Abstract
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.
Highlights
Osteosarcoma (OS) is the most common malignant bone tumor and ranks the leading causes of cancer-related deaths in the pediatric age group (Geller and Gorlick, 2010; Jafari et al, 2020)
Our results revealed that liver receptor homolog 1 (LRH-1) was clearly localized to the nuclear and cytoplasmic compartment of OS cells (Figures 1A,B)
We found that patients with high LRH-1 expression had more advanced TNM stage and poor differentiation than patients with low LRH-1 expression (Table 1 and Figure 1B)
Summary
Osteosarcoma (OS) is the most common malignant bone tumor and ranks the leading causes of cancer-related deaths in the pediatric age group (Geller and Gorlick, 2010; Jafari et al, 2020). With a particular focus on metastasis, a number of scientific studies were able to provide evidence that an implication of LRH-1 overexpression enhances metastatic potential as well as invasion of cancer cells, contributing to a more aggressive malignant phenotype in different types of human cancer, including gastric cancer (Liu et al, 2019), pancreatic cancer (Lin et al, 2014a), ovarian cancer (Sun et al, 2020), lung cancer (Ye et al, 2019), and colon cancer (Yan et al, 2017). It is unclear whether LRH-1 contributes to OS metastasis and tumor aggressiveness
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