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Genetic association of MMP14 promoter variants and their functional significance in gallbladder cancer pathogenesis

Abstract

Gallbladder cancer (GBC) is relatively rare but shows high frequency in certain geographical regions and ethnic groups, which include Northern and Eastern states of India. Previous studies in India have indicated the possible role of genetic predisposition in GBC pathogenesis. Although matrix metalloproteinase-14 (MMP14) is known modulator of tumour microenvironment and tumorigenesis and TCGA data also suggests its upregulation yet, its role in genetic predisposition for GBC is completely unknown. We explored MMP14 promoter genetic variants as risk factors and their implication in expression modulation and the pathogenesis of GBC. We genotyped all single nucleotide polymorphisms of MMP14 promoter by Sanger’s sequencing in approximately 300 GBC and 300 control study subjects of Indian ethnicity and, in 26 GBC tissue samples. Protein expression of MMP14 in GBC tissue samples was checked by immunohistochemistry. In vitro luciferase reporter assay was carried out to elucidate role of promoter genetic variants on expression levels in two different cell lines. MMP14 promoter variants, rs1003349 (p value = 0.0008) and rs1004030 (p value = 0.0001) were significantly associated with GBC. Luciferase reporter assay showed high expression for risk alleles of both the SNPs. Genotype–phenotype correlation for rs1003349 and rs1004030, in patient sample, confirmed that risk allele carriers had higher expression levels of MMP14; moreover, the correlation pattern matched with genetic association models. Overall, this study unravels the association of MMP14 promoter SNPs with GBC which contribute to pathogenesis by increasing its expression.

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References

  1. 1.

    Misra S, Chaturvedi A, Misra NC, Sharma ID. Carcinoma of the gallbladder. Lancet Oncol. 2003;4:167–76.

    PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Baiu I, Visser B. Gallbladder cancer. JAMA. 2018;320:1294.

    PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Rho YS, Barrera I, Metrakos P, Kavan P. Complete resolution of metastatic gallbladder cancer after standard gemcitabine-cisplatin combination therapy. Cureus. 2015;7:e415.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba II, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin. 2001;51:349–64.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update. World J Gastroenterol. 2017;23:3978–98.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Misra S, Chaturvedi A, Goel MM, Mehrotra R, Sharma ID, Srivastava AN, et al. Overexpression of p53 protein in gallbladder carcinoma in North India. Eur J Surg Oncol. 2000;26:164–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Hussain MA, Pati S, Swain S, Prusty M, Kadam S, Nayak S. Pattern and trends of cancer in odisha, India: a retrospective study. Asian Pac J Cancer Prev. 2012;13:6333–6.

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Dhir V, Mohandas KM. Epidemiology of digestive tract cancers in India IV. Gall bladder and pancreas. Indian J Gastroenterol. 1999;18:24–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Bustos BI, Perez-Palma E, Buch S, Azocar L, Riveras E, Ugarte GD, et al. Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry. Sci Rep. 2019;9:772.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Mhatre S, Wang Z, Nagrani R, Badwe R, Chiplunkar S, Mittal B, et al. Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study. Lancet Oncol. 2017;18:535–44.

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Cha P-C, Zembutsu H, Takahashi A, Kubo M, Kamatani N, Nakamura Y. A genome-wide association study identifies SNP in DCC is associated with gallbladder cancer in the Japanese population. J Hum Genet. 2012;57:235–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Rai R, Sharma KL, Tiwari S, Misra S, Kumar A, Mittal B. DCC (deleted in colorectal carcinoma) gene variants confer increased susceptibility to gallbladder cancer (Ref. No.: Gene-D-12-01446). Gene. 2013;518:303–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Srivastava K, Srivastava A, Mittal B. Polymorphisms in ERCC2, MSH2, and OGG1 DNA repair genes and gallbladder cancer risk in a population of Northern India. Cancer. 2010;116:3160–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Castro FA, Koshiol J, Hsing AW, Gao YT, Rashid A, Chu LW, et al. Inflammatory gene variants and the risk of biliary tract cancers and stones: a population-based study in China. BMC Cancer. 2012;12:468.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Hsing AW, Sakoda LC, Rashid A, Andreotti G, Chen J, Wang BS, et al. Variants in inflammation genes and the risk of biliary tract cancers and stones: a population-based study in China. Cancer Res. 2008;68:6442–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Vishnoi M, Pandey SN, Choudhuri G, Mittal B. IL-1 gene polymorphisms and genetic susceptibility of gallbladder cancer in a north Indian population. Cancer Genet Cytogenet. 2008;186:63–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Vishnoi M, Pandey SN, Choudhury G, Kumar A, Modi DR, Mittal B. Do TNFA -308 G/A and IL6 -174 G/C gene polymorphisms modulate risk of gallbladder cancer in the north Indian population? Asian Pac J Cancer Prev. 2007;8:567–72.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Bio. 2001;17:463–516.

