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
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Qingling Li1, Jie Li1, Ting Wen2, Weiqi Zeng1, Cong Peng1, Siyu Yan1, Jieqiong Tan3, Keda Yang4, Shuang Liu1, Aiyuan Guo1, Chong Zhang1, Juan Su1, Minghao Jiang5, Zhaoqian Liu6, Honghao Zhou6, Xiang Chen1
1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China
2 Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
3 State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, 410008, China
4 Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, China
5 Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, 410013, China
6 Institute of Clinical Pharmacology, Xiangya School of Medicine, Central South University, Changsha, 410008, China
Dr. Xiang Chen, e-mail: firstname.lastname@example.org
Dr. Jie Li, e-mail: email@example.com
Key words: high mobility group box 1; p53; p21; Sp1; melanoma
Received: April 25, 2014 Accepted: July 09, 2014 Published: July 15, 2014
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.
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