Clinical Impact of De-Regulated Notch-1 and Notch-3 in the Development and Progression of HPV-Associated Different Histological Subtypes of Precancerous and Cancerous Lesions of Human Uterine Cervix

Background: Cervical cancer is the leading cause of cancer related deaths among women in India. Limited reports are available for Notch-1 and Notch-3 protein in cervical carcinoma, which play crucial role in cell proliferation, differentiation, and apoptosis. Methods: This study was designed to evaluate the role of Notch-1 and Notch-3 with context to HPV infection in cervical carcinoma. A total of 168 tissue biopsy samples comprising of tumor specimens (n = 98), precancer (n = 30) and nonneoplastic cervical tissues (n = 40) were screened for HPV infection by PCR and expression of Notch-1 and Notch-3 protein by Immunohistochemistry and Immunoblotting. Results: 80% (24/30) were found to be positive for HPV in precancer and 86.7% (85/98) in cancer patients. Notch-1 expression of precancer and cancer cases was found to be significantly down-regulated with severity of disease in nuclear (3.43 +/- 0.29; 2.04 +/- 0.19, p = 0.0001, p = 0.0001) and cytoplasm (3.07 +/- 0.29; 2.29 +/- 0.17, p = 0.0001, p = 0.0001) obtained from different stages as compared to normal cervix tissue (5.40 +/- 0.19, 4.97 +/- 0.15; p<0.001; p<0.001). However, Notch-3 expression of above cases was significantly up-regulated with severity of disease and showed intense nuclear (4.17 +/- 0.39; 4.74 +/- 0.18, p = 0.0001, p = 0.0001) and cytoplasm (3.67 +/- 0.36; 4.48 +/- 0.18, p = 0.0001, p = 0.0001) of different stages as compared to normal cervix tissue (0.95 +/- 0.20, 0.70 +/- 0.20; p<0.001; p<0.001) respectively. Conclusions: These findings suggest that Notch-1 and Notch-3 may play an important role with synergistic effect of HPV in regulating development and proliferation of cervical cancer through the deregulation of Notch signalling. This study also shows the clinical utility of both proteins which may be used as predictable biomarkers in diagnosing different histological sub-types of HPV associated cervical cancer. Nevertheless, abnormal activation of this pathway may provide legitimate targets for cervical cancer therapy.