Abstract
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.
Highlights
Cutaneous melanoma, which begins with benign nevi and progresses to radial and vertical growth, is one of the fastest increasing malignancies worldwide [1]
The novel findings of the present study are: (i) that systemic POMC gene delivery by posttreatment shows that significant retards lung metastasis via reduced tumor invasion, colonization, and angiogenesis in established melanoma
The systemic POMC expression seems tolerable given no obvious changes in body weight and feeding behavior was observed in mice receiving POMC therapy. (ii) Our findings show that POMC gene delivery potentially inhibits epithelial–mesenchymal transition (EMT) change by E-cadherin upregulation and vimentin, a-smooth muscle actin (a-SMA) downregulation, which contributes to tumor cell invasion and metastasis in melanoma in vitro and in vivo. (iii) Through the microarray www.aacrjournals.org analysis, our data suggest that POMC gene delivery decreased the expression of hepatoma-derived growth factor (HDGF), which contribute to inhibition of tumor invasion via reducing EMT change
Summary
Cutaneous melanoma, which begins with benign nevi and progresses to radial and vertical growth, is one of the fastest increasing malignancies worldwide [1]. We have recently shown that HDGF overexpression promoted epithelial-to-mesenchymal transition (EMT) by E-cadherin downregulation and vimentin upregulation, thereby promoting the invasion and metastasis in breast cancer cell [15]. Recent studies indicate that the anti-inflammatory POMC therapy effectively suppresses the growth of murine primary tumors, including B16-F10 [20, 21] and Lewis lung carcinoma [22]. A recent study has indicated that prophylactic a-MSH treatment decreased the metastatic potential of melanoma cells in vitro and in vivo [27]. These findings suggested that peripheral POMC expression may inhibit invasive and metastasis. Microarray analysis was used to identify the involvement of HDGF downregulation in POMC-induced metastasis suppression
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