miRNA-200 家族在伴有胆管癌栓的肝细胞癌中的表达谱。

Expression profile of microRNA-200 family in hepatocellular carcinoma with bile duct tumor thrombus.

机构信息

Departments of *Surgery; and †Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taiwan.

出版信息

Ann Surg. 2014 Feb;259(2):346-54. doi: 10.1097/SLA.0000000000000223.

DOI:10.1097/SLA.0000000000000223

PMID:24135722

Abstract

OBJECTIVE

The aim of this study was to assess the role of the miR-200 family in the pathogenesis of hepatocellular carcinoma with bile duct tumor thrombus (HCC-BDTT).

BACKGROUND

Hepatocellular carcinoma with bile duct tumor thrombus is a challenging condition because of its rarity and dismal prognosis. Epithelial-to-mesenchymal transition (EMT) is considered a critical step in the progression and metastasis of HCC and is regulated by the microRNA-200 (miR-200) family.

METHODS

Thirty patients with HCC-BDTT were enrolled and 1240 patients with conventional HCC (cHCC) served as clinicopathologic controls. Sixty age- and sex-matched cHCC patients were selected to compare the miR-200 family expression profile and immunohistochemical characteristics. Gain- and loss-of-function studies of the miR-200 family were conducted using the hepatoma cell lines.

RESULTS

Although the mean size of HCC-BDTT was smaller than that of cHCC, the former had a higher incidence of vascular invasion and a poorer long-term survival. The expressions of miR-200c and miR-141 were downregulated in HCC-BDTT (4.5- and 4.8-fold decrease, respectively). Downregulation of both miR-200c and miR-141 independently predicted disease-free survival. The HCC-BDTT, but not cHCC, exhibited overexpression of ZEB1, Twist, transforming growth factor-β receptor type II, and vimentin, and aberrant E-cadherin expression, indicating EMT. The HCC-BDTT demonstrated increased expression in IL-6 and stemness factor Bmi1, but reduced level of metastasis-suppressive protein, insulin-like growth factor-binding protein 4. The invasive ability of the highly aggressive Mahlavu cell was attenuated by pre-miR-200c+141, whereas the invasive ability of the less aggressive Huh7 cell was enhanced by anti-miR-200c+141.

CONCLUSIONS

Simultaneous silencing of miR-200c and miR-141 was likely to be responsible for the development of HCC-BDTT via ZEB1-directed EMT activation and Sec23a-mediated secretome.

摘要

目的

本研究旨在评估 miR-200 家族在伴有胆管癌栓的肝细胞癌（HCC-BDTT）发病机制中的作用。

背景

伴有胆管癌栓的肝细胞癌因其罕见且预后不良而成为极具挑战性的疾病。上皮间质转化（EMT）被认为是 HCC 进展和转移的关键步骤，受 microRNA-200（miR-200）家族调控。

方法

纳入 30 例 HCC-BDTT 患者，以 1240 例常规 HCC（cHCC）患者作为临床病理对照。选择 60 例年龄和性别匹配的 cHCC 患者比较 miR-200 家族表达谱和免疫组织化学特征。利用肝癌细胞系进行 miR-200 家族的增益和缺失功能研究。

结果

尽管 HCC-BDTT 的平均大小小于 cHCC，但前者血管侵犯发生率更高，长期生存更差。miR-200c 和 miR-141 在 HCC-BDTT 中表达下调（分别下调 4.5 倍和 4.8 倍）。miR-200c 和 miR-141 的下调均独立预测无病生存期。HCC-BDTT 而非 cHCC 表达 ZEB1、Twist、转化生长因子-β受体 II 和波形蛋白，并出现 E-钙黏蛋白异常表达，表明 EMT。HCC-BDTT 中白细胞介素 6 和干细胞因子 Bmi1 表达增加，但转移抑制蛋白胰岛素样生长因子结合蛋白 4 水平降低。高侵袭性 Mahlavu 细胞的侵袭能力被前 miR-200c+141 减弱，而侵袭性较弱的 Huh7 细胞的侵袭能力则被抗 miR-200c+141 增强。