Translational Regulation of Oncoproteins by FXR1 CNV in Ovarian Cancer
Abstract
Rationale: Amplification of the 3q26 chromosomal locus is the most frequent amplification of chromosomal copy number gain event (> 40%) in high-grade serous epithelial ovarian cancer (HGSOC). We previously identified that 3q26 chromosomal locus amplification is a critical CNV in ovarian cancer patients. However, the exact mechanism regulated via 3q26 chromosomal locus is not understood, which is a critical gap in our knowledge. In this study, we found that FXR1 RNA Binding protein is a critical regulator by stabilizing a set of oncogenes for increased protein synthesis (translation) in ovarian cancer cells. Translation (protein synthesis) is a tightly regulated process that decides the accurate amount of protein is generated for cellular functions. We found that the over-production of FXR1 in ovarian cancer cells leads to the aberrant translation produce high amount oncoproteins such as cMYC, PRKC, KIT, and REL in normal ovarian and fallopian epithelial cells for cell transformation to become cancer cells and their progression to aggressive tumors. Objectives: The objective of this project is to understand the mechanism employed by ovarian cancer cells to synthesize large amounts of oncoproteins for aberrant cellular functions like hyperproliferation, survival in the presence of therapeutic agents, and promote metastasis. FXR1 is an understudied protein in ovarian cancer for their functions on the translation of oncogenes, which will be addressed by this study. In our therapeutic approach, we will determine and validate the effect of knocking down FXR1 in preclinical models of ovarian cancer in both nude mice and immune-competent mice by the delivery of nanoliposome vectors carry siRNA of FXR1. We expect that the delivery of siRNA of FXR1 will inhibit the tumor growth in mice and improve cisplatin sensitivity. We hypothesize that FXR1 improves the stability of mRNAs by binding to the sequence-specific motifs in the 3’UTR of several crucial oncogenes, including cMYC, PRKC, KIT, and REL. We further hypothesize that the binding of FXR1 stabilizes the above oncogene’s mRNA and enhances its conversion to protein, which are the key molecules for oncogenic signaling in cancer cells. Strikingly, we found a novel mechanism that FXR1 recruits the eukaryotic initiation factor 4F (eIF4F) complex for protein translation to the translation start site (TSS) in the 5’end of mRNAs after secondary modifications. We will perform the following three specific aims to address the specific objectives below. (1) Investigate the mechanism of how FXR1 stabilizes its target mRNAs. (2) Delineate the effects of FXR1 on the translation of its target mRNAs. (3) Determine the effects of FXR1 targets in the pathobiology of cancer. Ovarian Cancer Advocacy Plans: A highly experienced ovarian cancer advocate, Ms. Jody Elliot, will participate as the ovarian cancer advocate in this research (Letter of support attached). Ms. Elliot is an active participant in the Ray of Hope for Ovarian Cancer Cure, Inc. Ms. Elliot will bring the approaches she has used successfully in ovarian cancer advocacy to this grant. She will provide the patient perspective when research projects are designed and implemented and has been involved in all phases of the development of this proposal. Ms. Elliot will be actively involved in all aspects of the proposed research program, including planning and oversight, program evaluation, and/or dissemination of information to the public through her advocacy programs in the Wisconsin, Illinois, and Minnesota. Expected Outcome: Our multi-investigator team, with complementary expertise in the proposed approaches, will test the innovative concept of the molecular mechanism of FXR1-mediated posttranscriptional and translational regulation of oncogenes. The scientific question and the proposed research are significant because we expect that the completion of this proposal will identify novel therapeutic tar
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110365
Entities
People
- Pradeep Chaluvally-raghavan
Organizations
- Medical College of Wisconsin
- United States Army