Thyroid hormone receptor Alpha is expressed in a module highly correlated with prostate cancer traits without androgen receptor gene involvement

REY, LARA; JUAN MANUEL FERNÁNDEZ-MUÑOZ; CANO, ROCIO ; LÓPEZ FONTANA, CONSTANZA M.; CARÓN, RUBÉN W.

Simposio; 8vo Simposio Argentino de Jóvenes Investigadores en Bioinformática; 2024

Introduction: At present, the role of thyroid hormones (THs) in the development of prostate cancer (PCa) and the molecular mechanisms involved remains unclear. It is known that genes interact in modules (clusters) functionally coordinated, physically interacting and co- regulated that form complex biological networks. For that and the increasing evidence of an androgen-TH crosstalk we propose that gene network analysis that extract modules of highly correlated genes could be useful to better understand TH action. Methods: To investigate the role of THs through their receptor genes (THRA and THRB) and their interaction with androgen receptor (AR) in complex biology networks associated with PCa, we performed a weighted gene co-expression network analysis in the RNA-seq TGCA-PRAD dataset (including only primary tumor samples) by WGCNA package in R. Thus, we obtained modules of co-expressed genes and correlated them with clinical traits (PSA value, gleason score or GS, biochemical recurrence and clinical T grades). Modules highly correlated with PCa clinical traits were selected for further study. Module membership information (MM), a criterion indicating how close is a gene to the relevant modules, of THs and androgen receptor genes was reported. To identify biological process associated with TH action, we searched for enriched gene ontology (GO) terms. Results: From the 12 modules obtained (identified by colors), we selected two modules highly correlated with clinical traits, especially the GS, tan module (r = 0.46, p = 9e-24) and cyan module (r= 0.29, p= 7e-10). We found that, tan module only co-express AR gene (MM= 0.21, p=1e-05) and cyan module THRA (MM= 0.28, p= 1e-09). In tan module there were not significantly enriched GO terms related to TH action, whereas, in cyan module we found two terms, “Cellular Response to Thyroid Hormone Stimulus (GO:0097067)” and “Response to Thyroid Hormone (GO:0097066)”. Conclusion: TH action through THRA, that co-express in a module highly correlated to GS could act alone because AR is not involved in this module. Since MM value of THRA is not high enough to be consider hub gene (highly connected gene), it would be interesting to study the relationship of hub genes in cyan module with TH action. System based analysis is a promising strategy in endocrine related cancer to understand molecular interactions, discover new biomarkers and provide better treatments for patients.