Sorafenib Down-regulates Expression of HTATIP2 to Promote Invasiveness and Metastasis of Orthotopic Hepatocellular Carcinoma Tumors in Mice

Zhang, Wei; Sun, Hui‐Chuan; Wang, Wenquan; Zhang, Qiangbo; Zhuang, Peng–Yuan; Xiong, Ye; Zhu, Xiao‐Dong; Xu, Huaxiang; Kong, Ling‐Bin; Wu, Wei‐Zhong; Wang, Lu; Song, Tianqiang; Li, Qiang; Tang, Zhao–You

doi:10.1053/j.gastro.2012.08.032

Cited by 83 publications

(97 citation statements)

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“…Orthotopic liver transplantation models were also performed according to standard procedures described previously. 25 At the end of study, mice were sacrificed and tumor tissues were collected, photographed, and weighted. All procedures were performed in accord with the guidelines established by the Shanghai Medical Experimental Animal Care Commission.…”

Section: Methodsmentioning

confidence: 99%

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

et al. 2015

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Hepatocellular carcinoma (HCC) is the third-most lethal cancer worldwide. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients' prognosis. In this study, we report that protein tyrosine phosphatase receptor S (PTPRS) is significantly down-regulated in nearly 80% of HCCs, and its expression negatively correlates with aggressive pathological features, such as larger tumor size and advanced stage. In addition, PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients, although 16.7% of HCCs show intratumor heterogeneous expression of PTPRS. Restoration of wild-type, but not mutant, PTPRS expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo, whereas knockdown of its expression significantly promotes invasion and metastasis. Notably, PTPRS-regulated HCC invasiveness is accompanied by typical changes of epithelial-mesenchymal transition (EMT). Moreover, PTPRS forms a complex with epithermal growth factor receptor (EGFR) and regulates its tyrosine residues' phosphorylation. Ectopic expression of EGFR reverses the metastasis-inhibiting effects of PTPRS, whereas silencing of EGFR or inhibiting phosphorylation of key molecules in EGFR downstream pathways reinhibits EMT and metastasis caused by PTPRS down-regulation. Meanwhile, promoter hypermethylation of PTPRS is frequently detected in HCC samples and cell lines. Treatment with a demethylation agent, 5-aza-2 0 -deoxycytidine, recovers PTPRS expression in a dose-dependent manner. Conclusions: Epigenetic inactivation of PTPRS may increase phosphorylation and activity of EGFR signaling to promote EMT and metastasis in HCC. (HEPATOLOGY 2015;62:1201-1214 H epatocellular carcinoma (HCC), epidemic to Asia and Africa with an increasing incidence in Western countries, is the third-leading cause of cancer-related deaths worldwide.1 Less than 30% of HCCs are diagnosed at an early stage and are amenable for resection, liver transplantation, or local ablation.2 In advanced cases, the only effective systemic therapy is the multikinase inhibitor, sorafenib, with a partial response of only 2.2% and median overall survival (OS) of 9.2 months.3 Apart from sorafenib, several novel targeted agents or regimens have been tested; however, none of them showed any positive results, mandating alternative effective treatments.4 Therefore, understanding of the driving events of HCC progression and metastasis is of

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Section: Methodsmentioning

confidence: 99%

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

et al. 2015

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“…Despite the success of sorafenib in the treatment of some patients with (27). Meanwhile, factors in the tumor and host microenvironment should also have been considered in the resistance of sorafenib, for studies have shown that progression-free survival under sorafenib treatment is significantly shorter in patients with high levels of angiogenin-2 (Ang-2) and granulocyte colonystimulating factor (G-CSF), and that as the number of cytokines present at high concentrations increases, the treatment response deteriorates (28).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant sorafenib reduced mortality and prolonged overall survival and post-recurrence survival in hepatocellular carcinoma patients after curative resection: A single-center experience

Zhang

Zhao

Wei

et al. 2014

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“…However, some studies also demonstrated that antiangiogenic drugs may, in some conditions, accelerate cancer progression. [68][69][70] Moreover, TAMs can be recruited when sorafenib is administered, thus promoting the progression of hepatocellular carcinoma. 71 Interestingly, recent studies showed that sorafenib exerts a potent effect on macrophages by inducing autophagy and suppressing the expression of CD80, a marker of the M1 phenotype, suggesting the possible correlation between autophagy and macrophage polarization and highlighting the protumorigenic effect of sorafenib through modulation of macrophage polarization by autophagy.…”

Section: Autophagy-mediated Control Of Macrophage Polarizationmentioning

confidence: 99%

Autophagy-mediated regulation of macrophages and its applications for cancer

2013

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Sorafenib Down-regulates Expression of HTATIP2 to Promote Invasiveness and Metastasis of Orthotopic Hepatocellular Carcinoma Tumors in Mice

Cited by 83 publications

References 40 publications

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

Adjuvant sorafenib reduced mortality and prolonged overall survival and post-recurrence survival in hepatocellular carcinoma patients after curative resection: A single-center experience

Autophagy-mediated regulation of macrophages and its applications for cancer

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