Author ORCID Identifier
Semester
Fall
Date of Graduation
2024
Document Type
Dissertation
Degree Type
PhD
College
School of Medicine
Department
Not Listed
Committee Chair
Timothy Eubank
Committee Member
Jennifer Franko
Committee Member
Lori Hazlehurst
Committee Member
Gangqing Hu
Committee Member
Scott Weed
Abstract
Lung Cancer remains the leading cause of cancer-related deaths worldwide. While important improvements have been made to the treatment of non-small cell lung cancer (NSCLC), treatment resistance is a critical issue facing the majority of patients. Previously, our lab identified a group of long non-coding RNAs (lncRNAs) known as linc-SPRY3 RNAs, expressed on the Y-chromosome, that play a role in radiation sensitivity by decreasing tumor burden in vitro and in vivo after radiation. Through molecular cloning methods and further functional characterization, here we present evidence that the linc-SPRY3 RNAs were originally mischaracterized as individual linc-RNAs but are in fact parts of one big lncRNA. The work presented here describes the functions and therapeutic potential of this long non-coding RNA we named lnc-RAINY, for Radiation Induced Y chromosome linked lncRNA. Through ATAC-seq and immunoprecipitation experiments, we show that lnc-RAINY interacts with DNA in a triple helix to induce chromatin remodeling and gene expression. We also identified that lnc-RAINY regulates CDC6 and CDC25A gene expression. In silico analysis revealed that lnc-RAINY likely binds to the promoter regions of these critical genes, to prevent their transcription. This transcription inhibition then promoted a decrease in the migratory ability of cancer cells, and blocked cell cycle transition, leaving cells vulnerable during radiation treatment. Additionally, the triple helix interactions of lnc-RAINY promoted senescence through the inhibition of CDC25A, increasing senescence with or without radiation treatment. Furthermore, the administration of Lnc-RAINY encapsulated in FDA-approved nanoparticles into a lung cancer patient-derived xenograft model dramatically reduces tumor progression demonstrating therapeutic potential. This dissertation details the molecular function of a novel radio-sensitizing lncRNA, lnc-RANIY, and its ability to interact directly with DNA, decreasing the expression of pro-tumorigenic genes to decrease the tumors’ ability to grow and migrate, and increase the number of senescent cells. It also closely follows the treatment of this lncRNA into both Cancer Cell line xenografts and patient derived xenografts, markedly decreasing tumor burden, regardless of radiation status.
Recommended Citation
Rice, Emily S., "A Rainy Day for Cancer: The Characterization and Utilization of the long non-coding RNA lnc-RAINY in the Radiation Response of Non-Small Cell Lung Cancer" (2024). Graduate Theses, Dissertations, and Problem Reports. 12678.
https://researchrepository.wvu.edu/etd/12678