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Inactivation of PTCH1 is associated with the development of cervical carcinoma: clinical and prognostic implication

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Tumor Biology

Abstract

The aim of this study was to analyze the alterations of PTCH1 (deletion/promoter methylation/mutation/expression) during the development of cervical cancer (CACX). For this purpose, deletion/methylation of PTCH1 were analyzed in HPV16 positive exfoliated asymptomatic cervical swabs (n = 74), cervical intraepithelial neoplasia (CIN) (n = 32), CACX (n = 174) samples, and two CACX cell lines. The deletion of PTCH1 increased significantly from CIN (11.5 %) to stage I/II (42 %) and comparable in stage III/IV (46 %). Low frequency (14–16 %) of PTCH1 methylation was seen in the asymptomatic exfoliated cervical cells and in the normal epithelium adjacent to the tumor followed by a significant increase in CIN (31 %) to stage I/II (57 %) and comparable in stage III/IV (58 %). The overall alterations (deletion/methylation) of PTCH1 significantly increased from CIN (34 %) to stage I/II (70 %) and comparable in stage III/IV (69 %). Interestingly, in the normal epithelium, methylation of PTCH1 was high in basal/parabasal layers (83 %), followed by decrease in the spinous layer (33 %), and showed significant inverse correlation with its expression. Reduced expression of PTCH1 seen in tumors showed a significant association with its alterations (deletion/methylation). The expression pattern of PTCH1 showed an inverse correlation with the nuclear expression of GLI1 in the normal epithelium as well as in the tumors. High nuclear expression of HPV16, E6, and E7 were seen in basal/parabasal layers of the normal epithelium and also in tumors. The PTCH1 alterations (deletion and/or methylation) in tumors and its methylation in adjacent normal epithelium were associated with poor prognosis of patients. Thus, our data suggests that activation of the Hedgehog pathway due to PTCH1 inactivation along with HPV infection is important in CACX development.

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Acknowledgments

The authors thank the Director, Chittaranjan National Cancer Institute, Kolkata, India. They also thank Dr. Shyamsundar Mandal, Chittaranjan National Cancer Institute, for his assistance in solving statistical problems. They are also grateful to Professor (Dr.) H. zur Hausen and Professor (Dr. Mrs.) E.M. de Villiers for their generous gift of HPV16/18 plasmids. This work was supported by CSIR-JRF/NET grant [File No.09/030(0059)/2010-EMR-I] to Mr C. Chakraborty, CSIR-SRF grant [File No. 09/030(0065)/2011-EMR-I] to Mr S. Dutta, and CSIR-RA grant [File No.09/030(0071)/2013-EMRI] to Dr. N. Mukherjee from Council of Scientific and Industrial Research (CSIR), UGC-JRF/NET grant [Sr No. 2121130723] to Mr S. Samadder from University Grants Commission (UGC), Government of India, and grant [SR/SO/HS-116/2007] from the Department of Science and Technology (DST), Government of India, to Dr. C. K. Panda.

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Authors and Affiliations

  1. Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700026, India

    Chandraditya Chakraborty, Sankhadeep Dutta, Nupur Mukherjee, Sudip Samadder, Anirban Roychowdhury & Chinmay Kumar Panda

  2. North Bengal Medical College and Hospital, Siliguri, West Bengal, India

    Anup Roy

  3. Department of Gynecological Oncology, Chittaranjan National Cancer Institute, Kolkata, India

    Ranajit Kumar Mondal & Partha Basu

  4. Cancer Biology & Inflammatory Disorder Division, Indian Institute of Chemical Biology, Kolkata, India

    Susanta Roychoudhury

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  1. Chandraditya Chakraborty
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  2. Sankhadeep Dutta
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  3. Nupur Mukherjee
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Correspondence to Chinmay Kumar Panda.

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Chakraborty, C., Dutta, S., Mukherjee, N. et al. Inactivation of PTCH1 is associated with the development of cervical carcinoma: clinical and prognostic implication. Tumor Biol. 36, 1143–1154 (2015). https://doi.org/10.1007/s13277-014-2707-1

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