HIF-1a Plays a Role in the Chemotactic Migration of Hepatocarcinoma Cells Through the Modulation of CXCL6 Expression

Tian, Hui; Huang, Peixin; Zhao, Zhiying; Tang, Wenyi; Xia, Jinglin

doi:10.1159/000366357

Cited by 42 publications

(23 citation statements)

References 35 publications

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“…The half of new cases of death occurs in China every year [1][2][3]. The prognosis of patients with HCC is poor and once HCC invades other organs and tissues or spreads distantly, the clinical outcome may be even worse [4][5].…”

Section: Introductionmentioning

confidence: 99%

HULC and Linc00152 Act as Novel Biomarkers in Predicting Diagnosis of Hepatocellular Carcinoma

Wang

Tang

et al. 2015

Cell Physiol Biochem

194

151

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Background/Aims: The alterations of long non-coding RNAs (lncRNAs) are related to multiple diseases. They can be detected in plasma as biomarkers for the diagnosis of multiple diseases. In this study, we aimed to determine the expression of circulating lncRNAs in human, which may be promising biomarkers for the diagnosis of hepatocellular carcinoma (HCC). Methods: Eight lncRNAs were chosen as candidates on the basis of the literature to evaluate the diagnostic value and accuracy of the plasma lncRNA profiling system. The candidate lncRNAs were validated by qRT-PCR arranged in the training and validation sets. Additional double-blind testing was performed in 20 patients clinically suspected of having HCC. Results: Circulating HULC and Linc00152 were significantly up-regulated in plasma samples of HCC patients during training set and validation set. Areas under the receiver operating characteristic (ROC) curves of the validated two lncRNAs signature were 0.78 and 0.85, respectively. Combination of HULC and Linc00152 possessed a moderate ability to discrimination between HCC and control with an area under ROC value of 0.87 while the combination of AFP was 0.89 with a positive correlation with tissues expression. Conclusions: Our results suggest that both plasma levels of HULC and Linc00152 achieve a fine diagnostic accuracy in diagnosing ontogenesis and metastasis of HCC and may act as novel biomarkers for HCC.

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Section: Introductionmentioning

confidence: 99%

HULC and Linc00152 Act as Novel Biomarkers in Predicting Diagnosis of Hepatocellular Carcinoma

Wang

Tang

et al. 2015

Cell Physiol Biochem

194

151

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“…Hypoxia may activate various transcription factors, such as hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) in order to regulate gene expression and cellular signaling [13]. HIF1α modulates the EMT in several cell lines; HIF1α-induced EMT is involved in cancer progression, metastasis, and organ fibrosis [14,15,16,17]. In addition, transforming growth factor-β (TGF-β) signal transduction might play a pivotal role in HSC activation by HIF1α [18,19].…”

Section: Introductionmentioning

confidence: 99%

TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition

Kim

Park

Kim

et al. 2016

Cell Physiol Biochem

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Background/Aims: Hypoxia is an environmental factor that aggravates liver fibrosis. HIF1α activates hepatic stellate cells (HSCs) and increases transforming growth factor-β (TGF-β) signaling and the epithelial mesenchymal transition (EMT), accelerating the progression of fibrosis. We evaluated the anti-fibrotic therapeutic potential of a small-molecule inhibitor of TGF-β type I receptor kinase, EW-7197, on HIF1α-derived TGF-β signaling in cholestatic liver fibrosis. Methods: We used a bile duct ligation (BDL)-operated rat model to characterize the role of HIF1α-derived TGF-β signaling in liver fibrosis. Cellular assays were performed in LX-2 cells (human immortalized HSCs). The anti-fibrotic effects of EW-7197 in liver tissues and HSCs were investigated via biochemical assays, immunohistochemistry (IHC), immunofluorescence (IF), chromatin immunoprecipitation (ChIP) assays, real-time PCR, and western blotting. Results: In our BDL rat model, orally administered EW-7197 inhibited fibrosis and attenuated HIF1α-induced activation of HSCs and EMT in vivo. In addition, EW-7197 inhibited HIF1α-derived HSC activation and expression of EMT markers in LX-2 cells in vitro. Conclusion: This study suggests that EW-7197 exhibits potential as a treatment for liver fibrosis because it inhibits HIF1α-induced TGF-β signaling.

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“…27,28 During tumor development, HIF1 induces various cytokines, such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-2, transforming growth factor alpha (TGF-α), and interleukin-6/8, which stimulate angiogenesis, proliferation, and invasion. [29][30][31][32] Besides, under hypoxia condition, HIF1α was found to enhance the transcription of multidrug resistance (MDR)-related genes in HepG2 cells, conferring chemoresistance. 33 In this study, our findings revealed that HIF1α conferred the role of HDAC5 in accelerating the EMT of HCC cells, as shown by increased N-cadherin and Vimentin but reduced E-cadherin.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

Ye¹,

Fang²,

Gu³

et al. 2017

Tumour Biol.

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Hypoxia plays a critical role in the progression and metastasis of hepatocellular carcinoma by activating the key transcription factor, hypoxia-inducible factor-1. This study aims to identify the novel mechanisms underlying the dysregulation of hypoxia-inducible factor-1α in hepatocellular carcinoma. We found that histone deacetylase 5, a highly expressed histone deacetylase in hepatocellular carcinoma, strengthened the migration and invasion of hepatocellular carcinoma cells under hypoxia but not normoxia condition. Furthermore, histone deacetylase 5 induced the transcription of hypoxia-inducible factor-1α by silencing homeodomain-interacting protein kinase-2 expression, which was also dependent on hypoxia. And then knockdown of hypoxia-inducible factor-1α decreased the expressions of mesenchymal markers, N-cadherin, and Vimentin, as well as matrix metalloproteinases, MMP7 and MMP9; however, the epithelial marker, E-cadherin, increased. Phenotype experiments showed that the migration and invasion of hepatocellular carcinoma cells were impaired by knockdown of histone deacetylase 5 or hypoxia-inducible factor-1α but rescued when eliminating homeodomaininteracting protein kinase-2 in hepatocellular carcinoma cells, which suggested the critical role of histone deacetylase 5-homeodomain-interacting protein kinase-2-hypoxia-inducible factor-1α pathway in hypoxia-induced metastasis. Finally, clinical analysis confirmed the positive correlation between histone deacetylase 5 and hypoxia-inducible factor-1α in hepatocellular carcinoma specimens and a relatively poor prognosis for the patients with high levels of histone deacetylase 5 and hypoxia-inducible factor-1α. Taken together, our findings demonstrated a novel mechanism underlying the crosstalk between histone deacetylase 5 and hypoxia-inducible factor-1 in hepatocellular carcinoma.

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HIF-1a Plays a Role in the Chemotactic Migration of Hepatocarcinoma Cells Through the Modulation of CXCL6 Expression

Cited by 42 publications

References 35 publications

HULC and Linc00152 Act as Novel Biomarkers in Predicting Diagnosis of Hepatocellular Carcinoma

HULC and Linc00152 Act as Novel Biomarkers in Predicting Diagnosis of Hepatocellular Carcinoma

TGF-β Type I Receptor Kinase Inhibitor EW-7197 Suppresses Cholestatic Liver Fibrosis by Inhibiting HIF1α-Induced Epithelial Mesenchymal Transition

Histone deacetylase 5 promotes the migration and invasion of hepatocellular carcinoma via increasing the transcription of hypoxia-inducible factor-1α under hypoxia condition

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