. Thus, in this study, early GC and advanced GC cases consisted of 210 and 262 cases, respectively (unknown, 7 cases). The minor allele rs28362491 was significantly correlated to the progression of GC by ANCOVA (p=0.040) (Fig. 1), whereas that of rs72696119 was not. However, the distribution of the rs73696119 genotype was significantly different between advanced GC cases and early GC cases (p=0.039). The risk of the rs73696119 GG homozygote for advanced GC compared with early GC was OR, 1.78; 95% CI, 1.01–3.13 (p=0.046) (Table IV). In addition, the rs28362491 del/del homozygote conferred an increased risk for both tumor invasion over the muscle layer and lymph node metastasis (OR, 1.75; 95% CI, 1.02–3.00; p=0.041 and OR, 1.71; 95% CI, 1.01–2.89; p=0.047, respectively). The rs78366119 GG homozygote was also associated with an increased risk for both factors (OR, 2.33; 95% CI,1.32–4.11; p=0.0036 and OR, 1.83; 95% CI, 1.07–3.15; p=0.028, respectively).

Table IV

Association between cancer progression and genotype.

Table IV

Association between cancer progression and genotype.

NFKB1 rs28362491ins/insins/deldel/deldel/del vs. others; OR (95% CI)p-value
Early GC cases (210)a8210226Reference-
Advanced GC cases (262)86134421.34 (0.783–2.29)0.28
 ≤ T1 (234)9211626Reference-
 ≥ T2 (238)76120421.75 (1.02–3.00)0.041
 N(−) (266)9114431Reference-
 N(+) (206)7792371.71 (1.01–2.89)0.047

NFKB1 rs72696119CCCGGGGG vs. others; OR (95% CI)p-value

Early GC cases (210)909921Reference-
Advanced GC cases (262)95124431.78 (1.01–3.13)0.046
 ≤ T1 (234)10011321Reference-
 ≥ T2 (238)85110432.33 (1.32–4.11)0.0036
 N(−) (266)10313528Reference-
 N(+) (206)8288361.83 (1.07–3.15)0.028

{ label (or @symbol) needed for fn[@id='tfn11-or-30-06-3013'] } By logistical regression analysis after adjustment for gender, age and H. pylori infection status.

a (Number) of subjects.

{ label (or @symbol) needed for fn[@id='tfn13-or-30-06-3013'] } The cancer stage of 7 cases was unknown. GC, gastric cancer; OR, odds ratio; CI, confidence intervals.

Risk of the subjects with the rs28362491 del/del or rs72696119 GG genotype for gastric inflammation and carcinogenesis

When assessing the risk of the rs28362491 del/del or rs72696119 GG genotype (del/G group) for gastric carcinogenesis, a stronger association with GC was found (OR, 1.44; 95% CI, 1.02–2.03; p=0.037), particularly with the diffuse type of GC (OR, 1.88; 95% CI, 1.23–2.85; p=0.0033) (Table V). In addition, the inflammation score of the del/G group was significantly higher than that of the non-del/G group (p=0.0006), whereas the other updated Sydney system scores did not differ between the two groups (Fig. 2).

Table V

Association of del/del or GG genotype with gastric cancer.

Table V

Association of del/del or GG genotype with gastric cancer.

del/del or GGOthersdel/del or GG vs. others; OR (95% CI)p-value
Controls (880)a108772Reference
Overall GC cases (479)b714081.44 (1.02–2.03)0.037
 Intestinal (283)332501.13 (0.726–1.77)0.58
 Diffuse (191)381531.88 (1.23–2.85)0.0033

{ label (or @symbol) needed for fn[@id='tfn14-or-30-06-3013'] } By logistical regression analysis after adjustment for age, gender and H. pylori infection status.

a (Number) of subjects.

b The type of GC in 5 cases was unknown.

{ label (or @symbol) needed for fn[@id='tfn17-or-30-06-3013'] } GC, gastric cancer; OR, odds ratio; CI, confidence intervals.

Discussion

In the present study, we demonstrated the association between NFKB1 polymorphisms and gastric cancer risk. We revealed that the rs28362941 del/del genotype was significantly associated with an increased risk for the development of GC, and that both rs28362941 del/del and rs72696119 GG genotypes were closely associated with development of the diffuse type of GC. In addition, in the subjects with the rs28362941 del/del or rs73696119 GG genotype, the frequency of inflammatory cell infiltration into non-cancerous gastric mucosa was higher than this frequency in the other genotypes. Based on the fact that rs28362941 and rs73696119 are in linkage disequilibrium (18), these results suggest that more severe gastric inflammation may be induced in the homozygote of NFKB1 minor allele, subsequently developing diffuse type of GC.

