Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth

2013 ◽  
Vol 329 (1) ◽  
pp. 74-83 ◽  
Author(s):  
Hannah van Malenstein ◽  
Jeroen Dekervel ◽  
Chris Verslype ◽  
Eric Van Cutsem ◽  
Petra Windmolders ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Liver Cancer Cells

scholarly journals Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2883 ◽  
Author(s):  
Keiko Takagi ◽  
Yutaka Midorikawa ◽  
Tadatoshi Takayama ◽  
Hayato Abe ◽  
Kyoko Fujiwara ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Cancer Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Grade ◽  
Expression Level ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Liver Cancer Cells ◽  
Tgf Β1

Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. In liver cancer, transforming growth factor (TGF)-β expression is correlated with tumor grade, and high-grade liver cancer tissues express epithelial-mesenchymal transition markers. TGF-β1 was reported to be involved in cancer development by transforming precancer cells to cancer stem cells (CSCs). This study aimed to evaluate the effects of TGF-β1-targeting PI polyamide on the growth of liver cancer cells and CSCs and their TGF-β1 expression. We analyzed TGF-β1 expression level after the administration of GB1101, a PI polyamide that targets human TGF-β1 promoter, and examined its effects on cell proliferation, invasiveness, and TGF-β1 mRNA expression level. GB1101 treatment dose-dependently decreased TGF-β1 mRNA levels in HepG2 and HLF cells, and inhibited HepG2 colony formation associated with downregulation of TGF-β1 mRNA. Although GB1101 did not substantially inhibit the proliferation of HepG2 cells compared to untreated control cells, GB1101 significantly suppressed the invasion of HLF cells, which displayed high expression of CD44, a marker for CSCs. Furthermore, GB1101 significantly inhibited HLF cell sphere formation by inhibiting TGF-β1 expression, in addition to suppressing the proliferation of HLE and HLF cells. Taken together, GB1101 reduced TGF-β1 expression in liver cancer cells and suppressed cell invasion; therefore, GB1101 is a novel candidate drug for the treatment of liver cancer.

scholarly journals P4HB modulates epithelial‑mesenchymal transition and the β‑catenin/Snail pathway influencing chemoresistance in liver cancer cells

2020 ◽  
Vol 20 (1) ◽  
pp. 257-265
Author(s):  
Xing Ma ◽  
Jiening Wang ◽  
Juhua Zhuang ◽  
Xiaokun Ma ◽  
Ni Zheng ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Liver Cancer Cells

scholarly journals SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors -1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1933
Author(s):  
Stefania Cannito ◽  
Beatrice Foglia ◽  
Gianmarco Villano ◽  
Cristian Turato ◽  
Teresa C Delgado ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Therapeutic Targets ◽  
Cancer Cell Line ◽  
Cysteine Protease Inhibitor ◽  
Knock Out ◽  
Mesenchymal Transition

Background: SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2α-dependent cysteine-protease inhibitor up-regulated in hepatocellular carcinoma (HCC), released by cancer cells and able to stimulate proliferation and epithelial-to-mesenchymal-transition. Methods: In the study we employed transgenic and knock out SerpinB3 mice, liver cancer cell line, human HCC specimens, and mice receiving diethyl-nitrosamine (DEN) administration plus choline-deficient L-amino acid refined (CDAA) diet (DEN/CDAA protocol). Results: We provide detailed and mechanistic evidence that SB3 can act as a paracrine mediator able to affect the behavior of surrounding cells by differentially up-regulating, in normoxic conditions, HIF-1α and HIF-2α. SB3 acts by (i) up-regulating HIF-1α transcription, facilitating cell survival in a harsh microenvironment and promoting angiogenesis, (ii) increasing HIF-2α stabilization via direct/selective NEDDylation, promoting proliferation of liver cancer cells, and favoring HCC progression. Moreover (iii) the highest levels of NEDD8-E1 activating enzyme (NAE1) mRNA were detected in a subclass of HCC patients expressing the highest levels of HIF-2α transcripts; (iv) mice undergoing DEN/CDAA carcinogenic protocol showed a positive correlation between SB3 and HIF-2α transcripts with the highest levels of NAE1 mRNA detected in nodules expressing the highest levels of HIF-2α transcripts. Conclusions: These data outline either HIF-2α and NEDDylation as two novel putative therapeutic targets to interfere with the procarcinogenic role of SerpinB3 in the development of HCC.

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