HIF-1α-induced RIT1 promotes liver cancer growth and metastasis and its deficiency increases sensitivity to sorafenib

Song, Zhen; Liu, Tengfei; Chen, Jing; Ge, Chao; Zhao, Fangyu; Zhu, Ming; Chen, Taoyang; Cui, Ying; Tian, Hua; Yao, Ming; Li, Jinjun; Li, Hong

doi:10.1016/j.canlet.2019.06.016

Cited by 60 publications

(51 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The process of carbohydrate biosynthesis was mainly related to the energy metabolism of cancer cells. HIF-1 and its related genes actively promoted HCC growth, HCC cell proliferation and aggressive behavior, which was positively associated with the presence of intrahepatic metastasis and the histological grade of HCC [8,20]. Our analysis confirmed that HIF-1 signaling pathway was the most critical process for hypoxia leading to poor prognosis of HCC, which is consistent with the findings in most literatures [21,22].…”

Section: Discussionsupporting

confidence: 90%

“…In particular, the announcement of the 2019 Nobel Prize in physiology or medicine has increased researchers' enthusiasm for exploring the mechanism of hypoxia in the field of cancer. Increasing evidence indicates that hypoxia closely related to the migration and malignant progression of HCC [8,17].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the absence of indicators related to the prognosis of HCC. The 5-year survival rate for HCC patients was approximately less than 18% [8,9]. Therefore, finding the key molecular biomarkers focused on hypoxia which related to the occurrence and development of HCC patients has certain reference value for reliable estimation of the deterioration of HCC, and may be an effective measures against HCC.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

Guo

Zhang

et al. 2019

Preprint

View full text Add to dashboard Cite

Background Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research aims to mine the Hypoxic related genes (HRGs) on the role of clinical prognosis in HCC. Moreover, we construct and define a model of prognostic predictor (PP) to estimate and improve prognosis of HCC patients.Results 37 differentially expressed HRGs were obtained. It contained 28 up-regulated and 9 down-regulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer and 2 genes were protective factors. The PP was composed of the 10 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, PGK1, ERO1A, LDHA, ENO2, TPI1), and significantly divided patients of HCC into high- and low-risk groups according to overall survival (OS) ( P <0.001). We got the Area Under Curve(AUC) value of risk score calculated by PP was 0.777, which much bigger than other clinical parameters. Besides, PP was verified as an independent prognosis-related parameter (in univariate analyse, HR=1.484, 95% CI=1.342–1.642, P<0.001; in multivariate analyse, HR=1.414, 95% CI=1.258–1.588, P <0.001). Finally, the application of PP in clinic was concluded that the higher the patient's risk score, the higher the corresponding tumor stage and T stage, and the patient's prognosis was poor.Conclusions This study provides hypoxic related molecular targets for the therapeutic intervention. In addition, an individualized prognostic predictor was constructed to predict prognosis for HCC patients .

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

Guo

Zhang

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Surgical resection or liver transplantation is considered as the preferred therapy for HCC patients. Nonetheless, a majority of the HCC patients had missed the best treatment time due to the concealed onset, fast-paced progress and high malignancy [21]. Sorafenib is naturally emerging as a pivotal part of HCC treatment, but the clinical response to sorafenib is seriously limited by drug resistance [22].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

Mou

Pan

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Kinase inhibitor sorafenib is the first-line targeted drug for advanced hepatocellular carcinoma (HCC) patients. However, the appearance of anti-cancer agents’ resistance has limited its therapeutic effect. Methods: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in HCC sorafenib-resistant cells and their parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assay, plate colony formation assay and flow cytometric analysis. The potential mechanisms of PAK5 were evaluated via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib chemoresistant characteristics were investigated by a xenotransplantation model. Results: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in HCC sorafenib resistance cell lines. Mechanical studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 elevated the phosphorylation and nuclear translocation of β-catenin that enhanced the transcriptional activity of multidrug resistance protein ABCB1. Conclusions: PAK5 contributed to the sorafenib chemoresistant characteristics of HCC by activity β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated HCC sorafenib resistance, which provided a potential therapeutic target for advanced HCC patients.

show abstract

“…Sorafenib treatment resulted in decreased numbers of tumor vessels and pericyte depletion, and subsequent hypoxia that elicited EMT and resistance to sorafenib. [16] SIH promotes the nuclear accumulation and stabilization of HIF-1a and HIF-2a, and causes subsequent enhanced angiogenesis and transcription of oncogenes that enable HCC cells to adapt to sorafenib [17,18]. Moreover, sorafenib triggers the switch from HIF-1ato HIF-2a-dependent pathways [19], making such adaptation stronger and fairly flexible.…”

Section: Sorafenib-induced Hypoxia (Sih)mentioning

confidence: 99%

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

et al. 2020

View full text Add to dashboard Cite

A B S T R A C TIn most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

show abstract

HIF-1α-induced RIT1 promotes liver cancer growth and metastasis and its deficiency increases sensitivity to sorafenib

Cited by 60 publications

References 32 publications

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

Screening hypoxia-related genes as prognostic biomarkers and modeling the individualized prognostic predictor in hepatocellular carcinoma

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma

Contact Info

Product

Resources

About