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

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.

SUBMITTER: Song Y

PROVIDER: S-EPMC8005613 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RNA binding proteins (RBPs) are increasingly recognized as potential factors influencing the advancement, prognostication, and immune response in various solid tumors. Nevertheless, the comprehensive understanding of RBM34's biological mechanisms within the tumor microenvironment remains incomplete, necessitating further systematic pan-cancer investigations to ascertain its diagnostic, prognostic, and immunological significance. In this study, the TCGA, CCLE, HPA, GTEX, and TARGET databases were employed to analyze the expression abundance and subcellular localization of RBM34 in diverse tumor types. Kaplan-Meier survival analyses were used to investigate the impact of RBM34 on clinical prognosis. We implemented the TISIDB portal, CIBERSORT, and ESTIMATE algorithms to assess the correlation between RBM34 expression and immunomodulators, chemokines, and tumor-infiltrating lymphocytes (TILs) in both pan-cancer and osteosarcoma. The CGP database was applied to evaluate the half-maximal inhibitory concentrations of targeted drugs, while TMB, MSI, and MMR were utilized to predict the efficacy of tumor immunotherapy. Furthermore, an RBM34-derived prognostic index (RDPI) was constructed for osteosarcoma patients and linked to outcomes and immune status. Finally, we examined the modulation of RBM34 knockdown on osteosarcoma proliferation and migration capacity. Our results indicate that RBM34 was predominantly localized in the nucleus and differentially expressed in most human cancer types. Kaplan-Meier curve analysis and Cox regression demonstrated that RBM34 expression affected four survival metrics including overall survival (OS) in multiple tumors and was an independent prognostic factor for osteosarcoma. In immunological characterization, RBM34 expression was significantly associated with pan-cancer immunomodulator-related molecules, lymphocyte subpopulation infiltration, and biomarkers of immunotherapy response. Subsequent in vitro experiments provided additional evidence that the suppression of RBM34 impeded the migratory and invasive capabilities of osteosarcoma. Moreover, the utilization of RDPI demonstrated its reliability in prognosticating patient outcomes and estimating the individual immune landscape. Marked differences in multiple TILs (including naive B cells, CD8+ T cells, resting dendritic cells, and activated CD4+ memory T cells) and cancer-associated fibroblast proportion were observed in diverse RDPI score subgroups. Generally, RBM34 exhibited associations with clinical prognosis, immune infiltration, and immunotherapy across various cancer types, and may also serve as a viable therapeutic target for osteosarcoma.

Project description:Purpose: The purpose of this study was to explore the oncogenic role of small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) in human tumors. Materials and methods: Study cases were acquired from The Cancer Genome Atlas database, the Gene Expression Omnibus database, The Human Protein Atlas, and the Clinical Proteomic Tumor Analysis Consortium. We then used the R package and several online tools to analyze and visualize the role of SNRPB across tumors. Results: We found that the expression of SNRPB was significantly increased in 28 of 33 tumors, and higher expression was observed in late pathological and TNM stages. Significantly decreased levels of SNRPB promoter methylation were observed in 12 tumors. SNRPB was found to be a risk factor for decreased overall survival in 10 tumors (p < 0.05), a risk factor for decreased disease-specific survival in 8 tumors (p < 0.05), and a risk factor for decreased progression-free interval in 7 tumors (p < 0.05). The PPI network of SNRPB and the top 100 coexpressed genes revealed that CDK1, CDC6, AURKB, CCNB1, CCNA2, and CDC45 were the most closely interacting genes across tumors. The GO and KEGG enrichment analyses revealed that SNRPB and the above genes were mainly enriched with respect to functions in cell cycle-related genetic material replication, assembly, and distribution. SNRPB was significantly associated with immune cell infiltration and the expression of immunomodulation-related genes in several but not all tumors. Conclusion and limitations: The expression of SNRPB was significantly elevated in almost all tumors, and the decreased promoter methylation level may contribute to the elevated expression of SNRPB. SNRPB may facilitate the progression of pathological and TNM stages and is a risk factor for unfavorable prognosis across tumors. However, our research was based on data obtained from public databases, without further validation of our findings at the cellular and animal levels. Therefore, further studies are needed to clarify the oncogenic mechanism of SNRPB and its potential as a therapeutic target.

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

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