The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-Myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway

Jiabei Wang; Dalong Yin; Changming Xie; Tongsen Zheng; Yingjian Liang; Xuehui Hong; Zhaoyang Lu; Xuan Song; Ruipeng Song; Haiyan Yang; Boshi Sun; Nishant Bhatta; Xianzhi Meng; Shangha Pan; Hongchi Jiang; Lianxin Liu

doi:10.18632/oncotarget.2328

The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-Myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway

Oncotarget. 2014 Sep 30;5(18):8478-91. doi: 10.18632/oncotarget.2328.

Authors

Affiliations

¹ Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, Heilongjiang Province, China. These authors contributed equally to this work.
² Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, Heilongjiang Province, China.
³ Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, Heilongjiang Province, China. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.

Abstract

Here we showed that hepatocellular carcinoma (HCC) cell lines with high metastatic potential had low levels of NDRG2. The iron chelator Dp44mT up-regulated NDRG2, suppressed epithelial-mesenchymal transition (EMT) and inhibited tumor metastasis in HCC having high metastatic potential. Also Dp44mT attenuated the TGF-β1-induced EMT in HCC having low metastatic potential. In agreement, silencing endogenous NDRG2 with shNDRG2 in HCC cells attenuated the effect of Dp44mT. We showed that the NDRG2/gp130/STAT3 pathway can mediate Dp44mT effects. In agreement, we found that a combination of NDRG2 expression and p-STAT3 levels is a strong predictor of prognosis in HCC patients. We suggest that up-regulation of NDRG2 by Dp44mT is a promising therapeutic approach in HCC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / secondary
Cell Line, Tumor
Cell Movement / drug effects*
Cytokine Receptor gp130 / metabolism*
Epithelial-Mesenchymal Transition / drug effects
Female
Gene Expression Regulation, Neoplastic
Humans
Iron Chelating Agents / pharmacology*
Liver Neoplasms / drug therapy*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Male
Mice, Nude
Middle Aged
Neoplasm Invasiveness
Phosphorylation
RNA Interference
STAT3 Transcription Factor / metabolism*
Signal Transduction / drug effects
Thiosemicarbazones / pharmacology*
Time Factors
Transfection
Transforming Growth Factor beta1 / pharmacology
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
IL6ST protein, human
Iron Chelating Agents
NDRG2 protein, human
STAT3 Transcription Factor
STAT3 protein, human
TGFB1 protein, human
Thiosemicarbazones
Transforming Growth Factor beta1
Tumor Suppressor Proteins
di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone
Cytokine Receptor gp130