According to the Lauren classification (21), there are two histologically distinct types of GC, which is still widely accepted. The intestinal type consists of gland-like structures that mimic the intestinal glands, and a series of precancerous lesions are recognized. The diffuse type of gastric cancer lacks any glandular structures and arises closer to the advancing edge of gastric mucosal inflammation without any identifiable histological precursor lesion (22). The former develops in stomachs affected by chronic inflammation by passing through the intermediate steps of atrophic gastritis or intestinal metaplasia (23). On the other hand, the severity of mucosal inflammation and various host features may directly induce mutagenetic events that ultimately lead to the onset of the latter. Moreover, the diffuse type of GC develops in comparatively younger subjects (24). Therefore, we suspect that NFKB1 polymorphisms were significantly associated with susceptibility to GC in young subjects, not elder subjects, in the present study.

It has been reported that the NFKB1 −94 ATTG deletion mutant in the promoter region destroys a transcription factor binding site, resulting in lower expression of NF-κB (25). One study reported that the NFKB1 −94 deletion mutant had a reduced risk for auto-immune disorders in China (26). In the stomach, Lo et al(27) showed that the −94 deletion mutant had a significantly reduced risk for gastric carcinogenesis in China. Contrary to these results, several studies in Caucasians have shown that the −94 deletion mutant is associated with an increased risk for the development of inflammatory or auto-immune diseases (25,28). In colorectal carcinogenesis, Andersen et al(29) demonstrated that carriers of the NFKB1 −94 deletion were at a 1.45-fold higher risk than homozygous carriers of the insertion allele. On the other hand, other studies found no association of NFKB1 −94 ins/del polymorphism with inflammatory or auto-immune diseases (3032). These contrasting observations may be explained by differences in the genotypic composition of populations in different countries with different racial groups. In fact, the frequency of the −94 deletion allele appears to be rather higher in Chinese healthy subjects (45–55%). However, in our Japanese subjects, it was approximately 35–36%, similar to the value in Caucasians. Our Japanese study indicates, as well as the Caucasian study, that the −94 deletion allele may be an inflammation promoting allele.

NF-κB regulates a number of different transcription factors that are homodimers or heterodimers of p65, p50, p105, C-rel and relB (33). NF-κB is involved in both the inflammatory and the anti-inflammatory process (34). The role of NF-κB in inflammation is determined by subunit type. NFKB1 encodes both subunits p105 and p50 of the transcription factor NF-κB by alternative splicing (35). As part of the p65/p50 NF-κB transcription factor complex, it is pro-inflammatory, controlling transcription of pro-inflammatory cytokines (36). Conversely, since p50 lacks this COOH-terminal transactivation domain which is necessary for the positive regulation of gene expression, p50 has anti-inflammatory properties in the p50 homodimer by repressing transcription (37). The relative abundance of p65/p50 heterodimers and p50 homodimers may determine the magnitude of inflammation by balancing the pro-inflammatory and anti-inflammatory response (33). In fact, p50-deficient mice have an increased sensitivity to LPS and have increased LPS-induced inflammation (38,39). In subjects with the del/del genotype, decreased p50 synthesis may lead to decreased repressive homodimers and increased active heterodimers of the NF-κB complex. This balance may promote gastric inflammation, resulting in cancer development.

In the present study, NFKB1 polymorphisms appeared to be associated with GC progression. Sasaki et al(40) reported that NF-κB activation was correlated with gastric cancer invasion and lymphatic invasion. It has been shown that the NF-κB pathway has an important role in GC cell growth and metastatic function in vitro(41,42). In a study in a Korean population by Kim et al(43), however, no correlation was observed between the genotype or allelic frequency of rs28362941 and the T, N or M stage of gastric cancer. The distribution of genotype in their study was 107 ins/ins, 80 ins/del and 274 del/del, which was entirely different from that in the present study. The minor allele frequency in our controls was almost equal to that in JSA426 (426 anonymous unrelated Japanese individuals, from NCBI dbSNP). It is unclear why there is such a discrepancy between the two Asian studies. Further large scale study is needed, since the association observed in this study was significant but weak.

The present study was a hospital-based case-control study. Therefore, sample selection may have affected the outcome as our controls included patients who came to the hospital in order to seek treatment for various complaints and were not completely healthy subjects. Another limitation of this study was that the effect of type II error cannot be excluded in relatively small sample sizes.

In conclusion, the functional promoter polymorphism of NFKB1 is associated with an increased risk of gastric cancer, in particular, with the development of diffuse type of gastric cancer via severe gastric inflammation. In addition, this polymorphism appears to be associated with gastric cancer progression.

References

1 

Parkin DM, Pisani P and Ferlay J: Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer. 80:827–841. 1999. View Article : Google Scholar : PubMed/NCBI

2 

Parsonnet J, Friedman GD, Vandersteen DP, et al: Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 325:1127–1131. 1991. View Article : Google Scholar

3 

No authors listed. NIH Consensus Conference: Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA. 272:65–69. 1994.

4 

Uemura N, Okamoto S, Yamamoto S, et al: Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 345:784–789. 2001. View Article : Google Scholar

5 

El-Omar EM, Carrington M, Chow WH, et al: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 404:398–402. 2000. View Article : Google Scholar : PubMed/NCBI

6 

Wu MS, Wu CY, Chen CJ, Lin MT, Shun CT and Lin JT: Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int J Cancer. 104:617–623. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Ohyauchi M, Imatani A, Yonechi M, et al: The polymorphism interleukin 8 −251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut. 54:330–335. 2005.

8 

Arisawa T, Tahara T, Shibata T, et al: Functional promoter polymorphisms of the macrophage migration inhibitory factor gene in gastric carcinogenesis. Oncol Rep. 19:223–228. 2008.PubMed/NCBI

9 

Arisawa T, Tahara T, Shiroeda H, et al: Genetic polymorphisms of IL17A and pri-microRNA-938, targeting IL17A 3′-UTR, influence susceptibility to gastric cancer. Hum Immunol. 73:747–752. 2012.

10 

Kiechl S, Lorenz E, Reindl M, et al: Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 347:185–192. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Hoshino K, Takeuchi O, Kawai T, et al: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. 162:3749–3752. 1999.PubMed/NCBI

12 

Keates S, Hitti YS, Upton M and Kelly CP: Helicobacter pylori infection activates NF-kappaB in gastric epithelial cells. Gastroenterology. 113:1099–1109. 1997. View Article : Google Scholar

13 

Hatz RA, Rieder G, Stolte M, et al: Pattern of adhesion molecule expression on vascular endothelium in Helicobacter pylori-associated antral gastritis. Gastroenterology. 112:1908–1919. 1997. View Article : Google Scholar : PubMed/NCBI

14 

Maeda S, Yoshida H, Ogura K, et al: H pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Gastroenterology. 119:97–108. 2000. View Article : Google Scholar

15 

Smith MG, Hold GL, Tahara E and El-Omar EM: Cellular and molecular aspects of gastric cancer. World J Gastroenterol. 12:2979–2990. 2006.

16 

Le Beau MM, Ito C, Cogswell P, Espinosa R III, Fernald AA and Baldwin AS Jr: Chromosomal localization of the genes encoding the p50/p105 subunits of NF-kappaB (NFKB2) and the I kappaB/MAD-3 (NFKBI) inhibitor of NF-kappaB to 4q24 and 14q13, respectively. Genomics. 14:529–531. 1992.PubMed/NCBI

17 

Zou YF, Yuan FL, Feng XL, et al: Association between NFKB1 −94ins/del ATTG promoter polymorphism and cancer risk: a meta-analysis. Cancer Invest. 29:78–85. 2011.

18 

Arisawa T, Tahara T, Shiroeda H, et al: NFKB1 polymorphism is associated with age-related gene methylation in Helicobacter pylori-infected subjects. Int J Mol Med. 30:255–262. 2012.

19 

Dixon MF, Genta RM, Yardley JH and Correa P: Classification and grading of gastritis. The updated Sydney System International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 20:1161–1181. 1996.PubMed/NCBI

20 

Hayashi R, Tahara T, Yamaaki T, et al: −449 C>G polymorphism of NFKB1 gene, coding nuclear factor-kappaB, is associated with the susceptibility to ulcerative colitis. World J Gastroenterol. 47:6981–6986. 2012.

21 

Lauren P: The two histologic main types of gastric carcinoma: diffuse and so-called intestinal type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 64:31–49. 1965.PubMed/NCBI

22 

Yoshimura T, Shimoyama T, Fukuda S, Tanaka M, Axon AT and Munakata A: Most gastric cancer occurs on the distal side of the endoscopic atrophic border. Scand J Gastroenterol. 34:1077–1081. 1999. View Article : Google Scholar : PubMed/NCBI

23 

Go MF: Review article: Natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther. 16(Suppl 1): S3–S15. 2002. View Article : Google Scholar

24 

Kong X, Wang JL, Chen HM and Fang JY: Comparison of the clinicopathological characteristics of young and elderly patients with gastric carcinoma: a meta analysis. J Surg Oncol. 106:346–352. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Karban AS, Okazaki T, Panhuysen CI, et al: Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet. 13:35–45. 2004.PubMed/NCBI

26 

Li H, Gao L, Shen Z, et al: Association study of NFKB1 and SUMO4 polymorphisms in Chinese patients with psoriasis vulgaris. Arch Dermatol Res. 300:425–433. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Lo SS, Chen JH, Wu CW and Lui WY: Functional polymorphism of NFKB1 promoter may correlate to the susceptibility of gastric cancer in aged patients. Surgery. 145:280–285. 2009.

