LIN28B confers cancer stem-like phenotypes for neuroendocrine prostate cancer progression
department or school: Medicine, Faculty of
department or school: Obstetrics and Gynaecology, Department of
data provider: DSpace
degree campus: UBCV
creator: Lovnicki, Jessica Magdalena
issued: 2019-08-19T19:12:36Z
issued: 2019
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Due to the increased utilization of next generation anti-androgens to treat prostate adenocarcinoma (AdPC), therapy-induced neuroendocrine prostate cancer (t-NEPC) has become more prevalent. Although the mechanisms by which t-NEPC is established are not fully understood, emerging evidence suggests that AdPC cells can gain an intermediate pluripotent stem cell (SC)-like phenotype that can promote t-NEPC development. However, it remains unclear whether the core embryonic stem cell genes (ESCs) (LIN28, POU5F1, SOX2, and NANOG) regulate the stem-like state of prostate cancer cells and the switch from luminal epithelial to neuroendocrine lineage during the transition from AdPC to t-NEPC. We hypothesize that LIN28B plays a key role in the transition from AdPC to t-NEPC, and that the overexpression of LIN28B may promote proliferation and trans-differentiation, which may contribute to t-NEPC progression. By comparing the published RNA-seq data on AdPC and t-NEPC, we found that approximately 50% of t-NEPC patient tumors have gained LIN28B and SOX2 expression. Standard molecular and cellular biology techniques were applied to characterize the functions of LIN28B and its relationship with SOX2 using t-NEPC cell and xenograft models. We found that the mRNA levels of LIN28B and SOX2 are positively correlated in patient tumors, patient derived xenografts, transgenic mice, and multiple cell models. LIN28B and SOX2 expression was confirmed to be co-upregulated in a subset of t-NEPC patients by immunohistochemistry. Using our clinically relevant t-NEPC cell/xenograft model, DuNE, we demonstrated that LIN28B is essential for stem cell-like and neuroendocrine marker expression and cell morphology. LIN28B gene depletion by CRISPR inhibited DuNE xenograft initiation and tumor growth. These LIN28B functions are mainly mediated by its inhibitory effects on the microRNA let-7d, which resulted in the upregulation of HMGA2 and HGMA2 mediated SOX2 transcription. Overall, this thesis work adds…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/71328
note: LIN28B CONFERS CANCER STEM-LIKE PHENOTYPES FOR NEUROENDOCRINE PROSTATE CANCER PROGRESSION by JESSICA MAGDALENA LOVNICKI B.Sc. (Hon.), University of Guelph, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Reproductive and Developmental Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2019 © Jessica Magdalena Lovnicki, 2019 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: LIN28B CONFERS CANCER STEM-LIKE PHENOTYPES FOR NEUROENDOCRINE PROSTATE CANCER PROGRESSION Submitted by by Jessica Magdalena ovnicki in partial fulfillment of the requirements for the degree of Master of Science in Reproductive and Developmental Sciences Examining Committee: Xuesen Dong, Urological Sciences Supervisor Ralph Buttyan, Urological Sciences Supervisory Committee Member Nathan Lack, Urological Sciences Supervisory Committee Member Cathie Garnis, Integrative Oncology External Committee Member iii Abstract Due to the increased utilization of next generation anti-androgens to treat prostate adenocarcinoma (AdPC), therapy-induced neuroendocrine prostate cancer (t-NEPC) has become more prevalent. Although the mechanisms by which t-NEPC is established are not fully understood, emerging evidence suggests that AdPC cells can gain an intermediate pluripotent stem cell (SC)-like phenotype that can promote t-NEPC development. However, it remains unclear whether the core embryonic stem cell genes (ESCs) (LIN28, POU5F1, SOX2, and NANOG) regulate the stem-like state of prostate cancer cells and the switch from luminal epithelial to neuroendocrine lineage during the transition from AdPC to t-NEPC. We hypothesize that LIN28B plays a key role in the transition from AdPC to t-NEPC, and that the overexpression of LIN28B may promote proliferation and trans-differentiation, which ma…
has type: Thesis/Dissertation
date issued: 2019-09
is shown at: 10.14288/1.0380479
language: eng
degree discipline: Reproductive and Developmental Sciences
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/71328