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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 18 Pg. 8478-91 (Sep 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25261367 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, 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, genetics, metabolism, 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, metabolism)
• Xenograft Model Antitumor Assays