title: Hmgb1 inhibits Klotho expression and malignant phenotype in melanoma cells by activating NF-κB.
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.
authors: Deptment of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.|Department of Colorectal Surgery, Second Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan 410005, China.
authors: Biao
authors: B
authors: Xie
authors: Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
authors: Ke
authors: K
authors: Cao
authors: Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
authors: Jinjin
authors: J
authors: Li
authors: Deptment of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
authors: Jia
authors: J
authors: Chen
authors: Institute of Medical Physics and Engineering, Department of Engineering Physics, Tsinghua University, Beijing, 100084, China.
authors: Jintian
authors: J
authors: Tang
authors: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors: Xiang
authors: X
authors: Chen
authors: State Key Laboratory, Medical Genetic, Central South University, Changsha, Hunan 410008, China.
authors: Kun
authors: K
authors: Xia
authors: Department of Oncoplast & Reconstructure Surgery, Affiliated Tumor Hospital, Central South University, Changsha, Hunan 410013, China.
authors: Xiao
authors: X
authors: Zhou
authors: School of Pharmacy, Central South University, Changsha, Hunan 410013, China.
authors: Yan
authors: Y
authors: Cheng
authors: Deptment of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
authors: Jianda
authors: J
authors: Zhou
authors: Department of Rehabilitation, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
authors: Huiqing
authors: H
authors: Xie
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D000090265:Klotho Proteins; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C000597236:IGF1R protein, human; D016328:NF-kappa B; D017451:Receptors, Somatomedin; C546842:MTOR protein, human; D058543:Class Ia Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Hmgb1; Klotho; NF-κB; insulin signaling; melanoma