Downregulation of hepatoma-derived growth factor contributes to retarded lung metastasis via inhibition of epithelial-mesenchymal transition by systemic POMC gene delivery in melanoma
Tsai, HE and Liu, GS and Kung, ML and Liu, LF and Wu, JC and Tang, CH and Huang, CH and Chen, SC and Lam, HC and Wu, CS and Tai, MH, Downregulation of hepatoma-derived growth factor contributes to retarded lung metastasis via inhibition of epithelial-mesenchymal transition by systemic POMC gene delivery in melanoma, Molecular Cancer Therapeutics, 12, (6) pp. 1016-1025. ISSN 1535-7163 (2013) [Refereed Article]
Copyright 2013 American Association for Cancer Research
The prognosis of malignant melanoma is poor due to high incidence of metastasis, underscoring the demand for development of novel therapeutic strategies. Stress hormone pro-opiomelanocortin (POMC) is the precursor for several anti-inflammatory peptides that hold promise for management of cancer-related diseases. The present study evaluated the antimetastatic potential and mechanism of POMC therapy for metastatic melanoma. Adenovirus-mediated POMC gene delivery potently inhibited the invasiveness of human and mouse melanoma cells. Moreover, after induction of lung metastasis, systemic POMC expression significantly reduced the foci formation and neovascularization in lungs. Mechanistic studies revealed that POMC therapy inhibited the epithelial-mesenchymal transition (EMT) of melanoma cells by upregulation of E-cadherin and downregulation of vimentin and α-smooth muscle actin (α-SMA). In addition, microarray analysis unveiled POMC gene transfer reduced the mRNA level of multiple prometastatic factors, including hepatoma-derived growth factor (HDGF). Cell culture and immunohistochemical studies further confirmed that POMC gene delivery significantly decreased the expression of HDGF in melanoma cells and tissues. Despite stimulating the invasion and EMT, exogenous HDGF supply only partially attenuated the POMC-mediated invasion inhibition and EMT change in melanoma cells. Finally, we delineated the contribution of melanocortins to POMC-induced inhibition of invasion, HDGF downregulation, and E-cadherin upregulation. Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma.