CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

Jiang, Feng; Chen, Lei; Yang, Yuting; Wang, Xianming; Wang, Ruo–Yu; Li, Liang; Wen, Wen; Chang, Yan–Xin; Chen, Cai–Yang; Tang, Jing; Liu, Gao–Mi–Yang; Huang, Wentao; Xu, Lin; Wang, Hongyang

doi:10.1158/0008-5472.can-14-1589

Cited by 50 publications

(50 citation statements)

References 46 publications

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“…MMPs can degrade ECM, and the MMP activity is regulated by TIMPs. Many studies have confirmed that MMP expression is higher in human primary liver cancer and liver metastases compared to normal liver tissue, and some studies have shown relationships between MMP expressions and tumour progression, migration, and metastasis, indicating an important role of MMPs in tumour malignancy (31)(32)(33). In this study, the upregulation of miR-124a increased TIMP-2 expression and reduced MMP2 and MMP9 expression in HepG2 cells.…”

Section: Discussionsupporting

confidence: 70%

MicroRNA-124a inhibits cell proliferation and migration in liver cancer by regulating interleukin-11

Wang

Lin

et al. 2017

Mol Med Report

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Liver cancer is the sixth most common malignant tumour and ranks in the top three cancers with regard to mortality due to metastasis and postsurgical recurrence. It is significant to understand the mechanisms underlying liver cancer for diagnosis and treatment. Cumulative evidence suggests that the abnormal regulation of microRNAs (miRNAs/miRs) may contribute to the development and metastasis of cancer. miR‑124a acts as a tumour suppressor in osteosarcoma, endometrial carcinoma, prostate cancer, and glioblastoma. However, the effects of miR‑124a in liver cancer and its biological mechanism are not fully understood. It has been demonstrated that miR‑124a is downregulated and interleukin (IL)‑11 is upregulated in the liver cancer tissues. In the present study, miR‑124a upregulation inhibited cell proliferation, migration and promoted cell apoptosis. Through a dual‑luciferase reporter assay, it was verified that IL‑11 is a direct target of miR‑124a. Furthermore, the overexpression of miR‑124a repressed the secretion of IL‑11 from hepatoma cells. Finally, it was identified that mimics of miR‑124a increased the expression of tissue inhibitor of matrix metalloproteinase‑2 (TIMP‑2) and Caspase‑3 and decreased the expression levels of matrix metalloproteinase 2 (MMP2), MMP9, B‑cell lymphoma 2, signal transducer and activator of transcription 3 (STAT3), and phosphorylated‑STAT3. In conclusion, the results indicated that miR‑124a has an important role as a tumour suppressor gene by targeting IL‑11. These findings may provide novel insights for clinical treatments to prevent the development of liver cancer.

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Section: Discussionsupporting

confidence: 70%

MicroRNA-124a inhibits cell proliferation and migration in liver cancer by regulating interleukin-11

Wang

Lin

et al. 2017

Mol Med Report

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“…Also, Feng J et al indicated that CYP3A5 plays a protective role in the occurrence and metastasis of hepatocellular carcinoma. At the same time, they also con rmed that CYP3A5 over-expression in hepatocellular carcinoma cells inhibits the metastasis and invasion of cancer cells in vivo and in vitro, via manipulating ROS/mTORC2/p-AKT (S473) signaling pathway and limiting MMP2/9 function (Jiang, Chen et al 2015, Yu, Wang et al 2018. Research has found that a SNP within intron-3 (CYP3A5*3) results in aberrant mRNA splicing and a pronounced reduction in protein synthesis (Lamba, Lin et al 2002).…”

