MiR-146a enhances angiogenic activity of endothelial cells in hepatocellular carcinoma by promoting PDGFRA expression

Zhu, Kai; Pan, Qi; Zhang, Xin; Kong, Ling‐Bin; Fan, Jia; Dai, Zhi; Wang, Lu; Yang, Xin‐Rong; Hu, Jie; Wan, Jie; Zhao, Yiming; Tao, Zhen; Chai, Zong‐Tao; Zeng, Hai‐Ying; Tang, Zhao–You; Sun, Hui‐Chuan; Zhou, Jian

doi:10.1093/carcin/bgt160

Cited by 106 publications

(100 citation statements)

References 31 publications

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“…PDGFA only binds to PDGFR-a, activating their downstream pathways involved in several oncogenic mechanisms including angiogenesis. 36,37 Several studies have demonstrated that PDGFR-a is expressed by HUVECs and solid tumor endothelial cells, 38,39 and here we demonstrated an increased phosphorylation of PDGFR-a but not PDGFR-b in HUVECs upon SOX11-positive CM incubation. Furthermore, we have demonstrated the activation of AKT, ERK, and FAK upon SOX11-positive CM incubation.…”

Section: Discussionsupporting

confidence: 54%

SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma

Palomero¹,

Vegliante²,

Rodríguez³

et al. 2014

Blood

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Section: Discussionsupporting

confidence: 54%

SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma

Palomero¹,

Vegliante²,

Rodríguez³

et al. 2014

Blood

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“…Indeed, 20 of these 72 miRNAs were already known to be implicated in inflammation, fibrosis, and cancer development. This subset of miRNAs included miR-122, which is a key player in HCV infection and liver disease (reviewed in reference 4); miR-21-5p, which has consistently been shown to be implicated in HCV infection and liver disease (47)(48)(49); and miR-146a-5p, a well-known immunoregulatory miRNA further described to be associated with liver fibrosis and HCC (54,55,(64)(65)(66). Moreover, members of the miR-27 family of miRNAs, which contribute to the regulation of lipid metabolism, were recently reported to be increased by HCV and to contribute to liver steatosis (67,68).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Bandiera

Pernot

Saghire

et al. 2016

J Virol

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Hepatitis C virus (HCV)-induced chronic liver disease is a leading cause of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in homeostasis within the liver, and deregulation of miRNAs has been associated with liver disease, including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here we combined a hepatocyte-like cell-based model system, high-throughput small RNA sequencing, computational analysis, and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least 2-fold, including miRNAs that were previously described to target genes associated with inflammation, fibrosis, and cancer development. Further investigation demonstrated that the miR-146a-5p level was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes, as well as in liver tissue from HCV-infected patients. Genomewide microarray and computational analyses indicated that miR-146a-5p overexpression modulates pathways that are related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p has a positive impact on late steps of the viral replication cycle, thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. IMPORTANCEHCV is a leading cause of chronic liver disease and cancer. However, how HCV induces liver cancer remains poorly understood. There is accumulating evidence that a viral cure does not eliminate the risk for HCC development. Thus, there is an unmet medical need to develop novel approaches to predict and prevent virus-induced HCC. miRNA expression is known to be deregulated in liver disease and cancer. Furthermore, miRNAs are essential for HCV replication, and HCV infection alters miRNA expression. However, how miRNAs contribute to HCV-driven pathogenesis remains elusive. Here we show that HCV induces miRNAs that may contribute to liver injury and carcinogenesis. The miR-146a-5p level was consistently increased in different cell-based models of HCV infection and in HCV patient-derived liver tissue. Furthermore, miR-146a-5p increased HCV infection. Collectively, our data are relevant to understanding viral pathogenesis and may open perspectives for novel biomarkers and prevention of virus-induced liver disease and HCC. H epatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC) worldw...

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“…One group compared the microRNA expression profile of human umbilical vein endothelial cells (HUVECs) in the absence or presence of hepatocellular carcinoma (HCC) cells, and they found that miR-302c was the most highly downregulated micro-RNA in HUVECs exposed to HCC cells [23]. Further studies indicated that miR-302c suppresses the endothelial-mesenchymal transition (EndMT) of endothelial cells (Ecs) through the inhibition of metadherin (MTDH) expression [24].…”

Section: Discussionmentioning

confidence: 99%

Mir‐302c mediates influenza A virus‐induced IFNβ expression by targeting NF‐κB inducing kinase

et al. 2015

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a b s t r a c tLittle is known about the role of microRNA during influenza A virus (IAV) infection. We observed that NIK 3 0 UTR luciferase activity was elevated during IAV infection. Further studies demonstrated that miR-302c reduced NIK expression, resulting in the reduction of IFNb mRNA expression. We found that miR-302c prevented the translocation of NF-jB from the cytosol to the nucleus. Furthermore, IAV infection downregulated miR-302c expression, leading to the activation of IFNb expression and the inhibition of viral replication. Compared to miR-302c, miR-520e cannot promote viral replication and production, although the two microRNAs target the same site of the NIK 3 0 UTR. Collectively, our work defines a novel signaling pathway implicated in the control of IFNb mRNA expression during IAV infection.

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MiR-146a enhances angiogenic activity of endothelial cells in hepatocellular carcinoma by promoting PDGFRA expression

Cited by 106 publications

References 31 publications

SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma

SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma

Hepatitis C Virus-Induced Upregulation of MicroRNA miR-146a-5p in Hepatocytes Promotes Viral Infection and Deregulates Metabolic Pathways Associated with Liver Disease Pathogenesis

Mir‐302c mediates influenza A virus‐induced IFNβ expression by targeting NF‐κB inducing kinase

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