title: 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.
abstract: 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 non-neoplastic 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.
authors.affiliation: Division of Molecular Genetics & Biochemistry, Institute of Cytology and Preventive Oncology (ICPO), ICMR, Noida, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Department of Anatomy, VMMC & Safdarjang Hospital, New Delhi, India.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Rath
authors.affiliation: Department of Anatomy, VMMC & Safdarjang Hospital, New Delhi, India.
authors.forename: Poonam
authors.initials: P
authors.lastname: Jawanjal
authors.affiliation: Division of Molecular Genetics & Biochemistry, Institute of Cytology and Preventive Oncology (ICPO), ICMR, Noida, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Division of Molecular Genetics & Biochemistry, Institute of Cytology and Preventive Oncology (ICPO), ICMR, Noida, India.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Singhal
authors.affiliation: Division of Pathology, Institute of Cytology and Preventive Oncology (ICPO), ICMR, Noida, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Bhambhani
authors.affiliation: Division of Molecular Genetics & Biochemistry, Institute of Cytology and Preventive Oncology (ICPO), ICMR, Noida, India.
authors.forename: Showket
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Division of Molecular Genetics & Biochemistry, Institute of Cytology and Preventive Oncology (ICPO), ICMR, Noida, India.
authors.forename: Mausumi
authors.initials: M
authors.lastname: Bharadwaj
mesh_terms: D063646:Carcinogenesis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D027383:Papillomaviridae / Q000145:classification / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000821:virology
chemical_list: C497761:NOTCH1 protein, human; C499374:NOTCH3 protein, human; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch