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

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.

• Authors: Ta-Sen Yeh, Frank Wang, Tse-Ching Chen, Chun-Nan Yeh, Ming-Chin Yu, Yi-Yin Jan, Miin-Fu Chen
• Journal: Annals of surgery (Ann Surg) Vol. 259 Issue 2 Pg. 346-54 (Feb 2014) ISSN: 1528-1140 [Electronic] United States
• PMID: 24135722 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• MIRN141 microRNA, human
• MIRN200 microRNA, human
• MicroRNAs

Topics

• Adult
• Aged
• Bile Duct Neoplasms (genetics, metabolism, pathology, surgery)
• Bile Ducts, Intrahepatic (metabolism, pathology)
• Biomarkers, Tumor (metabolism)
• Blotting, Western
• Carcinoma, Hepatocellular (genetics, metabolism, pathology, surgery)
• Case-Control Studies
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Hepatectomy
• Humans
• Immunohistochemistry
• Liver Neoplasms (genetics, metabolism, pathology, surgery)
• Male
• MicroRNAs (metabolism)
• Middle Aged
• Neoplasm Invasiveness
• Real-Time Polymerase Chain Reaction
• Survival Analysis
• Up-Regulation