高尔基蛋白73作为肝细胞癌治疗的一个新型靶点

高尔基蛋白73（GP73）是个功能不清楚的高尔基体驻留分子。近年来在北美，西欧和东亚的许多临床研究已经确定在肝脏疾病患者的血清中高水平的GP73的“异常”分泌，特别是受乙肝和丙肝病毒感染后而发生的肝细胞癌。GP73是否以及如何在体内促进肝癌的发展及其发病机制尚无人知晓。.我们独立地发现了B淋巴瘤细胞能够自发分泌GP73，并确定它能够选择性地抑制树状细胞产生白细胞介素-12（IL-12），导致T细胞失活。我们还发现多种移植肿瘤在GP73缺陷型小鼠中的生长显著放缓。我们由此推测，受病毒感染的肝细胞分泌GP73并通过免疫和非免疫学的两种渠道促进肝癌的发生和发展。为了检验这一假设，我们将在GP73缺陷型小鼠中通过化学诱导肝细胞癌来研究在自发性肝癌发生和发展中GP73的免疫学作用。与此同时，我们也将在免疫缺陷小鼠中植入的人肝癌细胞模型中研究细胞内源性GP73在促进肝癌生长时与淋巴细胞无关的功能。

Golgi protein 73 (GP73) is a Golgi-residing molecule of obscure function. In recent years, a number of clinical studies across three major continents have identified high levels of GP73 “abnormally” secreted into the sera of patients with liver diseases, particularly hepatocellular carcinoma (HCC) developed on the background of infections by hepatitis B and C viruses. Whether and how GP73 directly contributes to HCC development and pathogenesis in vivo is unknown. .We independently identified GP73 spontaneously secreted by neoplastic B cells, and found that it was able to selectively suppress the production of the cytokine Interleukin-12 (IL-12) by dendritic cells (DCs), resulting in strong inhibition of the activation of T cells. IL-12 is a key factor in the induction of cytotoxic killer cells and anti-tumor responses. This is the first identification of a function of GP73..We hypothesize that virally infected hepatocytes, via producing GP73, promotes HCC initiation and progression through immunological and cell-intrinsic routes. .To test this hypothesis we will investigate the immunological role of the GP73 in HCC initiation and progression in an immunocompetent, chemically induced spontaneous mouse model of HCC in our genetically engineered GP73-deficient mice. In parallel, we will also investigate the T cell-independent, cell-intrinsic role of GP73 in HCC growth in a xenographic human liver cancer model in immunodeficient mice..The investigation will define the function of an obscure molecule of great potentials. The secreted GP73 could render itself an excellent therapeutic target. The study will aid in efforts to develop highly innovative and efficacious therapeutic strategies for HCC.