Hmgb1 inhibits Klotho expression and malignant phenotype in melanoma cells by activating NF-κB
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Biao Xie1,2,*, Ke Cao3,*, Jinjin Li3, Jia Chen1, Jintian Tang4, Xiang Chen5, Kun Xia6, Xiao Zhou7, Yan Cheng8, Jianda Zhou1, Huiqing Xie9
1Deptment of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
2Department of Colorectal Surgery, Second Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan 410005, China
3Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
4Institute of Medical Physics and Engineering, Department of Engineering Physics, Tsinghua University, Beijing, 100084, China
5Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
6State Key Laboratory, Medical Genetic, Central South University, Changsha, Hunan 410008, China
7Department of Oncoplast & Reconstructure Surgery, Affiliated Tumor Hospital, Central South University, Changsha, Hunan 410013, China
8School of Pharmacy, Central South University, Changsha, Hunan 410013, China
9Department of Rehabilitation, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
*These authors have contributed equally to this work
Jianda Zhou, email: [email protected]
Huiqing Xie, email: [email protected]
Keywords: Hmgb1, NF-κB, melanoma, Klotho, insulin signaling
Received: March 01, 2016 Accepted: September 26, 2016 Published: October 13, 2016
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.
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