Abstract
Melanoma is the most dangerous skin cancer due to its highly metastatic potential and resistance to chemotherapy. Currently, there is no effective treatment for melanoma once it is progressed to metastatic stage. Therefore, further study to elucidate the molecular mechanism underlying the metastasis of melanoma cells is urgently required for the improvement of melanoma treatment. In the present study, we found that diphthamide synthesis 3 (Dph3) is involved in the metastasis of B16F10 murine melanoma cells by insertional mutagenesis. We demonstrated that Dph3 disruption impairs the migration of B16F10 murine melanoma cells. The requirement of Dph3 in the migration of melanoma cells was further confirmed by gene silencing with siRNA in vitro. In corresponding to this result, overexpression of Dph3 significantly promoted the migratory ability of B16F10 and B16F0 melanoma cells. Moreover, down regulation of Dph3 expression in B16F10 melanoma cells strikingly inhibits their cellular invasion and metastasis in vivo. Finally, we found that Dph3 promotes melanoma migration and invasion through the AKT signaling pathway. To conclude, our findings suggest a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma.
Highlights
Melanoma is a highly aggressive and frequently chemoresistant skin cancer caused by malignant transformation of melanocytes which are pigment-producing cells mainly found in the skin and eyes [1]
The murine melanoma B16F10 cell line is a widely used model to study the metastasis of melanoma for its high metastatic potential after intravenous injections [30,31]
We identified a novel role for diphthamide synthesis 3 (Dph3) in the metastasis of murine melanoma cells
Summary
Melanoma is a highly aggressive and frequently chemoresistant skin cancer caused by malignant transformation of melanocytes which are pigment-producing cells mainly found in the skin and eyes [1]. Metastasis is the spread of malignant tumor cells from a primary site to distant tissues and is the most life-threatening factor of cancer [5]. A variety of metastasis-promoting and metastasis suppressor genes, as well as microRNAs have been recently identified to be related to the metastasis of melanoma cells, the molecular mechanisms governing this process are still not completely understood and the treatment efficiency of metastatic melanoma has not been significantly improved over the past 50 years with a 5-year survival rate less than 5% [7,8,9,10]. Further study to uncover related underlying mechanisms is urgently required to find new potential targets for the treatment of melanoma. Cell clones with increased or decreased migratory potential were subjected to 39RACE to identify genes involved in the metastasis of melanoma cells. We found that diphthamide synthesis 3 (Dph3) is involved in the cell migration of melanoma cells
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