81671

VMP1

vacuole membrane protein 1;VMP1;vacuole membrane protein 1

ectopic P-granules autophagy protein 3 homolog|transmembrane protein 49|transport and golgi organization 5 homolog

17q23.1

protein-coding

As the "master" microRNA that is induced by hypoxia, miR-210 is involved in multiple processes in the hypoxia pathway. However, whether miR-210 mediates hypoxia-induced tumor cell metastasis still remains unclear. Here, we demonstrate that miR-210 is frequently up-regulated in hepatocellular carcinoma (HCC) samples and promotes the migration and invasion of HCC cells. Furthermore, miR-210 can be induced by hypoxia in HCC cells and mediates hypoxia-induced HCC cell metastasis. We identify vacuole membrane protein 1 (VMP1) as the direct and functional downstream target of miR-210; in addition, we show that its expression is negatively correlated with the expression of miR-210 in HCC. Intriguingly, VMP1 is reduced by hypoxia, and down-regulation of VMP1 by miR-210 mediates hypoxia-induced HCC cell metastasis. CONCLUSION: These findings extend our understanding of the function of miR-210 in the hypoxia pathway, and this newly identified hypoxia/miR-210/VMP1 pathway should facilitate the development of novel therapeutics against hypoxic tumor cells.

Hepatocellular carcinoma (HCC) is one of the most deadly human cancers because of its high incidence of metastasis. Despite extensive efforts, therapies against metastasis of HCC remain underdeveloped. Vacuole membrane protein 1 (Vmp1) was recently identified to be involved in cancer-relevant processes; however, its expression, clinical significance and biological function in HCC progression are still unknown. Therefore, we evaluated the expression of Vmp1 in human HCC specimens. To functionally characterize Vmp1 in HCC, we upregulated its expression in HCCLM3 cells using a plasmid transfection approach, following which both in vitro and in vivo models were used to elucidate its role. A significant downregulation of Vmp1 was found in human HCC tissues and closely correlated with multiple tumor nodes, absence of capsular formation, vein invasion and poor prognosis of HCC. Such expression was verified with HCC cell lines including HepG2, MHCC97-L and HCCLM3, and the Vmp1 expression levels negatively correlated with metastatic potential. Interestingly, upregulation of Vmp1 significantly affects proliferation, migration, invasion and adhesion of HCCLM3 cells. Using a mouse model, we demonstrated that upregulation of Vmp1 was associated with suppression of growth and pulmonary metastases of HCC. Therefore, our data suggest Vmp1 is a novel prognostic marker and potential therapeutic target for metastasis of HCC.

Vacuole membrane protein 1 (Vmp1) is described as a cancer-relevant cell cycle modulator, but the function of this protein and its mode of action in tumor progression are still unknown. In this study, we show that the VMP1 mRNA level is significantly reduced in kidney cancer metastases as compared to primary tumors. Further, VMP1 expression is also decreased in the invasive breast cancer cell lines HCC1954 and MDA-MB-231 as compared to the non-invasive cell lines MCF-12A, T-47D and MCF-7. We show for the first time that Vmp1 is a plasma membrane protein and an essential component of initial cell-cell contacts and tight junction formation. It interacts with the tight junction protein Zonula Occludens-1 and colocalizes in spots between neighboring HEK293 cells. Downregulation of VMP1 by RNAi results in loss of cell adherence, and increases the invasion capacity of the non-invasive kidney cancer cell line Caki-2. In conclusion, our findings establish Vmp1 to be a novel cell-cell adhesion protein and that its expression level determines the invasion and metastatic potential of cancer cells.