|Year : 2016 | Volume
| Issue : 5 | Page : 50-53
The association between runt-related transcription factor 3 gene promoter methylation and gastric cancer: A meta-analysis
Xu Liu1, Lina Wang2, Yongtie Guo1
1 Department of Clinical Laboratory, First Teaching Hospital of Tianjin University of TCM, Tianjin 300193, China
2 Department of Clinical Laboratory, The Second People's Hospital, Tianjin 300192, China
|Date of Web Publication||7-Oct-2016|
Department of Clinical Laboratory, First Teaching Hospital of Tianjin University of TCM, Tianjin 300193
Source of Support: None, Conflict of Interest: None
Objective: To systematically evaluate the relationship of the methylation of the human-runt-related transcription factor 3 (RUNX3) promoter region and gastric cancer risk through meta-analysis.
Materials and Methods: The studies published in PubMed, EMBASE, Ovid, and CNKI were retrieved. The association between RUNX3 gene promoter methylation and gastric cancer was analyzed using Stata 11.0 (http://www.stata.com; Stata Corporation, College Station, TX, USA) and Review Man 5.0 software (http://ims.cochrane.org/revman/download).
Results: Seventeen studies are included in the analysis. Meta-analysis reveals that the odds ratio of the methylation of the RUNX3 promoter region in gastric was 7.32 (95% confidence interval: 5.12–10.47), which was significant higher than the normal gastric tissues (P < 0.05).
Conclusions: The RUNX3 gene promoter methylation rate was much higher in tumor tissue than that in normal gastric tissue in patient with gastric cancer, which indicates a close association between gastric cancer and RUNX3 gene promoter methylation.
Keywords: Gastric cancer, meta-analysis, methylation, runt-related transcription factor 3 gene
|How to cite this article:|
Liu X, Wang L, Guo Y. The association between runt-related transcription factor 3 gene promoter methylation and gastric cancer: A meta-analysis. J Can Res Ther 2016;12, Suppl S1:50-3
|How to cite this URL:|
Liu X, Wang L, Guo Y. The association between runt-related transcription factor 3 gene promoter methylation and gastric cancer: A meta-analysis. J Can Res Ther [serial online] 2016 [cited 2021 Apr 14];12:50-3. Available from: https://www.cancerjournal.net/text.asp?2016/12/5/50/191630
| > Introduction|| |
Gastric cancer is a common malignant tumor of the digestive system. Although the prevalence of this disease and the mortality rates of patients with gastric cancer have declined, gastric cancer ranks the highest in the list of gastrointestinal stromal tumors that seriously affect the health of human beings., Human-runt-related transcription factor 3 (RUNX3), which is a newly discovered antioncogene and member of a family of runt-related transcription factors, plays an important role in the transforming growth factor beta (TGF-β) signaling pathway. The methylation of the gene promoter region of RUNX3 may deactivate its corresponding gene and may subsequently induce the development and metastasis of gastric cancer. Our study systematically evaluates the relationship of the methylation of the RUNX3 promoter region with gastric cancer development.
| > Materials and Methods|| |
The studies related to relationship of the methylation of the RUNX3 promoter region with gastric cancer were searched in the databases of PubMed, EMBASE, Ovid, and CNKI following the keywords of “RUNX3,” “AML2,” “CBFA3,” “PEPB,” “gastric cancer,” “stomach cancer,” “gastric neoplasm,” or “stomach neoplasm.” The publication inclusion criteria (1) prospective or retrospective clinical research or cross-sectional studies, (2) patients pathologically diagnosed with gastric cancer, (3) methylation-specific polymerase chain reaction detection of the RUNX3 promoter region in cancer tissue and normal gastric tissues from patients with gastric cancer, and (4) result-based determination of the prevalence of methylation of the RUNX3 promoter region of each patient group.
The following data are extracted in parallel by two persons: (1) General information, including title, author, publication date, and journal title; (2) research features, including race and sample size of the investigated population; and (3) outcomes, including the prevalence of methylation of the RUNX3 promoter region in the tumor tissue and distant normal gastric tissues from patients with gastric cancer.
