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The protective role of the −1306C>T functional polymorphism in matrix metalloproteinase-2 gene is associated with cervical cancer: implication of human papillomavirus infection

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Tumor Biology

Abstract

Cervical cancer is the major reproductive health problem among women caused by persistent infection of high-risk human papillomavirus (HR-HPV). Metalloproteinase-2 (MMP-2) is an endopeptidase highly expressed in cervical cancer; however, the genetic link between aberrant expression of MMP-2 and cervical carcinogenesis is not known. The genotypic distribution, expression pattern of MMP-2 and HPV infection, was analyzed in a total of 300 fresh surgically resected cervical tissue biopsies. The MMP-2 C1306T (rs243865) promoter polymorphism dominant model (CC v/s CT + CT + TT) revealed that the CC genotype had a 4.33-fold significant increased risk for development of cervical cancer (OR = 4.33; 95 % CI = 2.36–4.02, p = 0.0001) compared to those with variant genotypes (−1306 CT + TT). The C allele was associated with 3-fold significant increased risk (OR = 2.95; 95 % CI = 1.90–4.60, p = 0.0002) compared to T allele. Interestingly, a significant correlation was found between high expression of MMP-2 protein and CC genotype in cancer patients (p = 0.001) compared to normal controls (p = 0.012). Further analysis showed that the risk of cancer was extremely pronounced in HPV positive patients (OR = 9.33; 95 % CI = 2.88–30.20, p = 0.0001) compared to HPV negative ones, implicating the possible interaction between −1306CC genotype and HPV infection in increasing the cancer risk (p = 0.0001). The leads from the present study suggest the protective role of gene variant −1306C>T at the promoter region of the MMP-2 against HPV-mediated cervical cancer. These findings substantiate the functional role of MMP-2 C1306T polymorphism in a significant downregulation of MMP-2 protein in women with variant genotype (CT/TT) compared to the normal wild CC genotype.

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Acknowledgments

We acknowledge the funding by Department of Biotechnology (DBT), Govt. of India. We highly appreciate the help done by the staff and patients of Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Authors’ contributions

NS conceived the study, collected the samples, and carried out all the experiments and primary manuscript writing. SH participated in data analysis and critically reviewed the manuscript. US participated in DNA extraction and PCR VS senior Gynaecologist provided clinical samples and critical revision of manuscript. RN senior pathologist did the histopathological analysis of the cervical specimens. MB contributed to critical revision of the manuscript. RCS senior scientist supervised and guaranteed the work. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Systems Biology Research Centre—Tumor biology, School of Life Sciences, University of Skövde, Skövde, SE-54128, Sweden

    Neha Singh

  2. Department of Biotechnology, Panjab University, Chandigarh, India

    Neha Singh & R. C. Sobti

  3. Division of Molecular Oncology, Institute of Cytology and Preventive Oncology (ICMR), Noida, India

    Showket Hussain

  4. Division of Molecular Genetics and Biochemistry, Institute of Cytology and Preventive Oncology (ICMR), Noida, India

    Upma Sharma & Mausumi Bharadwaj

  5. Department of Obstetrics and Gynecology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Vanita Suri

  6. Department of Cytology & Gynae. Pathology, Post Graduate Institute of Medical Education and Research, Sector-12, Chandigarh, India

    Raje Nijhawan

  7. Vice Chancellor BBA (Central) University, Lucknow, India

    R. C. Sobti

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  1. Neha Singh
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Singh, N., Hussain, S., Sharma, U. et al. The protective role of the −1306C>T functional polymorphism in matrix metalloproteinase-2 gene is associated with cervical cancer: implication of human papillomavirus infection. Tumor Biol. 37, 5295–5303 (2016). https://doi.org/10.1007/s13277-015-4378-y

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