Abstract
Melanoma originates from melanin-producing cells called melanocytes. Melanoma poses a great risk because of its rapid ability to spread and invade new organs. Cellular metastasis involves alteration in the gene expression profile and their transformation from epithelial to mesenchymal state. Despite of several advances, metastatic melanoma being a key cause of therapy failure and mortality remains poorly understood. p32 has been found to be involved in various physiological and pathophysiological conditions. However, the role of p32 in melanoma progression and metastasis remains underexplored. Here, we identify the role of p32 in the malignancy of both murine and human melanoma. p32 knockdown leads to reduced cell proliferation, migration, and invasion in murine and human melanoma cells. Furthermore, p32 promotes in vitro tumorigenesis, inducing oncogenes and EMT markers. Mechanistically, we show p32 regulates tumorigenic and metastatic properties through the Akt/PKB signaling pathway in both murine and human melanoma. Furthermore, p32 silencing attenuates melanoma tumor progression and lung metastasis in vivo, modulating the tumor microenvironment by inhibiting the angiogenesis, infiltration of macrophages, and leukocytes in mice. Taken together, our findings identify that p32 drives melanoma progression, metastasis, and regulates the tumor microenvironment. p32 can be a target of a novel therapeutic approach in the regulation of melanoma progression and metastasis.
Highlights
Melanoma is identified as one of the most invasive form of skin cancer derived from mutated melanin-producing cells or melanocytes, resides predominantly in the skin
We show the role of p32 in melanoma cell tumorigenesis both in mice and humans
In order to that mediate the p32-dependent in vitro tumorigenesis in melanoma identify the role of p32 in melanoma, we evaluated the expression cells, the phosphorylation levels of kinases were evaluated by levels of p32 in three different human melanoma SK-MEL-2, SK- immunoblot analysis in control and p32 shRNA transfected B16F10 MEL-28, and A375 cell lines through immunofluorescence and A375 cells. p32 knocking down decreased the phosphorylation (Supplementary Fig. 1) and further validated with western blot levels of Akt both in B16F10 and A375 cells and ERK in A375 cells as analysis (Supplementary Fig. 2A) and measuring transcript levels shown in immunoblot (Fig. 3A) and their densitometric quantification (Supplementary Fig. 2B) of p32 in these cells
Summary
Melanoma is identified as one of the most invasive form of skin cancer derived from mutated melanin-producing cells or melanocytes, resides predominantly in the skin. Metastasis is a complex process that modulates cancer cell’s ability to infiltrate into the vasculature including lymphatic vessels, migrate, and colonize at distant tissues/organs [4, 5]. Identification of biomarkers and the underlying mechanisms that regulate EMT will provide better insights of melanoma progression and metastasis [6]. Exogenous p32 promotes migration and invasion of melanoma cells [18]. The role of p32 in melanoma progression and metastasis remains poorly understood. We show the role of p32 in melanoma cell tumorigenesis both in mice and humans. P32 promotes tumorigenesis in mice and human melanoma cells by regulating the oncogenes expression, EMT markers, and Akt/protein kinase B (PKB) pathway activation. Our studies in in vivo mice models show that p32 promotes tumor progression and metastasis by controlling the tumor microenvironment
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