Abstract
BackgroundSince hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, it is still important to understand hepatocarcinogenesis mechanisms and identify effective markers for tumor progression to improve prognosis. Amplification and overexpression of Tropomyosin3 (TPM3) are frequently observed in HCC, but its biological meanings have not been properly defined. In this study, we aimed to elucidate the roles of TPM3 and related molecular mechanisms.MethodsTPM3-siRNA was transfected into 2 HCC cell lines, HepG2 and SNU-475, which had shown overexpression of TPM3. Knockdown of TPM3 was verified by real-time qRT-PCR and western blotting targeting TPM3. Migration and invasion potentials were examined using transwell membrane assays. Cell growth capacity was examined by colony formation and soft agar assays.ResultsSilencing TPM3 resulted in significant suppression of migration and invasion capacities in both HCC cell lines. To elucidate the mechanisms behind suppressed migration and invasiveness, we examined expression levels of Snail and E-cadherin known to be related to epithelial-mesenchymal transition (EMT) after TPM3 knockdown. In the TPM3 knockdown cells, E-cadherin expression was significantly upregulated and Snail downregulated compared with negative control. TPM3 knockdown also inhibited colony formation and anchorage independent growth of HCC cells.ConclusionsBased on our findings, we formulate a hypothesis that overexpression of TPM3 activates Snail mediated EMT, which will repress E-cadherin expression and that it confers migration or invasion potentials to HCC cells during hepatocarcinogenesis. To our knowledge, this is the first evidence that TPM3 gets involved in migration and invasion of HCCs by modifying EMT pathway.
Highlights
Since hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, it is still important to understand hepatocarcinogenesis mechanisms and identify effective markers for tumor progression to improve prognosis
We explored the biological roles of TPM3 in hepatocarcinogenesis and involved molecular mechanisms by TPM3 knockdown using small interfering RNA in human HCC cell lines
In eight out of the 10 HCC cell lines except for SNU-398 and SNU-886, both the messenger RNA (mRNA) (>1.5 fold) and protein expression levels of TPM3 were found to be increased with respect to the normal liver cell line (THLE-3) (Figure 1)
Summary
Since hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, it is still important to understand hepatocarcinogenesis mechanisms and identify effective markers for tumor progression to improve prognosis. In our recent study which reported the chromosomal alterations in HCC by genome-wide array-CGH analysis, we found that a 1q21.3 locus was recurrently amplified and that a Tropomyosin 3 (TPM3) gene located in this region was coherently overexpressed in primary HCC [6]. This evidence suggests that overexpression of TPM3 may play a role in HCC tumorigenesis. The function of TPM3 in non-muscular tissues is still obscure
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