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Role of hMLH1 and E-Cadherin Promoter Methylation in Gastric Cancer Progression

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Abstract

Introduction

Gastric cancer (GC) is one of the leading causes of cancer-related death in Iran. Genome stability is one of the main genetic issues in cancer biology which is governed via the different repair systems such as DNA mismatch repair (MMR). A clear correlation between MMR defects and tumor progression has been shown. Beside the genetic mutations, epigenetic changes also have a noticeable role in MMR defects.

Methods

Here, we assessed promoter methylation status and the level of hMLH1mRNA expression as the main component of MMR system in 51 GC patients using the methylation-specific PCR and real-time PCR, respectively. Moreover, we performed a promoter methylation study of the E-cadherin gene promoter.

Results

It was observed that, 12 out of 39 cases (23.5 %) had hMLH1 overexpression. Hypermethylation of hMLH1 and E-cadherin promoter regions were observed in 25.5 and 36.4 %, respectively. Although, there was no significant correlation between hMLH1 mRNA expression and clinicopathological features, there are significant correlations between E-cadherin promoter methylation and tumor stage (p = 0.028) and location (p = 0.025). The rate of hMLH1 promoter methylation in this study was lower than that in the other population, showing the importance of the other mechanisms, in gastric tumorigenesis.

Conclusion

The results of this study indicate that DNA repair system is adversely affected by hypermethylation of hMLH1 in a fraction of gastric cancer patients. Additionally, E-cadherin hypermethylation seen in a subset of our gastric cancer patients is consistent with other reports showing correlation with aggressiveness and metastasis of gastric cancer.

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References

  1. Sadjadi A, Nouraie M, Mohagheghi MA, Mousavi-Jarrahi A, Malekezadeh R, Parkin DM. Cancer occurrence in Iran in 2002, an international perspective. Asian Pac J Cancer Prev. 2005;6(3):359–63.

    PubMed  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225–49.

    Article  PubMed  Google Scholar 

  3. Wagner AD, Schneider PM, Fleig WE. The role of chemotherapy in patients with established gastric cancer. Best Pract Res Clin Gastroenterol. 2006;20(4):789–99.

    Article  CAS  PubMed  Google Scholar 

  4. Pharoah PD, Dunning AM, Ponder BA, Easton DF. Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer. 2004;4(11):850–60.

    Article  CAS  PubMed  Google Scholar 

  5. Li GM. DNA mismatch repair and cancer. Front Biosci. 2003;8:d997–d1017.

    Article  CAS  PubMed  Google Scholar 

  6. Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008;18(1):85–98.

    Article  CAS  PubMed  Google Scholar 

  7. Moghbeli M, Moaven O, Dadkhah E, Farzadnia M, Roshan NM, Asadzadeh-Aghdaee H, et al. High frequency of microsatellite instability in sporadic colorectal cancer patients in Iran. Genet Mol Res. 2011;10(4):3520–9.

    Article  CAS  PubMed  Google Scholar 

  8. Strickler JG, Zheng J, Shu Q, Burgart LJ, Alberts SR, Shibata D. p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail. Cancer Res. 1994;54(17):4750–5.

    CAS  PubMed  Google Scholar 

  9. Thibodeau SN, French AJ, Roche PC, Cunningham JM, Tester DJ, Lindor NM, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res. 1996;56(21):4836–40.

    CAS  PubMed  Google Scholar 

  10. Xiao XQ, Gong WD, Wang SZ, Zhang ZD, Rui XP, Wu GZ, et al. Polymorphisms of mismatch repair gene hMLH1 and hMSH2 and risk of gastric cancer in a Chinese population. Oncol Lett. 2012;3(3):591–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Abbaszadegan MR, Moaven O, Sima HR, Ghafarzadegan K, A'Rabi A, Forghani MN, et al. p16 promoter hypermethylation: a useful serum marker for early detection of gastric cancer. World J Gastroenterol. 2008;14(13):2055–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Mir MR, Shabir N, Wani KA, Shaff S, Hussain I, Banday MA, et al. Association between p16, hMLH1 and E-cadherin promoter hypermethylation and intake of local hot salted tea and sun-dried foods in Kashmiris with gastric tumors. Asian Pac J Cancer Prev. 2012;13(1):181–6.

