Abstract
Hepatocellular carcinoma (HCC) is a highly prevalent cancer with poor prognosis. The correlation between overexpression of fatty acid‐binding protein 5 (FABP5) and malignant potential of tumor growth and metastasis in several cancers has been previously reported. However, the correlation between FABP5 expression and HCC malignant behavior remains unknown. We compared FABP5 expression and patient characteristics in paired HCC and adjacent noncancerous liver tissues from 243 patients who underwent surgical resection of primary HCC. Cell proliferation, invasion, and migration assays were performed in HCC cell lines overexpressing FABP5 or downregulated for FABP5. Tumor growths were monitored in xenograft model, and liver and lung metastasis models were established. In the 243 HCC patients, FABP5‐positive staining (n = 139/243, 57.2%) was associated with poor prognosis and recurrence (P < 0.0001) and showed positive correlation with distant metastasis, tumor size and vascular invasion (P < 0.05). Cell proliferation, invasion, and migration in vitro were enhanced by upregulation of FABP5 and decreased by downregulation of FABP5 in HCC cell lines. Similar results in tumor formation and metastasis were obtained through in vivo analyses. PCR array results revealed upregulation of SNAI1 in FABP5‐overexpressing HepG2 cells. Western blot analysis showed significantly increased expression of E‐cadherin and ZO‐1 and decreased SNAI1 expression and nuclear translocation of β‐catenin by knockdown of FABP5. We revealed a significant role for FABP5 in HCC progression and metastasis through the induction of epithelial‐to‐mesenchymal transition. FABP5 may be a potential novel prognostic biomarker and new therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC) is a highly prevalent cancer and the third cause of cancer-related death worldwide [1]
The rate of recurrence of HCC in patients who underwent curative surgical or regional therapy is 75% at the fifth year [4], and the rate of recurrence is 86.5% for intrahepatic metastasis and 13.5% for extrahepatic metastasis [5]. Serum biomarkers, such as alpha-f etoprotein (AFP) and prothrombin induced by vitamin K absence II (PIVKA II), and many clinicopathological factors are used for prognostic markers of HCC [6, 7], but they are not adequate to predict survival or recurrence after curative hepatectomy [8]
A similar correlation of the expression of N-cadherin, E-cadherin with the expression of fatty acid-binding protein 5 (FABP5) was observed in mouse liver metastatic tissues (Fig. S1B). This is the first report describing the clinical significance of positive expression FABP5 in human HCC and its correlation with malignant behavior, recurrence and prognosis
Summary
Hepatocellular carcinoma (HCC) is a highly prevalent cancer and the third cause of cancer-related death worldwide [1]. Surgical treatments such as liver resection and transplantation are the best curative local treatments for HCC [2]. The rate of recurrence and metastasis are still high even after curative hepatectomy [3]. Serum biomarkers, such as alpha-f etoprotein (AFP) and prothrombin induced by vitamin K absence II (PIVKA II), and many clinicopathological factors are used for prognostic markers of HCC [6, 7], but they are not adequate to predict survival or recurrence after curative hepatectomy [8]. New biomarkers that are effective for predicting prognosis, recurrence, and metastasis in HCC are highly needed
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