Abstract
Hepatocellular carcinoma (HCC) is a common malignancy found worldwide and is associated with a high incidence of metastasis and vascular invasion. Elucidating the molecular mechanisms that underlie HCC tumorigenesis and progression is necessary for the development of novel therapeutics. By analyzing the Cancer Genome Atlas Network (TCGA) dataset, we identified Thrombospondin 4 (THBS4) is significantly overexpressed in HCC samples and is correlated with prognosis. Overexpression of THBS4 was also highly correlated with vascular invasion of advanced HCC. While THBS4 is often overexpressed in HCC it has also been shown to inhibit tumor growth by mediating cell-to-cell and cell-to-matrix interactions. Here, we identified that knockdown of THBS4 inhibits migration and invasion of HCC cells and inhibits HCC induced angiogenesis. MiRNAs are crucial regulators of multiple cellular processes, and aberrant expression of miRNAs has been observed to effect cancer development and progression. We further found that miR-142 is an upstream regulator of THBS4 in HCC cells. Moreover, miR-142 was significantly down-regulated in HCC tissue samples and correlated with overexpression of THBS4. Overexpression of miR-142 inhibited invasion and angiogenesis of HCC cells and re-expression of THBS4 overcame these effects of miR-142 expression. Stable over-expression of miR-142 significantly inhibited tumour growth in a xenograft tumour model through inhibiting THBS4 expression and tumor angiogenesis. In conclusion, our findings indicate that loss of miR-142 results in the over-expression of THBS4, which enhances HCC migration and vascular invasion. Thus, targeting THBS4 or miR-142 may provide a promising therapeutic strategy for treatment of advanced HCC.
Highlights
Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer worldwide and the third most common cause of cancer mortality
By analyzing HCC tumor samples in the the Cancer Genome Atlas Network (TCGA) database, we found that Thrombospondin 4 (THBS4) expression was significantly higher in HCC tumor samples compared with adjacent normal samples (Figure 1a)
The TGCA database showed that HCC had a higher expression of THBS4 (Figure 1f).(Expression of THBS1, THBS2, THBS3 and THBS5 in HCC of TCGA dataset was shown in Supplementary Figure 1.)
Summary
HCC ranks as the fifth most common cancer worldwide and the third most common cause of cancer mortality. It causes approximately 24,550 new deaths, accounting for 4% of all the cancer-related deaths in the United States during 2015 [1]. A number of potential therapeutic targets have been investigated, such as receptor tyrosine kinases (RTKs) and anti-angiogenesis antibodies, the longterm outcome of HCC following these treatment strategies remains unclear [6,7,8]. Further understanding of the underlying molecular mechanism should provide further impetus for the development of novel and effective therapeutic strategies for HCC patients
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