Suberoylanilide Hydroxamic Acid (SAHA) Reduces Fibrosis Markers and Deactivates Human Stellate Cells via the Epithelial–Mesenchymal Transition (EMT)

2021 ◽  
Author(s):  
Merve Özel ◽  
Mevlut Baskol ◽  
Hilal Akalın ◽  
Gulden Baskol
Keyword(s):  
Hydroxamic Acid ◽  
Epithelial Mesenchymal Transition ◽  
Stellate Cells ◽  
Suberoylanilide Hydroxamic Acid ◽  
Mesenchymal Transition

The effect of hepatic stellate cells on hepatocellular carcinoma progression.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 265-265
Author(s):  
Shuichi Iwahashi ◽  
Mitsuo Shimada ◽  
Yuji Morine ◽  
Satoru Imura ◽  
Tetsuya Ikemoto ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Stellate Cells ◽  
Stem Cell Marker ◽  
Cell Marker ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
And Migration ◽  
E Cadherin

265 Background: The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Some manuscripts mentioned that activated HSCs predicted prognoses of hepatocellular carcinoma. The aim of this study is to investigate the effect of HSCs and the role of IL-6 / Stat3 pathway on HCC progression. Methods: HCC cells (Hep G2 and Huh 7) were co-cultured with HSC (LX2 and Li90). The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44), TGF-b and p-STAT3 of cancer cells were evaluated. Then the IL-6 neutralization was performed during HCC cells and HSCs co-culture. The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44) and p-STAT3 of cancer cells were evaluated. Results: Co-culture with hepatic stellate cell increased cancer cell viability and migration ability. The expression of E-cadherin, EpCAM and CD44 of cancer cells also increased after co-culture with HSCs. The IL-6 expression and secretion of HSCs were elevated by cancer cell stimulation. The over-expressed IL-6 activated STAT3 of cancer cell showed as the level of phosphorylated STAT3 increased. Neutralized IL-6 during co-culture significantly decrease the viability and migration ability of cancer cells. Also, the expression of E-cadherin, EpCAM and CD44 of cancer cells decreased. Conclusions: HSCs might promote HCC progression through IL-6 / STAT3 pathway.

scholarly journals GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1459-1471
Author(s):  
Gengming Niu ◽  
Xiaotian Zhang ◽  
Runqi Hong ◽  
Ximin Yang ◽  
Jiawei Gu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Conditioned Medium ◽  
Hepatic Stellate Cells ◽  
Hepatic Cirrhosis ◽  
Epithelial Mesenchymal Transition ◽  
Stellate Cells ◽  
Gene Set Enrichment Analysis ◽  
Mesenchymal Transition ◽  
And Migration ◽  
Proliferation And Migration

Abstract Introduction Gap junction protein, alpha 1 (GJA1), which is correlated with recurrences and unfavorable prognoses in hepatocellular carcinomas (HCCs), is one of the specific proteins expressed by activated hepatic stellate cells (HSCs). Methods Expression of GJA1 was compared between HCCs and nontumor tissues (NTs), between hepatic cirrhosis and NTs, and between primary and metastatic HCCs using transcriptomic datasets from the Gene Expression Omnibus and the Integrative Molecular Database of Hepatocellular Carcinoma. The in vitro activities of GJA1 were investigated in cultured HSCs and HCC cells. The underlying mechanism was characterized using Gene Set Enrichment Analysis and validated by western blotting. Results The expression of GJA1 was significantly increased in HCCs and hepatic cirrhosis compared to that in NTs. GJA1 was also overexpressed in pulmonary metastases from HCCs when compared with HCCs without metastasis. Overexpression of GJA1 promoted while knockdown of GJA1 inhibited proliferation and transforming growth factor (TGF)-β-mediated activation and migration of cultured HSCs. Overexpression of GJA1 by lentivirus infection promoted proliferation and migration, while conditioned medium from HSCs overexpressing GJA1 promoted migration but inhibited proliferation of Hep3B and PLC-PRF-5 cells. Lentivirus infection with shGJA1 or conditioned medium from shGJA1-infected HSCs inhibited the proliferation and migration of HCCLM3 cells that had a high propensity toward lung metastasis. Mechanistically, GJA1 induced the epithelial–mesenchymal transition (EMT) in HSCs and HCCLM3 cells. Conclusion GJA1 promoted HCC progression by inducing HSC activation and the EMT in HSCs. GJA1 is potentially regulated by TGF-β and thus may be a therapeutic target to inhibit HCC progression.

scholarly journals Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1362 ◽  
Author(s):  
Wenwen Wang ◽  
Min Yan ◽  
Qiuhong Ji ◽  
Jinbiao Lu ◽  
Yuhua Ji ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Hydroxamic Acid ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Cdna Array ◽  
Stellate Cells ◽  
Type I ◽  
Suberoylanilide Hydroxamic Acid

Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I andα-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.

Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals

2016 ◽  
Vol 397 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Shao Wu ◽  
Zhi Luo ◽  
Peng-Jiu Yu ◽  
Hui Xie ◽  
Yu-Wen He
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Histone Deacetylases ◽  
Hydroxamic Acid ◽  
Triple Negative ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Cancer Agent

Abstract Inhibitor of histone deacetylases (HDACIs) have great therapeutic value for triple negative breast cancer (TNBC) patients. Interestingly, our present study reveals that suberoyl anilide hydroxamic acid (SAHA), one of the most advanced pan-HDAC inhibitor, can obviously promote in vitro motility of MDA-MB-231 and BT-549 cells via induction of epithelial-mesenchymal transition (EMT). SAHA treatment significantly down-regulates the expression of epithelial markers E-cadherin (E-Cad) while up-regulates the mesenchymal markers N-cadherin (N-Cad), vimentin (Vim) and fibronectin (FN). However, SAHA has no effect on the expression and nuclear translocation of EMT related transcription factors including Snail, Slug, Twist and ZEB. While SAHA treatment down-regulates the protein and mRNA expression of FOXA1 and then decreases its nuclear translocation. Over-expression of FOXA1 markedly attenuates SAHA induced EMT of TNBC cells. Further, silence of HDAC8, while not HDAC6, alleviates the down-regulation of FOXA1 and up-regulation of N-Cad and Vim in MDA-MB-231 cells treated with SAHA. Collectively, our present study reveals that SAHA can promote EMT of TNBC cells via HDAC8/FOXA1 signals, which suggests that more attention should be paid when SAHA is used as anti-cancer agent for cancer treatment.

scholarly journals Liver fibrosis mechanisms – the role of stellate cells, oxidative and nitrosative stress

2019 ◽  
Vol 73 ◽  
pp. 1-19
Author(s):  
Grażyna Czechowska ◽  
Krzysztof Celiński ◽  
Grażyna Wójcicka
Keyword(s):  
Liver Fibrosis ◽  
Proinflammatory Cytokines ◽  
Nitrosative Stress ◽  
Epithelial Mesenchymal Transition ◽  
Cell Cancer ◽  
Stellate Cells ◽  
Biliary Duct ◽  
Oxidative And Nitrosative Stress ◽  
Mesenchymal Transition ◽  
Therapeutic Goals

Liver fibrosis is a chronic and complex pathological process, occuring in patients with chronic liver diseases. The most common cause of liver fibrosis is the alcoholic liver disease, viral hepatitis type B, C and D, as well as autoimmune diseases. Other causes include metabolic dysfunctions like hemachromatosis and Wilson’s disease, biliary duct disorders, damaging effects of medicine and parasite infections. Fibrosis’ dynamics and progres speed depend on the nature of underlying mechanisms and are characterized by accumulation of ECM elements. They vary from patient to patient and are directly correlated to aberrations of homeostasis degradation and production of liver connective tissue. In liver fibrosis the main source of ECM are hepatic stellate cells (HSCS), although other cells are also able to produce ECM such as: portal fibroblasts, narrow-derived cells, biliary duct epithelial cells and epithelial mesenchymal transition hepatocytes. The HSCS activity is stimulated by proinflammatory cytokines, oxidative and nitrosative stress which lead to different pathologies such as: inflammation, steatosis, fibrosis, cirrhosis, liver-cell cancer. Alcohol, the main fibrotic agents is metabolized almost entirely in the liver, so the organ is extremely sensitive to its negative intermediate and mediate influence. Factors influencing alcoholic liver failure are not only oxidative and nitrosative stress and proinflammatory cytokines activity, but also reductive stress, hepatocytes; hypoxia, mucous membranę dysfunction and intestine flora influence, as well as genetic and immunological factors. Though in last several yers there has been a great advancement in our knowledge of liver fibrosis mechanisms, it remains tough to diagnose the proces in its early stages and consequently apply an efficient therapy. The challenge for the futur is finding useful biomarkers and new therapeutic goals.

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