Exploring the role of nuclear receptor NR5A2 in lung cancer

Postgraduate Thesis uoadl:2934588 110 Read counter

Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and Bioinnovation
Library of the School of Health Sciences
Deposit date:
2021-02-26
Year:
2021
Author:
Lala Maria
Supervisors info:
Παναγιώτης Πολίτης, Ερευνητής Β, Ίδρυμα Ιατροβιολογικών Ερευνών της Ακαδημίας Αθηνών
Κωνσταντίνος Ταμβακόπουλος, Ερευνητής Α, Ίδρυμα Ιατροβιολογικών Ερευνών της Ακαδημίας Αθηνών
Μαρία Ρουμπελάκη, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Original Title:
Exploring the role of nuclear receptor NR5A2 in lung cancer
Languages:
English
Translated title:
Exploring the role of nuclear receptor NR5A2 in lung cancer
Summary:
Lung cancer is the leading cause of cancer-related deaths worldwide with a poor overall prognosis and lower survival rates than most cancers. Non-small cell lung cancers (NSCLCs) account for about 80% of all lung cancers, with adenocarcinomas comprising up to 50% of NSCLCs. These clinical observations underscore the need for novel therapeutic insights and pharmacological targets. To this end, here we identify the orphan nuclear receptor NR5A2/LRH-1 as a negative regulator of epithelial cancer cell proliferation and promising pharmacological target for lung adenocarcinoma. In particular, publicly available clinical data from the Oncomine database reveal a downregulation of NR5A2 in lung adenocarcinoma patients. Consistently, we experimentally show that NR5A2 overexpression is able to suppress the proliferation of four different lung cancer cell lines representing either adenocarcinoma or large cell carcinoma. Notably, its anti-proliferative effect can be observed in vivo as well, since NR5A2 overexpression inhibits tumor growth in a mouse xenograft model. Cancer cell migration is also inhibited due to NR5A2 overexpression in vitro. Moreover, shRNA-mediated knockdown of the basal expression levels of NR5A2 in lung adenocarcinoma cells promotes cell cycle progression. The anti-proliferative effect of NR5A2 is possibly mediated by the transcriptional induction of negative cell cycle regulators, CDKN1A (encoding for p21cip1) and CDKN1B (encoding for p27kip1), and the simultaneous downregulation of a G1-S transition inducer, CCND1 (encoding for cyclin D1). Interestingly, a well-established agonist of NR5A2, dilauroyl phosphatidylcholine (DLPC) is able to mimic the anti-proliferative action of NR5A2 in human NSCLC cell lines, without however affecting cell migration. These data suggest a tumor suppressor role of NR5A2 in NSCLC and render this nuclear receptor a potential pharmacological target for the treatment of human lung adenocarcinoma.
Main subject category:
Health Sciences
Keywords:
Cancer, Lung, Receptor, NR5A2, LRH1
Index:
No
Number of index pages:
0
Contains images:
Yes
Number of references:
57
Number of pages:
75
Master Thesis Lala Maria.pdf (4 MB) Open in new window