    Article  PubMed  Google Scholar 

  13. Abbaszadegan MR, Raziee HR, Ghafarzadegan K, Shakeri MT, Afsharnezhad S, Ghavamnasiry MR. Aberrant p16 methylation, a possible epigenetic risk factor in familial esophageal squamous cell carcinoma. Int J Gastrointest Cancer. 2005;36(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  14. Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin–catenin cell–cell adhesion complex and human cancer. Br J Surg. 2000;87(8):992–1005.

    Article  CAS  PubMed  Google Scholar 

  15. Kim HJ, Karpeh MS. Surgical approaches and outcomes in the treatment of gastric cancer. Semin Radiat Oncol. 2002;12(2):162–9.

    Article  PubMed  Google Scholar 

  16. Ushijima T, Sasako M. Focus on gastric cancer. Cancer Cell. 2004;5(2):121–5.

    Article  CAS  PubMed  Google Scholar 

  17. Yasui W, Oue N, Aung PP, Matsumura S, Shutoh M, Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer. 2005;8(2):86–94.

    Article  CAS  PubMed  Google Scholar 

  18. Suzuki H, Tokino T, Shinomura Y, Imai K, Toyota M. DNA methylation and cancer pathways in gastrointestinal tumors. Pharmacogenomics. 2008;9(12):1917–28.

    Article  CAS  PubMed  Google Scholar 

  19. Moghbeli M, Abbaszadegan MR, Farshchian M, Montazer M, Raeisossadati R, Abdollahi A, et al. Association of PYGO2 and EGFR in esophageal squamous cell carcinoma. Med Oncol. 2013;30(2):516.

    Article  PubMed  Google Scholar 

  20. Rubie C, Kempf K, Hans J, Su T, Tilton B, Georg T, et al. Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues. Mol Cell Probes. 2005;19(2):101–9.

    Article  CAS  PubMed  Google Scholar 

  21. Fleisher AS, Esteller M, Tamura G, Rashid A, Stine OC, Yin J, et al. Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia. Oncogene. 2001;20(3):329–35.

    Article  CAS  PubMed  Google Scholar 

  22. Kang GH, Shim YH, Ro JY. Correlation of methylation of the hMLH1 promoter with lack of expression of hMLH1 in sporadic gastric carcinomas with replication error. Lab Invest. 1999;79(7):903–9.

    CAS  PubMed  Google Scholar 

  23. Kang YH, Bae SI, Kim WH. Comprehensive analysis of promoter methylation and altered expression of hMLH1 in gastric cancer cell lines with microsatellite instability. J Cancer Res Clin Oncol. 2002;128(3):119–24.

    Article  CAS  PubMed  Google Scholar 

  24. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21(6):1174–9.

    Article  CAS  PubMed  Google Scholar 

  25. Takai N, Kai K, Tsuno A, Nasu K, Kashima K, Narahara H. Synchronous ovarian endometrioid adenocarcinoma with a functioning stroma and endometrial endometrioid adenocarcinoma by different loss of heterozygosity findings. Arch Gynecol Obstet. 2011;284(4):951–5.

    Article  PubMed  Google Scholar 

  26. Li M, Liu L, Wang Z, Wang L, Liu Z, Xu G, et al. Overexpression of hMSH2 and hMLH1 protein in certain gastric cancers and their surrounding mucosae. Oncol Rep. 2008;19(2):401–6.

    PubMed  Google Scholar 

  27. Hamid AA, Mandai M, Konishi I, Nanbu K, Tsuruta Y, Kusakari T, et al. Cyclical change of hMSH2 protein expression in normal endometrium during the menstrual cycle and its overexpression in endometrial hyperplasia and sporadic endometrial carcinoma. Cancer. 2002;94(4):997–1005.

    Article  CAS  PubMed  Google Scholar 

  28. Starzynska T, Bromley M, Ghosh A, Stern PL. Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer. 1992;66(3):558–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Chang DK, Ricciardiello L, Goel A, Chang CL, Boland CR. Steady-state regulation of the human DNA mismatch repair system. J Biol Chem. 2000;275(24):18424–31.

    Article  CAS  PubMed  Google Scholar 

  30. Umar A, Buermeyer AB, Simon JA, Thomas DC, Clark AB, Liskay RM, et al. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell. 1996;87(1):65–73.

