Aberrant Expression of Disintegrin-Metalloprotease Proteins in the Formation and Progression of Uterine Cervical Cancer

Abstract

Objective: Dysregulated expression of disintegrin-metalloprotease proteins [a disintegrin and metalloproteases (ADAMs) and ADAMs with thrombospondin motif (ADAMTSs)] has been reported in many types of cancers and is believed to play an important role in cancer formation and metastasis. However, little is known about the expression of ADAMs and ADAMTSs in the development of human cervical cancer. Methods: Reverse transcriptase polymerase chain reaction and immunoblotting were performed to assess the expression of several disintegrin-metalloproteases and tissue inhibitors of metalloproteinases (TIMPs) in squamous-type cervical cancer cells and oncogenically modified keratinocytes (immortalized human cervical keratinocytes transduced with human papilloma virus-16 E6/E7 proteins with or without oncogenes). Immunohistochemistry of ADAM-9, ADAM-10 and TIMP-3 was performed on 31 primary human cervical tissue specimens of preinvasive and invasive cervical carcinoma. Results: mRNA levels of ADAM-9, ADAM-10, ADAM-12, TIMP-2 and TIMP-3 were upregulated as cervical cells progressed from dysplastic to malignant lesions compared to normal cervical cells. These results were corroborated at the protein level by Western blot analysis and immunohistochemistry. Conclusion: The expression of disintegrin-metalloproteases and their endogenous regulators was dysregulated during cervical carcinogenesis. The aberrant expression of ADAMs might contribute to the pathogenesis of cervical cancer formation and progression.