28 

Kurylowicz A, Hiromatsu Y, Jurecka-Lubieniecka B, et al: Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves’ disease. Genes Immun. 8:532–538. 2007.

29 

Andersen V, Christensen J, Overvad K, Tjønneland A and Vogel U: Polymorphisms in NFκB, PXR, LXR and risk of colorectal cancer in a prospective study of Danes. BMC Cancer. 10:4842010.

30 

Mirza MM, Fisher SA, Onnie C, et al: No association of the NFKB1 promoter polymorphism with ulcerative colitis in a British case control cohort. Gut. 54:1205–1206. 2005.PubMed/NCBI

31 

Glas J, Török HP, Tonenchi L, et al: Role of the NFKB1 −94ins/delATTG promoter polymorphism in IBD and potential interactions with polymorphisms in the CARD15/NOD2, IKBL, and IL-1RN genes. Inflamm Bowel Dis. 12:606–611. 2006.

32 

Bajwa EK, Cremer PC, Gong MN, et al: An NFKB1 promoter insertion/deletion polymorphism influences risk and outcome in acute respiratory distress syndrome among Caucasians. PLoS One. 6:e194692011.PubMed/NCBI

33 

Pereira SG and Oakley F: Nuclear factor-kappaB1: regulation and function. Int J Biochem Cell Biol. 40:1425–1430. 2008. View Article : Google Scholar : PubMed/NCBI

34 

de Winther MP, Kanters E, Kraal G and Hofker MH: Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol. 25:904–914. 2005.PubMed/NCBI

35 

Lin L, DeMartino GN and Greene WC: Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome. Cell. 92:819–828. 1998. View Article : Google Scholar : PubMed/NCBI

36 

Perkins ND: Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol. 8:49–62. 2007. View Article : Google Scholar : PubMed/NCBI

37 

Hayden MS and Ghosh S: Shared principles in NF-kappaB signaling. Cell. 132:344–362. 2008. View Article : Google Scholar : PubMed/NCBI

38 

Gadjeva M, Tomczak MF, Zhang M, et al: A role for NF-kappaB subunits p50 and p65 in the inhibition of lipopolysaccharide-induced shock. J Immunol. 173:5786–5793. 2004. View Article : Google Scholar : PubMed/NCBI

39 

Han W, Joo M, Everhart MB, et al: Myeloid cells control termination of lung inflammation through the NF-kappaB pathway. Am J Physiol Lung Cell Mol Physiol. 296:L320–L327. 2009. View Article : Google Scholar : PubMed/NCBI

40 

Sasaki N, Morisaki T, Hashizume K, et al: Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res. 7:4136–4142. 2001.PubMed/NCBI

41 

Kang MH, Oh SC, Lee HJ, et al: Metastatic function of BMP-2 in gastric cancer cells: the role of PI3K/AKT, MAPK, the NF-κB pathway, and MMP-9 expression. Exp Cell Res. 317:1746–1762. 2011.PubMed/NCBI

42 

Qin Y, Li L, Chen J, et al: Fentanyl inhibits progression of human gastric cancer MGC-803 cells by NF-κB downregulation and PTEN upregulation in vitro. Oncol Res. 20:61–69. 2012.PubMed/NCBI

43 

Kim JG, Sohn SK, Chae YS, et al: No association of the NFKB1 insertion/deletion promoter polymorphism with survival in patients with gastric cancer. Jpn J Clin Oncol. 39:497–501. 2009.

Related Articles

Journal Cover

December 2013
Volume 30 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
APA
Arisawa, T., Tahara, T., Shiroeda, H., Yamada, K., Nomura, T., Yamada, H. ... Shibata, T. (2013). Functional promoter polymorphisms of NFKB1 influence susceptibility to the diffuse type of gastric cancer. Oncology Reports, 30, 3013-3019. https://doi.org/10.3892/or.2013.2768
MLA
Arisawa, T., Tahara, T., Shiroeda, H., Yamada, K., Nomura, T., Yamada, H., Hayashi, R., Matsunaga, K., Otsuka, T., Nakamura, M., Shimasaki, T., Toshikuni, N., Kawada, N., Shibata, T."Functional promoter polymorphisms of NFKB1 influence susceptibility to the diffuse type of gastric cancer". Oncology Reports 30.6 (2013): 3013-3019.
Chicago
Arisawa, T., Tahara, T., Shiroeda, H., Yamada, K., Nomura, T., Yamada, H., Hayashi, R., Matsunaga, K., Otsuka, T., Nakamura, M., Shimasaki, T., Toshikuni, N., Kawada, N., Shibata, T."Functional promoter polymorphisms of NFKB1 influence susceptibility to the diffuse type of gastric cancer". Oncology Reports 30, no. 6 (2013): 3013-3019. https://doi.org/10.3892/or.2013.2768