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PMID: 25051367 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Overexpression of HMGB1 in melanoma predicts patient survival and suppression of HMGB1 induces cell cycle arrest and senescence in association with p21 (Waf1/Cip1) up-regulation via a p53-independent, Sp1-dependent pathway.

Oncotarget ·Vol. 5 ·No. 15 ·2014-08-15 ·Pages 6387-403

Li Q, Li J, Wen T, Zeng W, Peng C, Yan S, Tan J, Yang K, Liu S, Guo A, Zhang C, Su J, Jiang M, Liu Z, Zhou H, Chen X

Abstract

Although laboratory studies have implicated the high mobility group box 1 (HMGB1) in melanoma, its clinical relevance remains unclear. We analyzed nearly 100 cases of human melanoma and found that HMGB1 was highly overexpressed in melanoma samples relative to normal skin and nevi tissues. Significantly, higher levels of HMGB1 correlated with more advanced disease stages and with poorer survival in melanoma patients. Unlike the well-documented pro-inflammatory role of the extracellular HMGB1, we found that its intracellular activity is necessary for melanoma cell proliferation. An absolute dependency of melanoma cell proliferation on HMGB1 was underscored by the marked response of cell cycle arrest and senescence to HMGB1 knockdown. We demonstrated that HMGB1 deficiency-induced inhibition of cell proliferation was mediated by p21, which was induced via a Sp1-dependent mechanism. Taken together, our data demonstrate a novel oncogenic role of HMGB1 in promoting human melanoma cell proliferation and have important implications in melanoma patient care.

MeSH Terms
Animals Cell Cycle Checkpoints/physiology Cell Line, Tumor Cellular Senescence/physiology Cyclin-Dependent Kinase Inhibitor p21/genetics,metabolism Female HEK293 Cells HMGB1 Protein/biosynthesis,genetics Heterografts Humans Male Melanoma/genetics,metabolism,pathology Mice Mice, Inbred BALB C Mice, Nude Middle Aged Promoter Regions, Genetic Sp1 Transcription Factor/genetics,metabolism Survival Analysis Tumor Suppressor Protein p53/metabolism Up-Regulation
Chemicals
CDKN1A protein, human Cyclin-Dependent Kinase Inhibitor p21 HMGB1 Protein HMGB1 protein, human Sp1 Transcription Factor Sp1 protein, human TP53 protein, human Tumor Suppressor Protein p53
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Li Qingling
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Li Jie
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Wen Ting
Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
Zeng Weiqi
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Peng Cong
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Yan Siyu
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Tan Jieqiong
State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, 410008, China.
Yang Keda
Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China.
Liu Shuang
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Guo Aiyuan
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Zhang Chong
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Su Juan
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
Jiang Minghao
Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410013, China.
Liu Zhaoqian
Institute of Clinical Pharmacology, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
Zhou Honghao
Institute of Clinical Pharmacology, Xiangya School of Medicine, Central South University, Changsha, 410008, China.
Chen Xiang
Department of Dermatology; Xiangya Hospital, Central South University, Changsha, 410008, China.
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Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.2201
Published
2014-08-15
Pages
6387-403
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4171638
Subset
IM
External Links
PubMed source DOI: 10.18632/oncotarget.2201 PMC Full Text View journal details
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