Song Yang, An Weiwei, Wang Hongmei, Gao Yuanren, Han Jihua, Hao Chenguang, Chen Lin, Liu Shilong, Xing Ying
The First Department of Orthopedic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China.
Front Cell Dev Biol. 2021 Mar 15;9:643522. doi: 10.3389/fcell.2021.643522. eCollection 2021.
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.
骨肉瘤（OS）主要发生在儿童和青少年时期，是一种预后极差、具有极高转移率的毁灭性疾病。最近的研究表明，肝脏受体同源物1（LRH-1）在几种人类癌症的转移中起着至关重要的作用，但其在骨肉瘤转移中的作用尚不清楚。在本研究中，基于高通量RNA测序数据的基因本体（GO）富集分析表明，LRH-1在细胞迁移、运动和血管生成的正调控中起关键作用。一致地，LRH-1基因敲低抑制了人骨肉瘤细胞的迁移，这与间充质标志物的下调和上皮标志物的上调同时发生。此外，靶向LRH-1的短发夹RNA（shRNA）使转化生长因子β（TGF-β）信号通路失活。LRH-1基因敲低抑制了人脐静脉内皮细胞（HUVEC）的增殖、迁移和管腔形成。LRH-1基因敲低后，血管内皮生长因子A（VEGFA）的表达也下调。免疫组织化学（IHC）显示，肿瘤组织中LRH-1蛋白的表达明显高于正常骨组织。我们通过IHC发现，骨肉瘤患者中LRH-1高表达与低分化和晚期TNM分期相关。基于癌症基因组图谱（TCGA）数据库，LRH-1高表达预示着肺鳞状细胞癌（LUSC）、肾肾乳头状细胞癌（KIRP）和胰腺腺癌（PAAD）患者的生存率较低。LRH-1的下调显著阻碍了LUSC细胞的迁移和运动。使用多组学生物信息学方法，发现这三种癌症类型中LRH-1与上皮-间质转化（EMT）相关基因之间存在正相关。GO分析表明，LRH-1在KIRP的“血管形态发生”或“血管生成”中起重要作用。我们的结果表明，LRH-1在人类骨肉瘤中起促肿瘤作用，可预测早期转移潜能，并可能成为癌症治疗的潜在靶点。
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