HIF-1α Molecular Stress Pathway Associates with the Development of Cervical Carcinoma

Chandraditya Chakraborty

Dana-Farber Cancer Institute , USA

Biography :

Chandraditya Chakraborty has completed his PhD from Calcutta University in 2017 followed by postdoctoral studies from Dana-Farber/ Harvard Cancer Center and is presently a scientist at Dana-Farber Cancer Institute, Harvard Medical School. He is a recipient of NCI SPORE Career Enhancement Award and IMW Young Investiga- tor Award and published several papers in impactful journals like Blood, gastroenterology etc.

Abstract :

To understand the mechanism of cellular stress in different cell types of normal cervical ep- ithelium and during different stages of cervical carcinoma, we analyzed the expression/ methylation/copy number variation/mutation of HIF-1α and its associated genes LIMD1, VHL and VEGF in disease-free normal cervix, adjacent normal cervix of tumors, cervical intraep- ithelial neoplasia, cancer of uterine cervix samples and CACX cell lines. Interestingly, in bas- al-parabasal layers of normal cervical epithelium, LIMD1 showed high protein expression, while low protein expression of VHL was concordant with high expression of HIF-1α and VEGF irrespective of HPV-16 infection. Furthermore, there was significant concordance with the low promoter methylation of LIMD1 and high in VHL in the basal-parabasal layers of normal cer- vix. LIMD1 expression was significantly reduced while VHL expression was unchanged during different stages of cervical carcinoma. In different stages of cervical carcinoma, the expres- sion pattern of HIF-1α and VEGF was high as seen in basal-parabasal layers and inversely correlated with the expression of LIMD1 and VHL. Additional deletion of LIMD1 and VHL in CIN/ CACX provided an additional growth advantage during cervical carcinogenesis through re- duced expression of genes. We found that overexpression of HIF-1α and its target gene VEGF in the basal-parabasal layers of normal cervix was due to frequent inactivation of VHL by its promoter methylation. Thus, it was evident that molecular signature of key regulatory genes of the HIF1-α molecular stress pathway affecting cell fate and cell survival in the proliferating basal-parabasal layers of normal cervical epithelium is maintained during the development of cervical carcinoma through additional methylation/deletion/sequence variation leading to poor prognosis of CACX patients.