Section: Discussionmentioning

confidence: 96%

CYP4F2 And CYP3A5 Gene Polymorphisms And Lung Cancer In Chinese Han Population

et al. 2019

Preprint

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Objective: This study aimed to explore whether the polymorphisms of CYP4F2 and CYP3A5 are correlated to the risk of lung cancer development. Methods: A case-control study was conducted among 510 patients with pathologically confirmed lung cancer as the case group and 504 healthy individuals as the control group. Four single nucleotide polymorphisms (SNPs) of the CYP4F2 and CYP3A5 genes were genotyped and their correlations with the risk for lung cancer were examined using χ2 test and logistic regression analysis. Results: Stratified analysis found that the rs3093105 and rs3093106 locus of CYP4F2 gene were significantly associated with lower risk of lung cancer (P=0.012, OR=0.64, 95%CI: 0.45-0.91). The correlation was related to patients’ age and sex and pathological type of lung cancer. Similarly, the rs10242455 loci of CYP3A5 gene showed a statistical significance between the case group and the control group (P=0.018, OR=0.71, 95%CI: 0.53-0.94), which also was associated with reduced risk of squamous cell lung cancer in the dominant and additive models (Dominant: OR=0.66, 95%CI: 0.46-0.94, P=0.021; Additive: OR= 0.71, 95%CI: 0.53-0.95, P=0.023). Conclusion: CYP4F2 and CYP3A5 gene polymorphisms are associated with the reduced risk of non-small cell lung cancer (NSCLC), and its correlation is related to patients’ age and sex and pathological type of lung cancer.

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“…Given that HCC is more prevalent in males than in females, low CYP3A4 expression in males may contribute to gender differences in morbidity [54]. Moreover, CYP3A5 alone [55] or combined with CYP3A4 are candidate prognostic markers for patients with HCC [9]. CYP3A5 may interact with CYP3A4 and affect the transcription and activity of CYP3A4 [56].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Expression and Prognosis of 12 Cytochrome P450s in Human Hepatocellular Carcinoma from the Perspective of Network Pharmacology

Jiang

Wang

et al. 2020

Preprint

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Background: Cytochrome P450s (CYPs) are pivotal drug metabolic enzymes and play a crucial part in the development and prognosis of hepatocellular carcinoma (HCC). Among various CYPs, 12 (CYP1A2, 27A1, 2A6, 2A7, 2B6, 2C8, 2C9, 2E1, 2J2, 3A4, 3A5, and 4A11) are recognized as key therapeutic targets for HCC from the perspective of network pharmacology. However, the gene expression and prognosis of these 12 CYPs in HCC remain obscure.Methods: In the current study, the mRNA expression of these 12 CYPs and survival of patients with HCC were investigated by mining data from ONCOMINE, Kaplan–Meier plotter, UALCAN, Human Protein Atlas, cBioPortal, STRING, and DAVID databases. Network pharmacology analysis of sorafenib for HCC treatment was conducted using data from Therapeutic Target Database, Drugbank, Swiss Target Prediction, STITCH, OncoDB.HCC, Liverome, STRING, and DAVID databases.Results: Results showed that the mRNA expression levels of the 12 CYPs were markedly reduced in HCC and negatively correlated with tumor stages and grades (except for CYP3A5). The high expression level of nine CYPs, namely, CYP27A1, 2A6, 2A7, 2C8, 2C9, 2E1, 3A4, 3A5, and 4A11 was significantly correlated with favorable prognosis in patients with HCC, indicating that they may serve as candidate prognostic biomarkers for HCC. Additionally, overexpression of CYP27A1, CYP2A7, CYP2B6, CYP2C9, and CYP3A5 was markedly correlated with favorable overall survival in HCC patients who received sorafenib therapy. Network pharmacology analysis of the administration of sorafenib for HCC treatment suggested that this drug may exert its antihepatocarcinoma effects by regulating the FoxO and ErbB signaling pathways.Conclusion: Characterization of the expression and prognosis of 12 CYPs in HCC, as well as network pharmacology analysis of HCC treatment via sorafenib, may provide novel insights into the discovery of potential prognostic markers of and therapeutic targets in HCC.

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CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

Cited by 50 publications

References 46 publications

MicroRNA-124a inhibits cell proliferation and migration in liver cancer by regulating interleukin-11

MicroRNA-124a inhibits cell proliferation and migration in liver cancer by regulating interleukin-11

CYP4F2 And CYP3A5 Gene Polymorphisms And Lung Cancer In Chinese Han Population

Comprehensive Analysis of the Expression and Prognosis of 12 Cytochrome P450s in Human Hepatocellular Carcinoma from the Perspective of Network Pharmacology

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