肝癌中TGFβ 3型受体表达及其调控 M2型巨噬细胞促进肿瘤进展的机制研究

Down-regulation of type 3 transforming growth factor beta receptor (TGFβR3) is commonly observed in numerous malignancies. Studies indicated that TGFβR3 suppressed the disease progression via different mechanisms including the inhibition of cancer cells invasiveness, activation of anti-tumor immunity and blockage tumor promoting signaling pathways. Currently, the clinical significances and the underlying mechanisms are unclear in hepatocellular carcinoma (HCC). Moreover, we previously reported the novel roles of M2 macrophages in leading to poor prognosis in HCC patients. However, the mechanism of activating and recruiting M2 macrophages in HCC tumor is unknown. Our preliminary results showed the down-regulation of TGFβR3 in HCC patient particularly in the late stage group. Importantly, low expression level of the receptor contributed to poor clinical outcome in HCC patients accompanying with the accumulation of M2 macrophages. Based on these evidences, we hypothesize that the loss of TGFβR3 in HCC cells resulted in activating the tumor promoting phenotypes of macrophages. The aim of the study is to identify the clinical roles of TGFβR3 and its underlying mechanism with macrophages. To achieve this, 100 tumor specimens will be obtained from HCC patients who underwent curative resection. The expression level of tissue and plasma TGFβR3 will be determined by q-PCR and ELISA respectively. The tumor suppressive functions of GFβR3 will be studied in two HCC tumor models. Further functional and molecular analysis will be performed via forced TGFβR3 down-regulation with CRISPR knockout in hepatocyte cell-lines. Finally, cross-talk of TGFβR3-/- HCC cells and macrophages will be studied with co-cultivation approach. In summary, the proposal will study the clinical impact of TGFβR3 down-regulation in HCC patients, illustrating its potential in diagnostic and therapeutic development. A novel mechanism of HCC cells in activating M2 macrophages will be revealed.

由于其在肿瘤组织中的缺失，许多报道已将TGFβR3 鉴定为人类癌症中的肿瘤抑制物。通过抑制癌细胞侵袭和阻断促进肿瘤的信号通路等不同机制来抑制疾病。肝癌是在我国常见恶性肿瘤之一, 目前TGFβR3在肝细胞癌的临床意义和潜在机制尚不清楚。项目将会分析临床标本的TGFβR3表达量与各病人临床数据的关键。另外, 透过肝肿瘤动物模型及细胞实验证明其抑癌作用及机制。初步实验结果表明肝癌患者特别在晚期患者中TGFβR3呈下调趋势，低表达水平导致临床预后不良。通过肝肿瘤模型发现TGFβR3蛋白的抑癌作用, 每周注射25μg後比较对照组减少肝癌体积 2倍。机制方面发现新的免疫机制, TGFβR3的失调引起肝肿瘤细胞增加补体C5a 的分泌继而刺激M2巨噬细胞的促癌表现, 解释肝癌病人预後不良。总结来说, 项目将填补了现时的研究不足, 证明TGFβR3在诊断及治疗肝肿瘤的可行性, 为往後的临床转化研究带来基础。

由于其在肿瘤组织中的缺失，许多报道已将TGFβR3 鉴定为人类癌症中的肿瘤抑制物。通过抑制癌细胞侵袭和阻断促进肿瘤的信号通路等不同机制来抑制疾病。肝癌是在我国常见恶性肿瘤之一, 目前TGFβR3在肝细胞癌的临床意义和潜在机制尚不清楚。项目将会分析临床标本的TGFβR3表达量与各病人临床数据的关键。另外, 透过肝肿瘤动物模型及细胞实验证明其抑癌作用及机制。初步实验结果表明肝癌患者特别在晚期患者中TGFβR3呈下调趋势，低表达水平导致临床预后不良。通过肝肿瘤模型发现TGFβR3蛋白的抑癌作用, 每周注射25μg後比较对照组减少肝癌体积 2倍。机制方面发现新的免疫机制, TGFβR3的失调引起肝肿瘤细胞增加补体C5a 的分泌继而刺激M2巨噬细胞的促癌表现, 解释肝癌病人预後不良。总结来说, 项目将填补了现时的研究不足, 证明TGFβR3在诊断及治疗肝肿瘤的可行性, 为往後的临床转化研究带来基础。