Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and it carries a poor prognosis due to a high rate of recurrence or metastasis after surgery. Bmi-1 plays a significant role in the growth and metastasis of many solid tumours. However, the exact mechanisms underlying Bmi-1-mediated cell invasion and metastasis, especially in HCC, are not yet known. In the present study, we sought to evaluate the expression of Bmi-1 in HCC samples and its relationship with clinicopathological characteristics and prognostic value, we also investigated related mechanisms underlying Bmi-1-mediated cell invasion in HCC. Our results showed that Bmi-1 is upregulated in HCC tissues compared to matched non-cancer liver tissues; and its expression is positively associated with tumour size, metastasis, venous invasion and AJCC TNM stage, respectively; multivariate analysis showed that high expression of Bmi-1 was an independent prognostic factor for overall survival. In addition, the shRNA-mediated inhibition of Bmi-1 reduced the invasiveness of two HCC cell lines in vitro by upregulating phosphatase and the tensin homolog deleted on chromosome 10 (PTEN) expression, inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway and downregulating the expression and activities of matrix metalloproteinase (MMP)-2 and MMP-9 and vascular endothelial growth factor (VEGF). These data demonstrate that Bmi-1 plays a vital role in HCC invasion and that Bmi-1 is a potential therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the world and is the second leading cause of cancer-related death in China [1]
Treatment with LY294002 in HCC cells with Bmi-1 knockdown did not further reduce the invasion ability compared to HCC cells treated with LY294002 alone or HCC cells with Bmi-1 knockdown alone (Fig. 5I and J). These results suggested that Bmi-1 may promote HCC cell invasion through the activation of the phosphatidylinositol 3-kinase (PI3K)/ Akt pathway with subsequent regulation of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor (VEGF) expression
Our study demonstrates that Bmi-1 is overexpressed in HCC tissue and cells and its overexpression contributes to invasion and metastasis by increasing the expression of MMP-2, MMP-9 and VEGF via the PTEN/ PI3K/Akt pathway
Summary
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the world and is the second leading cause of cancer-related death in China [1]. Despite remarkable progress in HCC diagnosis and treatment, the prognosis of patients with HCC remains very poor due to the high rate of intrahepatic and distant metastasis after resection or transplantation [1]. The discovery of molecules and/or signal transduction pathways essential to the carcinogenesis and malignant behaviour of HCC cells, especially their invasion and metastasis, is important for improving the prognosis of HCC patients. Bmi-1 is involved in tumour development and progression and is associated with a poor prognosis [17]. Overexpression of Bmi-1 was associated with the invasion of nasopharyngeal carcinomas and predicted poor survival [20]. Inhibition of Bmi-1 leads to decreased invasion of cervical cancer cells [21]. The exact mechanisms by which Bmi-1 mediates tumour cell invasion and metastasis, especially in HCC, remain largely unknown
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