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LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer

Osteosarcoma (OS) that mainly occurs during childhood and adolescence is a devastating disease with poor prognosis presented by extreme metastases. Recent studies have revealed that liver receptor homolog 1 (LRH-1) plays a vital role in the metastasis of several human cancers, but its role is unknow...

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Autores principales: Song, Yang, An, Weiwei, Wang, Hongmei, Gao, Yuanren, Han, Jihua, Hao, Chenguang, Chen, Lin, Liu, Shilong, Xing, Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005613/
https://www.ncbi.nlm.nih.gov/pubmed/33791301
http://dx.doi.org/10.3389/fcell.2021.643522
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author Song, Yang
An, Weiwei
Wang, Hongmei
Gao, Yuanren
Han, Jihua
Hao, Chenguang
Chen, Lin
Liu, Shilong
Xing, Ying
author_facet Song, Yang
An, Weiwei
Wang, Hongmei
Gao, Yuanren
Han, Jihua
Hao, Chenguang
Chen, Lin
Liu, Shilong
Xing, Ying
author_sort Song, Yang
collection PubMed
description Osteosarcoma (OS) that mainly occurs during childhood and adolescence is a devastating disease with poor prognosis presented by extreme metastases. Recent studies have revealed that liver receptor homolog 1 (LRH-1) plays a vital role in the metastasis of several human cancers, but its role is unknown in the metastasis of OS. In this study, Gene Ontology (GO) enrichment analyses based on high-throughput RNA-seq data revealed that LRH-1 acted a pivotal part in the positive regulation of cell migration, motility, and angiogenesis. Consistently, LRH-1 knockdown inhibited the migration of human OS cells, which was concurrent with the downregulation of mesenchymal markers and the upregulation of epithelial markers. In addition, short hairpin RNAs (shRNAs) targeting LRH-1 inactivated transforming growth factor beta (TGF-β) signaling pathway. LRH-1 knockdown inhibited human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation. Vascular endothelial growth factor A (VEGFA) expression was also downregulated after LRH-1 knockdown. Immunohistochemistry (IHC) revealed that the expression of LRH-1 protein was significantly higher in tumor tissues than in normal bone tissues. We found that high LRH-1 expression was associated with poor differentiation and advanced TNM stage in OS patients using IHC. Based on The Cancer Genome Atlas (TCGA) database, high LRH-1 expression predicts poor survival in lung squamous cell carcinoma (LUSC), kidney renal papillary cell carcinoma (KIRP), and pancreatic adenocarcinoma (PAAD). The downregulation of LRH-1 significantly hindered the migration and motility of LUSC cells. Using multi-omic bioinformatics, the positive correlation between LRH-1- and EMT-related genes was found across these three cancer types. GO analysis indicated that LRH-1 played a vital role in “blood vessel morphogenesis” or “vasculogenesis” in KIRP. Our results indicated that LRH-1 plays a tumor-promoting role in human OS, could predict the early metastatic potential, and may serve as a potential target for cancer therapy.
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spelling pubmed-80056132021-03-30 LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer Song, Yang An, Weiwei Wang, Hongmei Gao, Yuanren Han, Jihua Hao, Chenguang Chen, Lin Liu, Shilong Xing, Ying Front Cell Dev Biol Cell and Developmental Biology Osteosarcoma (OS) that mainly occurs during childhood and adolescence is a devastating disease with poor prognosis presented by extreme metastases. Recent studies have revealed that liver receptor homolog 1 (LRH-1) plays a vital role in the metastasis of several human cancers, but its role is unknown in the metastasis of OS. In this study, Gene Ontology (GO) enrichment analyses based on high-throughput RNA-seq data revealed that LRH-1 acted a pivotal part in the positive regulation of cell migration, motility, and angiogenesis. Consistently, LRH-1 knockdown inhibited the migration of human OS cells, which was concurrent with the downregulation of mesenchymal markers and the upregulation of epithelial markers. In addition, short hairpin RNAs (shRNAs) targeting LRH-1 inactivated transforming growth factor beta (TGF-β) signaling pathway. LRH-1 knockdown inhibited human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation. Vascular endothelial growth factor A (VEGFA) expression was also downregulated after LRH-1 knockdown. Immunohistochemistry (IHC) revealed that the expression of LRH-1 protein was significantly higher in tumor tissues than in normal bone tissues. We found that high LRH-1 expression was associated with poor differentiation and advanced TNM stage in OS patients using IHC. Based on The Cancer Genome Atlas (TCGA) database, high LRH-1 expression predicts poor survival in lung squamous cell carcinoma (LUSC), kidney renal papillary cell carcinoma (KIRP), and pancreatic adenocarcinoma (PAAD). The downregulation of LRH-1 significantly hindered the migration and motility of LUSC cells. Using multi-omic bioinformatics, the positive correlation between LRH-1- and EMT-related genes was found across these three cancer types. GO analysis indicated that LRH-1 played a vital role in “blood vessel morphogenesis” or “vasculogenesis” in KIRP. Our results indicated that LRH-1 plays a tumor-promoting role in human OS, could predict the early metastatic potential, and may serve as a potential target for cancer therapy. Frontiers Media S.A. 2021-03-15 /pmc/articles/PMC8005613/ /pubmed/33791301 http://dx.doi.org/10.3389/fcell.2021.643522 Text en Copyright © 2021 Song, An, Wang, Gao, Han, Hao, Chen, Liu and Xing. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Song, Yang
An, Weiwei
Wang, Hongmei
Gao, Yuanren
Han, Jihua
Hao, Chenguang
Chen, Lin
Liu, Shilong
Xing, Ying
LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer
title LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer
title_full LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer
title_fullStr LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer
title_full_unstemmed LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer
title_short LRH1 Acts as an Oncogenic Driver in Human Osteosarcoma and Pan-Cancer
title_sort lrh1 acts as an oncogenic driver in human osteosarcoma and pan-cancer
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005613/
https://www.ncbi.nlm.nih.gov/pubmed/33791301
http://dx.doi.org/10.3389/fcell.2021.643522
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