The odds ratio (OR) of the methylation of the RUNX3 promoter region in cancer tissue/normal gastric tissues is a measure as effect size. This parameter is expressed with a 95% confidence interval (95% CI) and is considered statistically different at P ≤ 0.05. I2 test was applied to examine heterogeneity. Statistical analysis is conducted in Stata 11.0 (http://www.stata.com; Stata Corporation, College Station, TX, USA).
| > Results|| |
A total of 166 related studies were initially retrieved. Of these documents, 116 are unqualified and excluded after their titles and abstracts are carefully read. Moreover, 33 studies are excluded after their full-text read. Finally, 17 studies are included in the meta-analysis [Table 1]. Of the included documents, 11 were written in English and 6 were written in Chinese.
Seventeen studies were included in the analysis. Meta-analysis reveals that the OR of the methylation of the RUNX3 promoter region in gastric cancer tissue is 7.32 (95% CI: 5.12–10.47), and this value is different from that in distant normal gastric tissues. The rate of methylation of the RUNX3 promoter region in cancer tissue is significantly higher than that in normal tissues [Figure 1].
|Figure 1: Forest plot of the association between runt-related transcription factor 3 gene promoter methylation and gastric cancer|
Click here to view
Subgroup analysis demonstrates that the methylation rate of the RUNX3 promoter region is significantly higher in the gastric cancer tissue of the subjects from China, Japan, Korea, and Europe than that in the corresponding normal gastric tissues (P < 0.05) [Table 2].
|Table 2: Subgroup analysis the association between runt-related transcription factor 3 gene promoter methylation and gastric cancer|
Click here to view
The publication bias was evaluated by Egger' test (t = −0.93, P = 0.37) and Begg' funnel plot. Begg's funnel plot demonstrated that all points in [Figure 2] were arranged along with the natural logarithm (logOR) of the measure of the effect size. Thus, publication bias is not observed [Figure 2].
|Figure 2: Funnel plot of the publication bias evaluated by the Begg's test|
Click here to view
| > Discussion|| |
RUNX3 participates in the expression and regulation of various genes in human growth and development; RUNX3 has also been identified as a key gene that mediates the TGF-β signaling pathway. With its important role in regulating the growth of gastric mucosa, RUNX3 can mediate TGF-β-induced growth inhibition and apoptosis and regulate the differentiation and maturation of epithelial cells in gastric mucosa. The inactivation of genes or loss of heterozygosity can trigger intestinal metaplasia and atypical hyperplasia. The methylation of the RUNX3 promoter region is the main cause of gene inactivation and may stimulate the normal gastric mucosa to become cancerous. Waki et al. investigated methylation in ten gastric cancer cell lines and found that seven of these cell lines in the RUNX3 promoter region are highly methylated. He et al. detected methylation in the RUNX3 promoter region in the cancer tissue of surgical specimens from patients with gastric cancer; they found that methylation occurs in the promoter region of 45% of the cancer tissue (42/93) and the RUNX3 expression in cancer tissue is significantly lower than that in normal gastric tissues. Nakase et al. found that the prevalence of RUNX3 methylation in gastric cancer tissue is 64%; by comparison, the prevalence of RUNX3 methylation in distant normal gastric mucosa tissues is 27%. These results indicate that the high degree of methylation in the RUNX3 promoter region is the main cause of gene inactivation and downregulation; furthermore, antioncogene inactivation is closely related to the occurrence and development of gastric cancer. The prevalence of the methylation of the RUNX3 promoter region in the cancer tissue of patients with gastric cancer is compared with that in distant normal gastric tissues through meta-analysis. The relationship of the methylation of the RUNX3 promoter region with gastric cancer development is further evaluated. Of the 17 documents included in our analysis, 11 are written in English and 6 are presented in Chinese. Our meta-analysis reveals that the OR of the methylation of the RUNX3 promoter region in gastric cancer tissue is 7.32 (95% CI: 5.12–10.47), and this value is different from that in distant normal gastric tissues. The methylation rate of the RUNX3 promoter region in the cancer tissue is significantly higher than that in the normal tissues.
In our study, the prevalence of the methylation of the RUNX3 promoter region in the cancer tissue of the patients with gastric cancer is compared with that in distant normal gastric tissues through meta-analysis. The combined results indicate that the RUNX3 promoter is highly methylated in about half of the cancer tissue of patients with gastric cancer, and the prevalence of methylation in cancer tissue is higher than that in distant normal tissues. The results further reveal that DNA methylation prevails in gastric cancer development, and the methylation of the RUNX3 promoter region is an important mechanism of gene inactivation. Gene inactivation may play an important role in gastric cancer development; therefore, reversing the methylation in the antioncogene promoter may provide a basis for new cancer treatments.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
Ji JF, Ji X. A review of gastric cancer after radical operation. J Med Res 2012;41:2-3, 15.
