SART3通过Wnt/β-catenin信号通路诱导EMT和肿瘤干细胞特性促进肝细胞癌转移复发的研究

It is crucial to clarify the molecular mechanisms underlying epithelial-mesenchymal transition(EMT) and cancer stem cells(CSCs), which have become the major obstacle in improving long term survival of patients with hepatocellular carcinoma(HCC). SART3 is a multifaceted nuclear protein and has been shown to function in tumor antigenicity, regulation of gene transcription, pre-mRNA splicing, stem cell proliferation and differentiation, and embryogenesis. However, its biological role in HCC progression is still unclear. Our previous research showed that high expression of SART3 in HCC tissues was significantly associated with aggressive clinicopathological characteristics and poor prognosis of HCC patients after liver resection. Furthermore, SART3 showed the ability to induce EMT and CSCs properties and activate the Wnt/β-catenin signaling pathway in HCC cells. Therefore, we have a hypothesis that SART3 may promote HCC metastasis and recurrence via Wnt/β-catenin-induced EMT and CSCs properties. In this research, we intend to clarify the prognostic value of SART3 in HCC patients after radical resection, the biological function of SART3 in the regulation of EMT and the acquirement of CSCs properties, followed by the downstream target genes and the involved signaling pathways modulated by SART3 using molecular biotechnology, cell and animal models, series of rescue experiments and clinical specimen detection. This work will provide a new prognostic biomarker and the candidates of therapeutic targets for anti-metastasis and recurrence of HCC.

阐明上皮间质转化（EMT）和肿瘤干细胞（CSCs）分子机制对改善肝细胞癌（HCC）患者预后至关重要。SART3是一个多功能核蛋白，具有肿瘤抗原性和调节基因转录、pre-mRNA剪接、干细胞增殖分化、胚胎形成等重要生理功能，但其在HCC进展中的作用尚不清楚。前期研究发现SART3在HCC高表达，且与肿瘤进展及不良预后密切相关。SART3可明显诱导EMT表型和CSCs特性，并激活Wnt/β-catenin通路。提示SART3可能通过Wnt/β-catenin通路诱导EMT及CSCs特性促进HCC转移复发。为此，本项目拟采用分子生物学技术，通过细胞与动物模型、系列回复实验，结合生物信息学分析和临床标本检测，明确SART3作为HCC预后标志物的临床价值；验证其对EMT和CSCs特性的诱导作用；阐明SART3调控下游靶基因及相关通路的具体机制。研究结果有望为HCC治疗和预后评估提供新思路、新靶点。

上皮间质转化（EMT）和肿瘤干细胞（CSCs）特性可促进肿瘤侵袭和转移，了解其分子机制对改善肝细胞癌（HCC）患者预后至关重要。SART3是一个多功能核蛋白，具有肿瘤抗原性和调节基因转录、pre-mRNA剪接、干细胞增殖分化、胚胎形成等重要生理功能，但其在HCC进展中的作用尚不清楚。我们发现SART3在HCC组织和细胞系中表达显著上调。SART3高表达与肝癌患者差的临床病理特征和预后密切相关，是肝切除术后肝癌患者整体生存时间和无瘤生存时间的独立危险因素。体外和体内实验均表明，过表达SART3可通过诱导EMT和CSCs特性促进肝癌细胞的迁移、侵袭和转移，而敲减SART3则会产生相反的效果。机制分析发现SART3可通过上调β-catenin表达激活Wnt信号通路并诱导EMT和CSCs特性，促进肝癌的侵袭和转移。上述研究结果揭示了SART3在HCC细胞中通过激活Wnt/β-catenin信号通路诱导EMT和CSCs特性的促癌作用，有望为HCC治疗和预后评估提供新思路、新靶点。