VEGF restricts murine β Coronavirus Infectivity and Replication in Ovarian Cancer Cells by modulating ERp29 and Cx-43 mediated GJIC

Banerjee, Anurag (2022) VEGF restricts murine β Coronavirus Infectivity and Replication in Ovarian Cancer Cells by modulating ERp29 and Cx-43 mediated GJIC. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Anurag Banerjee (17MS046)) 17MS046_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (3MB)

Abstract

High-Grade Serous Ovarian Carcinoma (HGSOC) is considered to be the most lethal and aggressive gynecological malignancy to date. Due to its aggressiveness, the majority of the diagnosed cases report a later stage of cancer where secondary tumors have metastasized throughout the peritoneum, which poses a major problem in its treatment. Conventional treatments like debulking surgery followed by neoadjuvant Chemotherapy or Radiotherapy are associated with a poor prognosis for the patient and a high risk for the re-occurrence of cancer. Thus, effective therapeutic strategies where specificity toward cancer cells is introduced become desirable in the treatment of peritoneal carcinomas. Viruses have emerged as a novel and effective therapeutic target for cancer treatment as when viruses are redirected specifically towards cancer cells by reverse genetics, they have been shown to induce direct oncolysis and trigger the adaptive immune response towards cancerous lesions, turning immunologically “cold” tumors “hot”. In our study, Epithelial Ovarian Cancer cell lines ID8 derived from C57BL/6 mice and ID8 transfected with Vascular Endothelial Growth Factor-A (ID8-VEGF) were used in vitro to generate a Syngeneic Ovarian Cancer Mouse Model. Our studies aim to understand the effects of murine beta-coronavirus infections in the progression of Ovarian Carcinoma, both in vitro in Ovarian Cancer Cell Lines and C57BL/6 mice. Our findings suggest that MHV-RSA59, a demyelinating strain of MHV (Murine Hepatitis Virus) readily infects and replicates within the Ovarian Cancer Cell line ID8, in vitro, thus modulating cellular and oxidative stress factors and differential trafficking of the gap junction protein Connexin-43, which previous studies have shown to have a major role in the progression of metastasis of Ovarian Cancer. Our studies have also shown that ID8 Cells transfected with VEGF-A, which in turn upregulates ERp29, a molecular chaperone for Connexin-43 mediated ER Stress, heavily restricts the infectivity and replication of MHV in vitro. Further studies on findings would lay the foundation for developing an experimental mouse model to study SARS-CoV-2 mediated Ovarian cell dystrophy and injury as well as developing MHV and other coronaviruses as oncolytic agents for peritoneal cancers due to its robust immunomodulatory properties that can be redirected towards cancer cells as an effective therapy in addition to direct oncolysis.

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