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Aberrant promoter methylation and loss of Suppressor of Cytokine Signalling-1 gene expression in the development of uterine cervical carcinogenesis

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Abstract

Background

Cervical cancer is a leading cause of cancer related deaths in women worldwide caused due to infection of high-risk human papillomaviruses. As JAK/STAT signalling pathway has been shown to play an important role during carcinogenesis, we studied the role of silencing of Suppressor of Cytokine Signalling-1 (SOCS-1) gene, a negative regulator of JAK/STAT pathway in cervical cancer.

Methods

The expression pattern of SOCS-1 mRNA and protein was analyzed in different stages of cervical tumor biopsies while normal cervical tissues served as controls. RT-PCR, immunohistochemistry and methylation-specific PCR (MSP) were performed to assess the expression pattern and promoter methylation of SOCS-1 gene in a total of 120 fresh surgically resected cervical tissue specimens comprising precancer (n = 12), cancer (n = 78) and normal controls (n = 30).

Results

Compared with expression of SOCS-1 in normal tissues, 64% of the tumor tissues expressed either undetectable or reduced expression. Aberrant promoter methylation of SOCS-1 was found in 61% of the cervical tumor tissues. SOCS-1 expression and methylation were significantly associated with severity of the disease (p < 0.01).

Conclusion

We demonstrate for the first time the transcriptional inactivation of SOCS-1 gene due to hypermethylation and synergism with HPV infection which may play an important role in cervical carcinoma.

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Acknowledgements

We acknowledge the funding by UGC and DBT, Government of India to RCS. Fellowship to NS by DBT. We highly appreciate the help done by the staff and patients of Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh.

Conflict of interest

The authors declare no conflict of interest.

Authors’ contributions

RCS senior scientist who conceived the study, supervised and guaranteed the work. NS participated in design of the study, collected the samples and carried out the experiments and primary manuscript writing. SH carried out few experiments and primary manuscript writing. VS senior Gynaecologist who provided clinical samples and critical revision of manuscript. RN senior pathologist who did the histopathological analysis of the cervical specimens. ACB who contributed to critical revision of the manuscript. MB conceived and participated in the study. BCD who oversaw and gave critical inputs. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Biotechnology, Panjab University, Sector-14, Chandigarh, India

    R. C. Sobti & Neha Singh

  2. Division of Molecular Genetics and Biochemistry, Institute of Cytology & Preventive Oncology (ICMR), I-7, Sector-39, Noida, India

    Showket Hussain & Mausumi Bharadwaj

  3. Department of Gynaecology and Obstetrics, PGIMER, Sector-12, Chandigarh, India

    Vanita Suri

  4. Department of Cytology & Gynae Pathology, PGIMER, Sector-12, Chandigarh, India

    Raje Nijhawan

  5. Division of Molecular Oncology, Institute of Cytology & Preventive Oncology (ICMR), I-7, Sector-39, Noida, India

    A. C. Bharti

  6. Dr. B.R. Ambedkar Research Centre for Biomedical Research (ACBR), University of Delhi, (North Campus), Delhi, India

    B. C. Das

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  1. R. C. Sobti
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Supplementary Fig. I

Detection of HPV infection in cervical cancer cases. Representative ethidium bromide-stained 2% agarose gel showing presence of HPV infection in cervical cancer as indicated by appearance of L1 consensus amplimer of 450 bp along with amplification of 268 bp fragment of β-Globin gene that was used as PCR internal control. P-positive control DNA, N-negative control (Placental DNA/Blank), samples number 1 to 11 are DNA from cervical biopsy samples; M-Φx174 HaeIII- digested molecular weight marker (PDF 36 kb)

Supplementary Table I

Clinico-pathological and demographic characteristics and HPV status of cervical cancer cases, pre-cancerous lesions and normal controls investigated from North Indian population (PDF 56 kb)

Supplementary Table II

HPV diagnosis of patients and healthy controls recruited for the study of SOCS-1 methylation and expression and its correlation with other clinicopathological characteristics (PDF 38 kb)

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Sobti, R.C., Singh, N., Hussain, S. et al. Aberrant promoter methylation and loss of Suppressor of Cytokine Signalling-1 gene expression in the development of uterine cervical carcinogenesis. Cell Oncol. 34, 533–543 (2011). https://doi.org/10.1007/s13402-011-0056-2

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