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Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer

Oncogene volume 22, pages 4889–4897 (2003)Cite this article

Abstract

Mutations in Smads, intermediates of transforming growth factor-β signaling, are known to contribute to the loss of sensitivity to transforming growth factor-β, a common feature of many neoplastic cells. However, not much information is available on Smad alterations in cervical cancer and so we probed, for the first time, for alterations in Smad 2 and Smad 4 genes using human cervical cancer cell lines and human cervical tissue samples. Using PCR/reverse transcription–PCR, single-stranded conformation polymorphism analysis and DNA sequencing, we observed a deletion of ‘G’ in the L3 loop (crucial in Smad–receptor interaction) in C-33A cells, and an insertion of ‘A’ in codon 122 (loss of MH2 domain) from a cervical tumor sample, both of which caused frame shift and pretermination in Smad 2. In addition, a G/A transition at 31 bp upstream-nontranslated regions of exon 8 of Smad 4 was found in Bu 25TK cells. Smad 2 expression was less in some of the cervical tumor samples than that of nonmalignant samples and six cancer samples showed C-terminal deletions that abolish Smad 2 phosphorylation sites. The loss of expression of Smad 4 found in some cervical tumor samples was due to transcription loss rather than deletion of the gene. Our results highlight an important role for Smad 2 and Smad 4 in human cervical tumors.

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Abbreviations

TGF-β:

transforming growth factor-β

TβRI:

transforming growth factor receptor type I

TβRII:

transforming growth factor receptor type II

RT–PCR:

reverse transcription–PCR

SQRT–PCR:

semiquantitative reverse transcription–PCR

EMSA:

electrophoretic mobility shift assay

SSCP:

single-strand conformation polymorphism

CIN:

cervical intraepithelial neoplasia

LSIL:

low-grade squamous intraepithelial lesion

HSIL:

high-grade squamous intraepithelial lesion

SCC:

squamous cell carcinoma

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Acknowledgements

We thank Dr PK Shyamala Devi for providing fresh cervical tissues, and Dr Balaraman Nair, Ms Indu Ramachandran and Ms Sheela for technical advice and help. A research grant from the Department of Science and Technology (to DK), program support to the Rajiv Gandhi Center by the Department of Biotechnology, a Research Associate Fellowship (to AN) and a Senior Research Fellowship (to TTM) by the Council of Scientific and Industrial Research, Government of India are gratefully acknowledged.

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  1. Division of Cancer Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, 695 014, Kerala, India

    Tessy T Maliekal, Marie-Lue Antony, Ramasamy Paulmurugan & Devarajan Karunagaran

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  1. Tessy T Maliekal
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  2. Marie-Lue Antony
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Correspondence to Devarajan Karunagaran.

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Maliekal, T., Antony, ML., Nair, A. et al. Loss of expression, and mutations of Smad 2 and Smad 4 in human cervical cancer. Oncogene 22, 4889–4897 (2003). https://doi.org/10.1038/sj.onc.1206806

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