Abstract
BackgroundSpecific gene expression is tightly regulated by various transcription factors. Osteopontin (OPN) is a phosphoprotein that mediates hepatocellular carcinoma (HCC) progression and metastasis. However, the mechanism of OPN up-regulation in HCC metastasis remains to be clarified.MethodsOligonucleotide array-based transcription factor assays were applied to compare different activities of transcription factors in two human HCC cell lines with different OPN expression levels. The effects of one selected transcription factor on OPN expression were further evaluated.ResultsEleven transcription factors were over-expressed in metastatic HCC cell line HCCLM6 cells whereas twelve transcription factors were down-regulated. Electrophoretic mobility shift assays (EMSA) and reporter gene assays showed that one of up-regulated transcription factors c-Myb could bind the OPN promoter and increase its transcription activity. In addition, small interfering RNA targeting c-Myb could inhibit OPN expression and significantly decrease migration and invasion of HCCLM6 cells in vitro.ConclusionOur data first demonstrate that c-Myb has a functionally important role in the regulation of OPN expression in HCC cells, suggesting that c-Myb might be a new target to control HCC metastasis.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies [1]
With > 2-fold or < 0.5-fold expression as the cutoff point, analysis of transcription factor profiles revealed that eleven transcription factors including c-Myb, MAZ and E4BP4 were highly up-regulated twelve transcription factors were reduced in HCCLM6 cells (Table 2)
3.3 OPN expression was down-regulated after c-Myb was inhibited in HCCLM6 cells To further validate c-Myb regulating OPN expression in HCCLM6 cells, we examined the level of OPN expression in HCCLM6 cells transfected with Small Interfering RNA (siRNA) targeting c-Myb
Summary
Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies [1]. Osteopontin (OPN) is a secreted extracellular matrix protein, which has been linked to tumor progression and metastasis in a variety of cancers including HCC [4,5]. OPN has been identified as the lead gene overexpressed in the metastatic HCC [6]. Increased OPN expression is associated with clinical stage, portending a poor prognosis [7,8,9]. OPN increases cell proliferation, migration and extracellular matrix invasion in vitro. Osteopontin (OPN) is a phosphoprotein that mediates hepatocellular carcinoma (HCC) progression and metastasis. The mechanism of OPN up-regulation in HCC metastasis remains to be clarified
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