HMGB1 promotes HCC progression partly by downregulating p21 via ERK/c-Myc pathway and upregulating MMP-2.
High-mobility group box 1 (HMGB1) was found to be over-expressed in many kinds of human cancer, which binds with several receptors and activates RAGE-Ras-MAPK, Toll-like receptors, NF-κB, and Src family kinase signaling pathways and plays a crucial role in tumorigenesis and cancer progression. However, the function and mechanism of HMGB1 in hepatocellular carcinoma (HCC) remain unclear. The aim of this study was to investigate the effect of HMGB1 on HCC progression and explore new molecular mechanism. HMGB1 transient knockdown, stable knockdown, and re-expression were performed by transfection with specific siRNA, shRNA, or expression vector in HCCLM3 cells. Results showed that transient knockdown HMGB1 prevented cell proliferation, promoted apoptosis, induced S phase arrest, and inhibited migration and invasion in vitro, and stable knockdown HMGB1 inhibited xenograft growth in Balb/c athymic mice in vivo. Molecular mechanism investigation revealed that knockdown HMGB1 significantly reduced the activation of MAPKs, including ERK1/2, p38, SAPK/JNK, as well as MAPKKs (MEK1/2, SEK1) and its substrates (c-Jun, c-Myc); downregulated NF-κB/p65 expression and phosphorylation level; decreased MMP-2 expression and activity; and upregulated p21 expression. Interestingly, c-Myc was firstly found to be involved in the promoting function of HMGB1 on HCC progression, which provided a novel clue for the inhibitory effect of HMGB1 on p21 expression by a p53-independent pathway. Collectively, these findings indicated that HMGB1 promoted HCC progression partly by enhancing the ERK1/2 and NF-κB pathways, upregulating MMP-2, and downregulating p21 via an ERK/c-Myc pathway.
Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Yixueyuan Rd 138, Shanghai, 200032, China.
Yanmei
Y
Chen
Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Yixueyuan Rd 138, Shanghai, 200032, China.
Chengzhao
C
Lin
Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Yixueyuan Rd 138, Shanghai, 200032, China.
Yang
Y
Liu
Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Yixueyuan Rd 138, Shanghai, 200032, China. jiangyan515@fudan.edu.cn.|Department of Chemistry, Fudan University, Shanghai, China. jiangyan515@fudan.edu.cn.
Yan
Y
Jiang
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D024243:HMGB1 Protein; C489427:MYC protein, human; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D020778:Matrix Metalloproteinase 2
HCC; HMGB1; MAPKs; MMP-2; c-Myc; p21