    Article  CAS  PubMed  Google Scholar 

  31. Chen F, Arseven OK, Cryns VL. Proteolysis of the mismatch repair protein MLH1 by caspase-3 promotes DNA damage-induced apoptosis. J Biol Chem. 2004;279(26):27542–8.

    Article  CAS  PubMed  Google Scholar 

  32. Huang Q, Ai L, Zhang ZY, Fan CY, Weiss LM. Promoter hypermethylation and protein expression of the p16 gene: analysis of 43 cases of B-cell primary gastric lymphomas from China. Mod Pathol. 2004;17(4):416–22.

    Article  CAS  PubMed  Google Scholar 

  33. Ksiaa F, Ziadi S, Amara K, Korbi S, Trimeche M. Biological significance of promoter hypermethylation of tumor-related genes in patients with gastric carcinoma. Clin Chim Acta. 2009;404(2):128–33.

    Article  CAS  PubMed  Google Scholar 

  34. Chan AO, Lam SK, Wong BC, Wong WM, Yuen MF, Yeung YH, et al. Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut. 2003;52(4):502–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Carvalho B, Pinto M, Cirnes L, Oliveira C, Machado JC, Suriano G, et al. Concurrent hypermethylation of gene promoters is associated with a MSI-H phenotype and diploidy in gastric carcinomas. Eur J Cancer. 2003;39(9):1222–7.

    Article  CAS  PubMed  Google Scholar 

  36. Corn PG, Heath EI, Heitmiller R, Fogt F, Forastiere AA, Herman JG, et al. Frequent hypermethylation of the 5' CpG island of E-cadherin in esophageal adenocarcinoma. Clin Cancer Res. 2001;7(9):2765–9.

    CAS  PubMed  Google Scholar 

  37. Nass SJ, Herman JG, Gabrielson E, Iversen PW, Parl FF, Davidson NE, et al. Aberrant methylation of the estrogen receptor and E-cadherin 5' CpG islands increases with malignant progression in human breast cancer. Cancer Res. 2000;60(16):4346–8.

    CAS  PubMed  Google Scholar 

  38. Rocha AS, Soares P, Seruca R, Maximo V, Matias-Guiu X, Cameselle-Teijeiro J, et al. Abnormalities of the E-cadherin/catenin adhesion complex in classical papillary thyroid carcinoma and in its diffuse sclerosing variant. J Pathol. 2001;194(3):358–66.

    Article  CAS  PubMed  Google Scholar 

  39. Nagini S. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 2012;4(7):156–69.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Nobili S, Landini I, Mazzei T, Mini E. Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Med Res Rev. 2012;32(6):1220–62.

    Article  CAS  PubMed  Google Scholar 

  41. Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, et al. Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley. Asian Pac J Cancer Prev. 2012;13(8):4177–81.

    Article  PubMed  Google Scholar 

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Acknowledgment

This work was supported by two grants from the Vice Chancellor for Research at Mashhad University of Medical Sciences, no. 85031 and no. 85366.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran

    Meysam Moghbeli, Hamid Reza Raziei, Azadeh Aarabi, Ezzat Dadkhah, Fatemeh Manzari & Mohammad Reza Abbaszadegan

  2. Department of surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Omeed Moaven

  3. Department of Pathology, Omeed Hospital, MUMS, Mashhad, Iran

    Bahram Memar

  4. School of Systems Biology, George Mason University, Fairfax, VA, USA

    Ezzat Dadkhah

  5. Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran

    Mohammad Mahdi Forghanifard

  6. Medical Genetics Research Center, Medical School, MUMS, Mashhad, Iran

    Mohammad Reza Abbaszadegan

  7. Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, 9196773117, Iran

    Mohammad Reza Abbaszadegan

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  1. Meysam Moghbeli
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  2. Omeed Moaven
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  9. Mohammad Reza Abbaszadegan
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Correspondence to Mohammad Reza Abbaszadegan.

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Moghbeli, M., Moaven, O., Memar, B. et al. Role of hMLH1 and E-Cadherin Promoter Methylation in Gastric Cancer Progression. J Gastrointest Canc 45, 40–47 (2014). https://doi.org/10.1007/s12029-013-9548-9

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  • DOI: https://doi.org/10.1007/s12029-013-9548-9

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