Abstract
The molecular and cellular mechanisms behind the involvement of inflammation in melanoma have not been fully elucidated. In this study, knockdown of Hmgb1 expression increased apoptosis, reduced invasion and p-NF-κB expression, but increased Klotho protein level in melanoma tumor cells. The effect of Hmgb1 knockdown was overcome by LPS. Introduction of exogenous Hmgb1 significantly decreased apoptosis, increased invasion, elevated p-NF-κB, but lowered Klotho protein level in melanoma cells. The effect of exogenous Hmgb1 was agonized by NF-κB inhibitor CAPE. Hmgb1 knockdown activated, but exogenous Hmgb1 inactivated, p-IGF1R/p-PI3K p-85/p-Akt/p-mTOR signaling. Knockdown of Klotho gene expression significantly decreased apoptosis, increased invasion in melanoma cells, and inhibited xenograft A375 tumor growth. A significantly high percentage of cells stained positive for p-NF-κB, but negative for Klotho, in melanoma tissues compared to normal and benign skin tissues. The positive p-NF-κB and negative Klotho protein expression correlated with poor prognosis in melanoma patients. Multivariate analysis revealed an independent association between p-NF-κB / Klotho protein level and overall survival. In conclusion, Hmgb1 can inhibit Klotho gene expression and malignant phenotype in melanoma cells through activation of NF-κB signaling.
Highlights
Melanoma is a highly malignant tumor that is associated with the deaths of 50,000 people worldwide each year [1]
Western blot showed that low Klotho protein expression and high Hmgb1 protein expression were detected in WM35 and WM451 cells, whereas high Klotho protein expression and low Hmgb1 protein expression were detected in SK28 and A375 cells (Figure 1A)
The Transwell assay in A375 (Figure 1D, 1E) and SK-28 (Figure 1D, 1F) cells showed that shHmgb1 transfection significantly reduced invasion, whereas LPS treatment significantly increased cell invasion compared to NC and BC cells (p
Summary
Melanoma is a highly malignant tumor that is associated with the deaths of 50,000 people worldwide each year [1]. The incidence of melanoma is increasing worldwide [2]. The molecular mechanisms driving melanoma carcinogenesis and progression have not been fully elucidated. Many tumors develop as a result of inflammation, and many biological characteristics of tumors exhibit a close relationship with the biological processes of inflammation [3]. NF-κB is an important nuclear transcription factor involved in tumor inflammation and development [4]. NF-κB can stimulate the expression of various cytokines and chemokines involved in epithelial cell growth and activity [5].
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