EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma

Leung, Hareton; Leung, Chun Sing; Lau, Eunice Y.; Chung, Katherine Po Sin; Mok, Etienne Ho Kit; Lei, Martina Mang Leng; Leung, Rainbow Wing Hei; Tong, Man; Keng, Vincent W.; Ma, Cong; Zhao, Qian; Ng, Irene Oi Lin; Ma, Stephanie

doi:10.1158/0008-5472.can-21-0184

Cited by 75 publications

(52 citation statements)

References 32 publications

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“…In the established ceRNA networks, the 22 DEmRNAs attracted the researchers' attention, and they found that they were effective regulators during cancer progression [ 43 – 49 ]. EPHB2 has been associated with cancer stemness and acquired sorafenib resistance via the β -catenin/TCF1 axis [ 43 ]. CXCL5 as a tumor angiogenic factor promoted the expression of FOXD1 by activating the AKT/NF- κ B pathway in colorectal cancer [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Differentially Expressed and Prognostic lncRNAs for the Construction of ceRNA Networks in Lung Adenocarcinoma

Cui

Liu

et al. 2021

Journal of Oncology

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Background. Long noncoding RNAs (lncRNAs) could function as competitive endogenous RNAs (ceRNAs) to competitively adsorb microRNAs (miRNAs), thereby regulating the expression of their target protein-coding mRNAs. In this study, we aim to identify more effective diagnostic and prognostic markers for lung adenocarcinoma (LUAD). Methods. We obtained differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs) for LUAD by using The Cancer Genomes Atlas (TCGA) portal. Weighted gene coexpression network analysis (WGCNA) was performed to unveil core gene modules associated with LUAD. The Cox proportional hazards model was performed to determine the prognostic significance of DElncRNAs. The diagnostic and prognostic significance of DElncRNAs was further verified based on the receiver operating characteristic curve (ROC). Cytoscape was used to construct the ceRNA networks comprising the lncRNAs-miRNAs-mRNAs axis based on the correlation obtained from the miRcode, miRDB, and TargetScan. Results. Compared with normal lung tissues, 2355 DElncRNAs, 820 DEmiRNAs, and 17289 DEmRNAs were identified in LUAD tissues. We generated 8 WGCNA core modules in the lncRNAs coexpression network, 5 modules in the miRNAs, and 12 modules in the mRNAs coexpression network, respectively. One lncRNA module (blue) consisting of 441 lncRNAs, two miRNA modules (blue and turquoise) containing 563 miRNAs, and one mRNA module (turquoise), which consisted of 15162 mRNAs, were mostly significantly related to LUAD status. Furthermore, 67 DEmRNAs were found to be tumor-associated as well as the target genes of the DElncRNAs-DEmiRNAs axis. Survival analyses showed that 6 lncRNAs (LINC01447, WWC2-AS2, OGFRP1, LINC00942, LINC01168, and AC005863.1) were significantly correlated with the prognosis of LUAD patients. Ultimately, the potential ceRNA networks including 6 DElncRNAs, 4 DEmiRNAs, and 22 DEmRNAs were constructed. Conclusion. Our study indicated that 6 DElncRNAs had the possibilities as diagnostic and prognostic biomarkers for LUAD. The lncRNA-mediated ceRNA networks might provide novel insights into the molecular mechanisms of LUAD progression.

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Section: Discussionmentioning

confidence: 99%

Identification of Differentially Expressed and Prognostic lncRNAs for the Construction of ceRNA Networks in Lung Adenocarcinoma

Cui

Liu

et al. 2021

Journal of Oncology

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“…Many studies have verified that EphB2 is abnormally expressed in many cancer types Table 1 . EphB2 is overexpressed in most tumors, such as hepatocellular carcinoma, breast cancer, glioma, and malignant mesothelioma ( Leung et al, 2021 ; Wu et al, 2004 ; Nakada et al, 2004 ; Goparaju et al, 2013 ), and it functions as a tumor promoter. However, the expression of EphB2 is low in other tumors, such as colorectal cancer and bladder cancer ( Xi et al, 2012 ; Lee et al, 2021 ), indicating that it exerts a tumor-suppression effect.…”

Section: Ephb2 In Various Human Tumorsmentioning

confidence: 99%

“…It is widely known that Eph receptors have essential roles in embryonic development, and in the past decade their critical roles in the occurrence and progression of human disease, especially in tumorigenesis, have become more and more clear ( Pasquale, 2008 ; Xi et al, 2012 ; Husa et al, 2016 ). Undoubtedly, enriching our understanding of the roles Eph receptors play in the potential biomarkers, stemness, and drug resistance of cancer will provide new opportunities for tumor therapy ( Pasquale, 2010 ; Leung et al, 2021 ). Eph receptor B2 (EphB2) has been demonstrated to play a crucial modulatory role in tumor progression ( Guo et al, 2006 ; Lam et al, 2014 ; Buckens et al, 2020 ; Morales et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Roles of EphB2 in Cancer

Liu

Yu²,

Li³

et al. 2022

Front. Cell Dev. Biol.

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The erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their Eph receptor-interacting (ephrin) ligands together constitute a vital cell communication system with diverse roles. Experimental evidence revealed Eph receptor bidirectional signaling with both tumor-promoting and tumor-suppressing activities in different cancer types and surrounding environment. Eph receptor B2 (EphB2), an important member of the Eph receptor family, has been proved to be aberrantly expressed in many cancer types, such as colorectal cancer, gastric cancer and hepatocellular carcinoma, resulting in tumor occurrence and progression. However, there are no reviews focusing on the dual roles of EphB2 in cancer. Thus, in this paper we systematically summarize and discuss the roles of EphB2 in cancer. Firstly, we review the main biological features and the related signaling regulatory mechanisms of EphB2, and then we summarize the roles of EphB2 in cancer through current studies. Finally, we put forward our viewpoint on the future prospects of cancer research focusing on EphB2, especially with regard to the effects of EphB2 on tumor immunity.

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“…Similarly, AKT and MAPK have emerged as critical players in the sorafenib resistance process [61,62]. Of note, enhancing cancer stem cell properties also promoted sorafenib resistance in HCC [63]. In addition to that, HIF-1α/VEGF pathway adapted HCC cells to hypoxic microenvironment and blunted the antiangiogenic actions of sorafenib [64].…”

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. 2021

J Biomed Sci

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Background Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. Methods In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and 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 assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined 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 resistant characteristics were investigated by a xenotransplantation model. Results We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic 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 enhanced the phosphorylation and nuclear translocation of β-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1. Conclusions PAK5 contributed to the sorafenib resistant characteristics of HCC via β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.

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EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma

Cited by 75 publications

References 32 publications

Identification of Differentially Expressed and Prognostic lncRNAs for the Construction of ceRNA Networks in Lung Adenocarcinoma

Identification of Differentially Expressed and Prognostic lncRNAs for the Construction of ceRNA Networks in Lung Adenocarcinoma

The Roles of EphB2 in Cancer

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

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