Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells

Chai, Stella; Ng, Kai Yu; Tong, Man; Lau, Eunice Y.; Lee, Terence; Chan, Kwok Wah; Yuan, Yunfei; Cheung, Tan To; Cheung, Siu Tim; Wang, Xiao Qi; Wong, Nathalie; Lo, Chung Mau; Man, Kwan; Guan, Xin Yuan; Ma, Stephanie

doi:10.1002/hep.28821

Cited by 161 publications

(135 citation statements)

References 37 publications

(86 reference statements)

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“…For example, miR-183-3p was validated as a potent prognostic marker for lung adenocarcinoma in female nonsmokers[40], and declining expression of let-7e-3p was associated with cell cycle arrest and the inhibition of proliferation of cervical cancer cells[41]. High endogenous and circulating miR-1246 modulated by the direct upstream regulator octamer 4 (Oct4) was shown to be a novel diagnostic marker as well as a tool for therapeutic intervention in hepatocellular carcinoma (HCC) by cooperatively driving Wnt/β-catenin signaling activation[42]. In addition, miRNA-1246 was found to be a target gene of p53 in the progression of various cancers, including cervical, colorectal, esophageal, hepatic, and pancreatic cancers[43–45].…”

Section: Discussionmentioning

confidence: 99%

Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing

Zheng

et al. 2017

PLoS ONE

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Enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) remain the predominant pathogens in hand, foot, and mouth disease (HFMD), but the factors underlying the pathogenesis of EV71 and CA16 infections have not been elucidated. Recently, the functions of microRNAs (miRNAs) in pathogen-host interactions have been highlighted. In the present study, we performed comprehensive miRNA profiling in EV71- and CA16-infected human umbilical vein endothelial cells (HUVECs) at multiple time points using high-throughput sequencing. The results showed that 135 known miRNAs exhibited remarkable differences in expression. Of these, 30 differentially expressed miRNAs presented opposite trends in EV71- and CA16-infected samples. Subsequently, we mainly focused on the 30 key differentially expressed miRNAs through further screening to predict targets. Gene ontology (GO) and pathway analysis of the predicted targets showed the enrichment of 14 biological processes, 9 molecular functions, 8 cellular components, and 85 pathways. The regulatory networks of these miRNAs with predicted targets, GOs, pathways, and co-expression genes were determined, suggesting that miRNAs display intricate regulatory mechanisms during the infection phase. Consequently, we specifically analyzed the hierarchical GO categories of the predicted targets involved in biological adhesion. The results indicated that the distinct changes induced by EV71 and CA16 infection may be partly linked to the function of the blood-brain barrier. Taken together, this is the first report describing miRNA expression profiles in HUVECs with EV71 and CA16 infections using high-throughput sequencing. Our data provide useful insights that may help to elucidate the different host-pathogen interactions following EV71 and CA16 infection and offer novel therapeutic targets for these infections.

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Section: Discussionmentioning

confidence: 99%

Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing

Zheng

et al. 2017

PLoS ONE

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“…Therefore, some miRNAs are considered to be carcinogenic. miR-1246 decreases the expression of AXIN2 and GSK3β by activating the Wnt/β-catenin signaling pathway, which in turn promotes the selfrenewal and metastasis of HCSCs [35]. Studies have shown that miR-155 is up-regulated in tumors and down-regulation of miR-155 can inhibit the formation of CSCs.…”

Section: The Function Of Micrornas In Carcinogenesis Of Hcscsmentioning

confidence: 99%

Characterization of the Role of MicroRNAs in Hepatic Cancer Stem Cells

Daia¹,

Zhang²

2017

Chemotherapy (Los Angel)

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Liver cancer is one of the most malignant tumors and is prone to relapse, metastasis and drug resistance. These phenomena can be explained by the existence of cancer stem cells (CSCs). CSCs have a strong ability to proliferate, are highly carcinogenic, exhibit multi-directional differentiation, develop drug resistance, and play critical roles in tumor radiotherapy, chemotherapy and tumor recurrence. miRNAs exert effects on oncogenes and tumor suppressor genes. There are distinctive miRNA expression profiles in different types of tumors, and these profiles are closely related to tumorigenesis, differentiation, metastasis and prognosis. Studies have shown that miRNAs are abnormally expressed in hepatocellular carcinoma and have important regulatory effects on the self-renewal and differentiation of hepatic cancer stem cells (HCSCs) as well as on the initiation of tumorigenesis. Therefore, it is critical to understand the impact of miRNAs in HCSC and the associated molecular mechanisms to develop new methods for the clinical diagnosis and treatment of liver cancer.

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“…Therefore, the key factors involved in embryonic development may play critical roles in carcinogenesis. Studies have shown that Oct4 is overexpressed in human cancers such as bladder [2], breast [3], cervical cancer [4], oral squamous cell carcinoma [5], hepatocellular carcinoma [6] and lung cancer [7, 8]. In embryonic stem cells, Oct4 has been identified to regulate transcriptions of other transcription factors, chromatin modifiers, long non-coding RNAs (lncRNAs) and microRNAs [9, 10].…”

Section: Introductionmentioning

confidence: 99%

Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression

et al. 2017

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BackgroundOct4, a key stemness transcription factor, is overexpressed in lung cancer. Here, we reveal a novel transcription regulation of long non-coding RNAs (lncRNAs) by Oct4. LncRNAs have emerged as important players in cancer progression.MethodsOct4 chromatin-immunoprecipitation (ChIP)-sequencing and several lncRNA databases with literature annotation were integrated to identify Oct4-regulated lncRNAs. Luciferase activity, qRT-PCR and ChIP-PCR assays were conducted to examine transcription regulation of lncRNAs by Oct4. Reconstitution experiments of Oct4 and downstream lncRNAs in cell proliferation, migration and invasion assays were performed to confirm the Oct4-lncRNAs signaling axes in promoting lung cancer cell growth and motility. The expression correlations between Oct4 and lncRNAs were investigated in 124 lung cancer patients using qRT-PCR analysis. The clinical significance of Oct4/lncRNAs signaling axes were further evaluated using multivariate Cox regression and Kaplan-Meier analyses.ResultsWe confirmed that seven lncRNAs were upregulated by direct binding of Oct4. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and urothelial carcinoma-associated 1 (UCA1) were validated as Oct4 transcriptional targets through promoter or enhancer activation. We showed that lung cancer cells overexpressing NEAT1 or MALAT1 and the Oct4-silenced cells reconstituted with NEAT1 or MALAT1 promoted cell proliferation, migration and invasion. In addition, knockdown of NEAT1 or MALAT1 abolished Oct4-mediated lung cancer cell growth and motility. These cell-based results suggested that Oct4/NEAT1 or Oct4/MALAT1 axis promoted oncogenesis. Clinically, Oct4/NEAT1/MALAT1 co-overexpression was an independent factor for prediction of poor outcome in 124 lung cancer patients.ConclusionsOur study reveals a novel mechanism by which Oct4 transcriptionally activates NEAT1 via promoter and MALAT1 via enhancer binding to promote cell proliferation and motility, and led to lung tumorigenesis and poor prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0674-z) contains supplementary material, which is available to authorized users.

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Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells

Abstract: These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).

Cited by 161 publications

References 37 publications

Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing

Different microRNA profiles reveal the diverse outcomes induced by EV71 and CA16 infection in human umbilical vein endothelial cells using high-throughput sequencing

Characterization of the Role of MicroRNAs in Hepatic Cancer Stem Cells

Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression

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