Abstract
BackgroundF-box only protein 8 (FBX8), a novel component of F-box proteins, is lost in several cancers and has been associated with invasiveness of cancer cells. However, its expression pattern and role in the progression of hepatocellular carcinoma remain unclear. This study investigated the prognostic significance of FBX8 in hepatocellular carcinoma samples and analyzed FBX8 function in hepatocellular carcinoma cells by gene manipulation.MethodologyThe expression of FBX8 was detected in 120 cases of clinical paraffin-embedded hepatocellular carcinoma tissues, 20 matched pairs of fresh tissues and five hepatocellular carcinoma cell lines by immunohistochemistry with clinicopathological analyses, real-time RT-PCR or Western blot. The correlation of FBX8 expression with cell proliferation and invasion in five HCC cell lines was analyzed. Moreover, loss of function and gain of function assays were performed to evaluate the effect of FBX8 on cell proliferation, motility, invasion in vitro and metastasis in vivo.ConclusionsWe found that FBX8 was obviously down-regulated in HCC tissues and cell lines (P<0.05). The FBX8 down-regulation correlated significantly with poor prognosis, and FBX8 status was identified as an independent significant prognostic factor. Over-expression of FBX8 decreased proliferation, migration and invasion in HepG2 and 97H cells, while knock-down of FBX8 in 7721 cells showed the opposite effect. FBX8 negatively correlated with cell proliferation and invasion in 7701, M3, HepG2 and 97H cell lines. In vivo functional assays showed FBX8 suppressed tumor growth and pulmonary metastatic potential in mice. Our results indicate that down-regulation of FBX8 significantly correlates with invasion, metastasis and poor survival in hepatocellular carcinoma patients. It may be a useful biomarker for therapeutic strategy and control in hepatocellular carcinoma treatment.
Highlights
Hepatocellular carcinoma (HCC) is a common malignancy worldwide, but especially in China and other East Asian countries [1,2]
We found that F-box only protein 8 (FBX8) was obviously down-regulated in HCC tissues and cell lines (P,0.05)
The FBX8 downregulation correlated significantly with poor prognosis, and FBX8 status was identified as an independent significant prognostic factor
Summary
Hepatocellular carcinoma (HCC) is a common malignancy worldwide, but especially in China and other East Asian countries [1,2]. F-box proteins are critical components of the SCF uniquitin-protein ligase complex and are involved in the ubiquitin-dependent proteolytic pathway. FBX8 was originally identified as a Skp1-binding protein [10,11]. It has E3 ligase activity mediating the ubiquitination of the GTP-binding protein ARF6 [12]. FBX8 over-expression could inhibit ARF6-mediated cell invasion activity in breast cancer cells [12]. FBX8 was found to be a novel c-Myc binding protein and cMyc induced cell invasive activity through the inhibition of FBX8 effects on ARF6 function [13]. F-box only protein 8 (FBX8), a novel component of F-box proteins, is lost in several cancers and has been associated with invasiveness of cancer cells. This study investigated the prognostic significance of FBX8 in hepatocellular carcinoma samples and analyzed FBX8 function in hepatocellular carcinoma cells by gene manipulation
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