    CAS  Article  Google Scholar 

  20. 20.

    Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 1998;58:1048–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Vihinen P, Kahari VM. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer. 2002;99:157–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Sharma KL, Misra S, Kumar A, Mittal B. Higher risk of matrix metalloproteinase (MMP-2, 7, 9) and tissue inhibitor of metalloproteinase (TIMP-2) genetic variants to gallbladder cancer. Liver Int. 2012;32:1278–86.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Sabbota AL, Kim HR, Zhe X, Fridman R, Bonfil RD, Cher ML. Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration. Cancer Res. 2010;70:5558–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Karadag N, Kirimlioglu H, Isik B, Yilmaz S, Kirimlioglu V. Expression of matrix metalloproteinases in gallbladder carcinoma and their significance in carcinogenesis. Appl Immunohistochem Mol Morphol. 2008;16:148–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Munkert A, Helmchen U, Kemper MJ, Bubenheim M, Stahl RA, Harendza S. Characterization of the transcriptional regulation of the human MT1-MMP gene and association of risk reduction for focal-segmental glomerulosclerosis with two functional promoter SNPs. Nephrol Dial Transplant. 2009;24:735–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Sambrook J, Russell DW. Purification of nucleic acids by extraction with phenol:chloroform. CSH Protoc. 2006;2006:169–70.

    Google Scholar 

  28. 28.

    Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser. 1999;41:95–8.

    CAS  Google Scholar 

  29. 29.

    Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue—a review. Diagn Pathol. 2014;9:221.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Gross J, Lapiere CM. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA. 1962;48:1014–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Sun J. Matrix metalloproteinases and tissue inhibitor of metalloproteinases are essential for the inflammatory response in cancer cells. J Signal Transduct. 2010;2010:985132.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

    Nyalendo C, Sartelet H, Gingras D, Beliveau R. Inhibition of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation blocks tumor progression in mice. Anticancer Res. 2010;30:1887–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Qiang L, Cao H, Chen J, Weller SG, Krueger EW, Zhang L, et al. Pancreatic tumor cell metastasis is restricted by MT1-MMP binding protein MTCBP-1. J Cell Biol. 2019;218:317–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Dufour A, Overall CM. Missing the target: matrix metalloproteinase antitargets in inflammation and cancer. Trends Pharmacol Sci. 2013;34:233–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Kasurinen A, Gramolelli S, Hagstrom J, Laitinen A, Kokkola A, Miki Y, et al. High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1. Cancer Med. 2019;8:6995–7005.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Duan F, Peng Z, Yin J, Yang Z, Shang J. Expression of MMP-14 and prognosis in digestive system carcinoma: a meta-analysis and databases validation. J Cancer. 2020;11:1141–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Cui G, Cai F, Ding Z, Gao L. MMP14 predicts a poor prognosis in patients with colorectal cancer. Hum Pathol. 2019;83:36–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Kirimlioglu H, Turkmen I, Bassullu N, Dirican A, Karadag N, Kirimlioglu V. The expression of matrix metalloproteinases in intrahepatic cholangiocarcinoma, hilar (Klatskin tumor), middle and distal extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma: role of matrix metalloproteinases in tumor progression and prognosis. Turk J Gastroenterol. 2009;20:41–7.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Ridley AJ. Life at the leading edge. Cell. 2011;145:1012–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Chen TY, Li YC, Liu YF, Tsai CM, Hsieh YH, Lin CW, et al. Role of MMP14 gene polymorphisms in susceptibility and pathological development to hepatocellular carcinoma. Ann Surg Oncol. 2011;18:2348–56.

    PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Wang Y, Ye Y, Lin J, Meyer L, Wu X, Lu K, et al. Genetic variants in matrix metalloproteinase genes as disposition factors for ovarian cancer risk, survival, and clinical outcome. Mol Carcinog. 2015;54:430–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Weng CJ, Chen MK, Lin CW, Chung TT, Yang SF. Single nucleotide polymorphisms and haplotypes of MMP-14 are associated with the risk and pathological development of oral cancer. Ann Surg Oncol. 2012;19:S319–27.

    PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    de Vos I, Tao EY, Ong SLM, Goggi JL, Scerri T, Wilson GR, et al. Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. Hum Mol Genet. 2018;27:2775–88.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Qi Y, Wang J, Sun M, Ma C, Jin T, Liu Y, et al. MMP-14 single-nucleotide polymorphisms are related to steroid-induced osteonecrosis of the femoral head in the population of northern China. Mol Genet Genom Med. 2019;7:e00519.

    Google Scholar 

  47. 47.

    Zhang J, Sun X, Liu J, Liu J, Shen B, Nie L. The role of matrix metalloproteinase 14 polymorphisms in susceptibility to intervertebral disc degeneration in the Chinese Han population. Arch Med Sci. 2015;11:801–6.

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Zhou QH, Huang XF, Wang JH, Lin CW, Yang YY, Huang CS, et al. Association of MMP14 gene polymorphisms and osteoporosis in Zhuang men from Baise region of Guangxi. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012;29:309–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Tee YT, Liu YF, Chang JT, Yang SF, Chen SC, Han CP, et al. Single-nucleotide polymorphisms and haplotypes of membrane type 1-matrix metalloproteinase in susceptibility and clinical significance of squamous cell neoplasia of uterine cervix in Taiwan women. Reprod Sci. 2012;19:932–8.

    PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Shen HX, Song HW, Xu XJ, Jiao ZY, Ti ZY, Li ZY, et al. Clinical epidemiological survey of gallbladder carcinoma in northwestern China, 2009-2013: 2379 cases in 17 centers. Chronic Dis Transl Med. 2017;3:60–6.

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Roa I, Ibacache G, Munoz S, de Aretxabala X. Gallbladder cancer in Chile: pathologic characteristics of survival and prognostic factors: analysis of 1,366 cases. Am J Clin Pathol. 2014;141:675–82.

    PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Lau CSM, Zywot A, Mahendraraj K, Chamberlain RS. Gallbladder Carcinoma in the United States: a population based clinical outcomes study involving 22,343 patients from the surveillance, epidemiology, and end result database (1973-2013). HPB Surg. 2017;2017:1532835.

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Batra Y, Pal S, Dutta U, Desai P, Garg PK, Makharia G, et al. Gallbladder cancer in India: a dismal picture. J Gastroenterol Hepatol. 2005;20:309–14.

    PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Dutta U, Nagi B, Garg PK, Sinha SK, Singh K, Tandon RK. Patients with gallstones develop gallbladder cancer at an earlier age. Eur J Cancer Prev. 2005;14:381–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Sakai K, Loza E, Roig GV, Nozaki R, Asai T, Ikoma T, et al. CYP1A1, GSTM1, GSTT1 and TP53 polymorphisms and risk of gallbladder cancer in Bolivians. Asian Pac J Cancer Prev. 2016;17:781–4.

    PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Rodriguez S, Gaunt TR, Guo Y, Zheng J, Barnes MR, Tang W, et al. Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array. Eur J Hum Genet. 2016;24:106–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Pandey SN, Dixit M, Choudhuri G, Mittal B. Lipoprotein receptor associated protein (LRPAP1) insertion/deletion polymorphism: association with gallbladder cancer susceptibility. Int J Gastrointest Cancer. 2006;37:124–8.

    PubMed  PubMed Central  Google Scholar 

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J., V., Mishra, D., Meher, D. et al. Genetic association of MMP14 promoter variants and their functional significance in gallbladder cancer pathogenesis. J Hum Genet (2021). https://doi.org/10.1038/s10038-021-00917-x

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