骨肉瘤是最常见的原发性恶性骨肿瘤之一，具有生长速度快、转移发生早的特点。目前认为骨肉瘤干细胞是介导肿瘤生长、转移和耐药的关键群体，然而关于骨肉瘤干细胞恶性生物学行为的分子机制尚不清楚。本课题组在前期研究中发现了一种以乳酸为配体的GPCR受体（HCAR1）在骨肉瘤干细胞中显著高表达，并与患者的生存时间呈负相关；上调或下调HCAR1的表达能够显著影响骨肉瘤干细胞的增殖、迁移能力；HCAR1的非经典信号传导分子arrestin2与HIF1α存在显著的相互作用，并影响了HIF1α的核转位及转录活性。课题组计划从大量骨肉瘤临床样本入手，从分子、细胞、动物水平阐明HCAR1通过arrestin2调控HIF1α的转录活性，以此揭示HCAR1介导骨肉瘤干细胞恶性生物学行为的分子机制，为骨肉瘤的治疗提供新的理论依据和药物靶点。

Osteosarcoma (OS) is one of the most commonly primary malignant bone tumors, with the characteristics of fast growth and early metastasis. It is well established that osteosarcoma stem cells (OSCs) are identified as a key subpopulation of cells from osteosarcoma tissue samples and cell lines, which appear to play vital roles in tumor growth, metastasis and chemoresistance. But the molecular mechanisms of their malignant activities remain unclear. Through the technology of single cell sequencing, we found that a comprehensive G protein-coupled receptor (GPCR) with lactic acid as ligand, named HCAR1, was highly expressed in OSCs, which was negative correlation with survival time of patients. Decline or overexpression of HCAR1 had significant effect on the proliferation and migration of OSCs. In addition, as the noncanonical signaling molecules of HCAR1, arrestin2 could interact with HIF1α remarkably and have an effect on the nuclear translocation as well as transcriptional activity of HIF1α. We plan to conduct this study starting with detection of a large number of OS samples, and to confirm the molecular mechanism underlying HCAR1 could control the transcriptional activity of HIF1α by the arrestin2 from molecular, cellular levels and animal models. This study aim to reveal the specific molecular mechanisms of HCAR1 modulating the malignant biological behavior of OSCs and provide a new theoretical basis and drug targets for the OS treatment.