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.

scholarly journals Interleukin-8 Promotes Epithelial-to-Mesenchymal Transition via Downregulation of Mir-200 Family in Breast Cancer Cells

2020 ◽  
Vol 19 ◽  
pp. 153303382097967
Author(s):  
Jin Zhang ◽  
Nan Shao ◽  
Xiaoyu Yang ◽  
Chuanbo Xie ◽  
Yawei Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Cancer Cell Line ◽  
Control Group ◽  
Mesenchymal Transition ◽  
Mcf 7

The microRNA-200 (miR-200) family has been reported to be vital for the inhibition of epithelial-to-mesenchymal transition (EMT) in tumor cells. The miR-200 family represents a complex multi-factorial regulatory network which has not been well described in breast cancer. This study aimed to clarify the underlying regulatory association between IL-8 and miR-200 family in the process of EMT in breast cancer cell. In estrogen-receptor (ER) positive breast cancer cell line MCF-7, IL-8 overexpression cells were performed by lentivirus transfection as endogenous regulation with additional exogenous IL-8 stimulation. Transient overexpressions of miR-200 family were performed after endogenous or exogenous IL-8 overexpression in MCF-7 cells. IL-8 knockdown cells were constructed via siRNA and shRNA transfection in triple negative breast cancer cell line MDA-MB-231. N-cadherin, vimentin and ZEB2 were down-regulated and E-cadherin was up-regulated in IL-8 knockdown group compared with control group. On the other hand, N-cadherin, vimentin and ZEB2 were up-regulated and E-cadherin was down-regulated in IL-8 overexpression group compared with control group. This indicated IL-8 promotes EMT in breast cancer cells. Transwell assay showed that IL-8 increased the migration and invasiveness of tumor cells. Furthermore, we performed transient overexpression of miR-200 family after endogenous or exogenous IL-8 overexpression in MCF-7 cells, which showed that the miR-200 family could inhibit EMT induced by IL-8. IL-8 promoted EMT via downregulation of miR-200 family expression in breast cancer cells and increases tumor cell migration and invasion.

scholarly journals Rab31-dependent regulation of transforming growth factor ß expression in breast cancer cells

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Susanne Soelch ◽  
Nathalie Beaufort ◽  
Daniela Loessner ◽  
Matthias Kotzsch ◽  
Ute Reuning ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Cancer Cell Line ◽  
Underlying Mechanism ◽  
Mrna Levels ◽  
Down Regulation ◽  
Mesenchymal Transition

Abstract Background The small GTP-binding protein Rab31 plays an important role in the modulation of tumor biological-relevant processes, including cell proliferation, adhesion, and invasion. As an underlying mechanism, Rab31 is presumed to act as a molecular switch between a more proliferative and an invasive phenotype. This prompted us to analyze whether Rab31 overexpression in breast cancer cells affects expression of genes involved in epithelial-to-mesenchymal transition (EMT)-like processes when compared to Rab31 low-expressing cells. Methods Commercially available profiler PCR arrays were applied to search for differentially expressed genes in Rab31 high- and low-expressing CAMA-1 breast cancer cells. Differential expression of selected candidate genes in response to Rab31 overexpression in CAMA-1 cells was validated by independent qPCR and protein assays. Results Gene expression profiling of key genes involved in EMT, or its reciprocal process MET, identified 9 genes being significantly up- or down-regulated in Rab31 overexpressing CAMA-1 cells, with the strongest effects seen for TGFB1, encoding TGF-ß1 (> 25-fold down-regulation in Rab31 overexpressing cells). Subsequent validation analyses by qPCR revealed a strong down-regulation of TGFB1 mRNA levels in response to increased Rab31 expression not only in CAMA-1 cells, but also in another breast cancer cell line, MDA-MB-231. Using ELISA and Western blot analysis, a considerable reduction of both intracellular and secreted TGF-ß1 antigen levels was determined in Rab31 overexpressing cells compared to vector control cells. Furthermore, reduced TGF-ß activity was observed upon Rab31 overexpression in CAMA-1 cells using a sensitive TGF-ß bioassay. Finally, the relationship between Rab31 expression and the TGF-ß axis was analyzed by another profiler PCR array focusing on genes involved in TGF-ß signaling. We found 12 out of 84 mRNAs significantly reduced and 7 mRNAs significantly increased upon Rab31 overexpression. Conclusions Our results demonstrate that Rab31 is a potent modulator of the expression of TGF-ß and other components of the TGF-ß signaling pathway in breast cancer cells.

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

DLC-1 down-regulation via exosomal miR-106b-3p exchange promotes CRC metastasis by the epithelial-to-mesenchymal transition

2020 ◽  
Vol 134 (8) ◽  
pp. 955-959 ◽  
Author(s):  
Francesco Mannavola ◽  
Gaetano Pezzicoli ◽  
Marco Tucci
Keyword(s):  
Colorectal Cancer ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Prognostic Biomarker ◽  
Great Effort ◽  
Down Regulation ◽  
Potential Implication ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms

Abstract Exosomes (Exo) have emerged as potent amplifiers of pro-tumorigenic signals to distant cells. The knowledge of their role in colorectal cancer (CRC) is continuously up-growing, although their contribution to metastasis remains largely unclear. Liu et al. (Clinical Science (2020) 134, https://doi.org/10.1042/CS20191087) in their work have described a novel mechanism by which CRC-derived Exo promote metastasis through the down-regulation of the deleted in liver cancer-1 (DLC-1), a gene involved in the epithelial-to-mesenchymal transition (EMT) event in cancer cells. The Authors also demonstrated an increase in serum exosomal miR-106b-3p in patients with metastatic CRC, suggesting its potential implication as a prognostic biomarker. These findings may be of great effort in clarifying the underlying mechanisms of CRC metastasis and provide new targets for future researches.

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