Ito K, Chuang LS, Ito T, Chang TL, Fukamachi H, Salto-Tellez M, et al.
Loss of Runx3 is a key event in inducing precancerous state of the stomach. Gastroenterology 2011;140:1536-46.e8.
Waki T, Tamura G, Sato M, Terashima M, Nishizuka S, Motoyama T. Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia. Cancer Sci 2003;94:360-4.
Nakase Y, Sakakura C, Miyagawa K, Kin S, Fukuda K, Yanagisawa A, et al.
Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography. Br J Cancer 2005;92:562-9.
So K, Tamura G, Honda T, Homma N, Endoh M, Togawa N, et al.
Quantitative assessment of RUNX3 methylation in neoplastic and non-neoplastic gastric epithelia using a DNA microarray. Pathol Int 2006;56:571-5.
Li Q, Zhao LZ, Wang YF, Guo CL. Runx3 gen promoter methylation and gastric cancer. Chin J Lab Diagn 2007;11:152-4.
Yang SH, Dai DQ. Runx3gene hypermethylation and gastric cancer. World Chin J Digestology 2007;15:1283-7.
Gargano G, Calcara D, Corsale S, Agnese V, Intrivici C, Fulfaro F, et al.
Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study. Ann Oncol 2007;18:103-9.
Li LY, Li JK, Shen Y. Promoter methylation of Runx3 gene and its protein expression in gastric carcinoma. Chin J Gastrointest Surg 2008;11:379-81.
Kitajima Y, Ohtaka K, Mitsuno M, Tanaka M, Sato S, Nakafusa Y, et al
. Helicobacter pylori
infection is an independent risk factor for Runx3 methylationin gastric cancer. Oncol Rep 2008;19:197-202.
Song HJ, Shim KN, Joo YH, Kim SE, Jung SA, Yoo K. Methylation of the tumor suppressor gene RUNX3 in human gastric carcinoma. Gut Liver 2008;2:119-25.
Kim WJ, Lee JW, Quan C, Youn HJ, Kim HM, Bae SC. Nicotinamide inhibits growth of carcinogen induced mouse bladder tumor and human bladder tumor xenograft through up-regulation of RUNX3 and p300. J Urol 2011;185:2366-75.
Chen W, Gao N, Shen Y, Cen JN. Hypermethylation downregulates Runx3 gene expression and its restoration suppresses gastric epithelial cell growth by inducing p27 and caspase3 in human gastric cancer. J Gastroenterol Hepatol 2010;25:823-31.
Hiraki M, Kitajima Y, Sato S, Mitsuno M, Koga Y, Nakamura J, et al.
Aberrant gene methylation in the lymph nodes provides a possible marker for diagnosing micrometastasis in gastric cancer. Ann Surg Oncol 2010;17:1177-86.
Lin H, Zhang B. The relationship between RUNX3, RASSF1A promoter methylation and the progression of gastric cancer metastasis. World Chin J Digestology 2010;18:889-96.
Hu SL, Huang DB, Sun YB, Wu L, Xu WP, Yin S, et al.
Pathobiologic implications of methylation and expression status of Runx3 and CHFR genes in gastric cancer. Med Oncol 2011;28:447-54.
Mikata R, Fukai K, Imazeki F, Arai M, Fujiwara K, Yonemitsu Y, et al.
BCL2L10 is frequently silenced by promoter hypermethylation in gastric cancer. Oncol Rep 2010;23:1701-8.
Tang GH, Sun SW, He XS. The relationship between CpG island methylation of Runx3 gene and gastric carcinoma. Chin J Pathol 2012;41:314-9.
He XB, Zhang HY. Methylation of Runx3 gene in gastric carcinoma and adjacent tissues and its clinical significance. Jilin Med J 2012;33:227-8.
Lee YM. Control of RUNX3 by histone methyltransferases. J Cell Biochem 2011;112:394-400.
[Figure 1], [Figure 2]
[Table 1], [Table 2]