PTP1B负调控Wnt/β-catenin信号通路抑制肝癌细胞自我更新、侵袭转移的机制研究

Hepatocellular carcinoma (HCC) is the sixth most common solid cancer in the world and the third leading cause of cancer-related mortality globally. The protein-tyrosine phosphatase 1B (PTP1B) is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and can exert both tumor suppressing and tumor promoting effects in different cancers depending on the substrate involved and the cellular context. However, the expression level and function of PTP1B in hepatocellular carcinoma (HCC) remain unclear. In our previous study, we found that decreased PTP1B expression was significantly associated with aggressive clinicopathologic features and poor prognosis. Overexpression of PTP1B decreased clone formation, sphere formation, migration and invasion ability in SMMC7721 cells. Additionally, we observed that expression of PTP1B inhibited Wnt/β-catenin signaling activity. In this project, by using molecular and cellular biology methods (spheroid assay, migration and invasion assay, nude mice tumorigenicity experiments, experimental metastasis model, human HCC PDX model, DEN-induced rat liver cancer model), we will test the role of PTP1B on regulating HCC function（e.g. self-renewal, invasion and metastasis ability）. We will also clarify the molecular mechanism involved. Success of the project will contribute to further understanding the role of PTP1B in HCC progression.

PTP1B对代谢和肿瘤具重要调控作用，但其在肝细胞癌中的表达和功能仍知之甚少。申请人在前一青年基金资助下，对二甲双胍抑制肝癌的作用及分子机制进行了系统研究，论文发表于Clinical Cancer Research、Medicine杂志。前期通过肝癌组织样本和细胞系研究，发现PTP1B在肝癌中低表达，过表达PTP1B能抑制肝癌细胞自我更新和侵袭，并初步发现PTP1B对Wnt/β-catenin通路具抑制作用。本项目拟在此基础上，结合原代肝癌标本、人肝癌PDX模型、细胞系从体外和体内两个水平详细研究PTP1B对肝癌自我更新、侵袭、转移等表型的调控，阐明其调控Wnt/β-catenin信号通路的具体分子机制，并结合大鼠DEN肝癌模型和人肝癌PDX模型进一步探索PTP1B在抑制肝癌发生、发展中的潜在应用价值。本研究将为肝细胞癌的预后判断提供新的标志物，为肝癌的靶向治疗提供具有潜在应用价值的靶点。

肿瘤代谢与肿瘤的发生、发展密切相关。酪氨酸磷酸酶PTP1B对代谢和肿瘤具重要调控作用。本项目结合人肝癌样本、公共数据库、人肝癌细胞系、肝癌移植瘤模型等手段，一方面，从体外和体内不同水平阐明了PTP1B对肝癌生物学特性的调控；另一方面，结合PTP1B的代谢功能，发现了PTP1B与炎症因子、肿瘤免疫的新关联。本项目的主要研究发现包括：1）PTP1B在肝细胞癌中低表达，其低表达与侵袭性病理特征、较差的预后生存相关，PTP1B可作为预测肝癌术后生存的独立危险因素；2）过表达PTP1B可抑制肝癌细胞的干性、迁移、侵袭等特性；3）明确了PTP1B通过抑制Wnt/β-catenin信号通路调控肝癌细胞干性、迁移、侵袭等特性的分子学机制；4）在肝癌移植瘤模型中，通过注射过表达PTP1B的慢病毒，可抑制肝癌细胞生长；5）发现了PTP1B通过代谢影响炎症微环境的新证据；6）初步阐明了PTP1B通过抑制IFNγ诱导的PD-L1表达调控肝癌免疫逃避的新机制。项目研究期间，共发表标注本基金号的SCI论文2篇，培养博士研究生2名、硕士研究生1名。