Department of Surgery, The University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, 310003, China.
Cell Oncol (Dordr). 2017 Oct;40(5):443-456. doi: 10.1007/s13402-017-0332-x. Epub 2017 Jun 19.
Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/β-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients.
We found that SPINK1 acts as a downstream effector of the CDH17/β-catenin axis in HCC. In addition, we found that SPINK1 expression exhibited a positive correlation with CDH17 expression in human HCCs and was over-expressed in up to 70% of the tumors. We identified SPINK1 as a downstream effector of the CDH17/β-catenin axis using a spectrum of in vitro assays, including gene expression modulation and inhibitor assays, bioinformatics analyses and luciferase reporter assays. These in vitro results were validated in primary human HCCs, including the observation that alteration in β-catenin expression (a core component of the CDH17/β-catenin axis) in tumors affects SPINK1 serum levels in HCC patients. Similar to CDH17, SPINK1 expression in HCC cells was found to be associated with specific tumor-related properties via activating the c-Raf/MEK/ERK pathway.
Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/β-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients.
肝细胞癌（HCC）是全球最常见的肝癌类型。此前，我们报道过，钙黏蛋白 17（CDH17）及其相关的 CDH17/β-连环蛋白轴可能导致部分 CDH17 过表达的患者发生 HCC。在此，我们旨在更深入地了解 CDH17 相关 HCC 生物学，并为设计针对 CDH17 过表达 HCC 患者的靶向治疗提供进一步的依据。
我们发现丝氨酸蛋白酶抑制剂 Kazal 型 1（SPINK1）是 HCC 中 CDH17/β-连环蛋白轴的下游效应物。此外，我们发现 SPINK1 表达与人 HCC 中的 CDH17 表达呈正相关，在高达 70%的肿瘤中过表达。我们通过一系列体外实验，包括基因表达调控和抑制剂实验、生物信息学分析和荧光素酶报告基因实验，确定了 SPINK1 是 CDH17/β-连环蛋白轴的下游效应物。这些体外实验结果在原发性人 HCC 中得到了验证，包括观察到肿瘤中β-连环蛋白表达的改变（CDH17/β-连环蛋白轴的核心成分）影响 HCC 患者 SPINK1 的血清水平。与 CDH17 相似，HCC 细胞中的 SPINK1 表达通过激活 c-Raf/MEK/ERK 通路与特定的肿瘤相关特性相关。
我们目前的数据证实了 CDH17 在 HCC 生物学中的作用，并表明 CDH17/β-连环蛋白轴的成分可能成为 CDH17 过表达 HCC 患者的治疗靶点。
