HER2 Interacts With CD44 to Up-regulate CXCR4 via Epigenetic Silencing of microRNA-139 in Gastric Cancer Cells

Bao, Wei; Fu, Haijing; Xie, Qiaosheng; Wang, Lei; Zhang, Rui; Z, Guo; Zhao, Jing; Meng, Yanyan; Ren, Xue; Wang, Tao; Li, Qing; Jin, Boquan; Yao, Libo; Wang, Rui‐An; Fan, Daiming; Chen, Siyi; Jia, Lintao; Yang, An‐Gang

doi:10.1053/j.gastro.2011.08.050

Cited by 140 publications

(106 citation statements)

References 37 publications

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“…In our network, miR-139 targets ETS1, TCF4, ZEB1, and CCND2. This miRNA was found to be downregulated in other cancers and target chemokine (C-X-C motif) receptor 4 (CXCR4) and FBJ murine osteosarcoma viral oncogene homolog (FOS) (40,41 ). All 3 miRNAs (miR-124, miR-204, and miR-139) target TCF4 and CCND2.…”

Section: Discussionmentioning

confidence: 99%

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

et al. 2014

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BACKGROUND The outcome of clear cell renal cell carcinoma (ccRCC) is still unpredictable. Even with new targeted therapies, the average progression-free survival is dismal. Markers for early detection and progression could improve disease outcome. METHODS To identify efficient and hitherto unrecognized pathogenic factors of the disease, we performed a uniquely comprehensive pathway analysis and built a gene interaction network based on large publicly available data sets assembled from 28 publications, comprising a 3-prong approach with high-throughput mRNA, microRNA, and protein expression profiles of 593 ccRCC and 389 normal kidney samples. We validated our results on 2 different data sets of 882 ccRCC and 152 normal tissues. Functional analyses were done by proliferation, migration, and invasion assays following siRNA (small interfering RNA) knockdown. RESULTS After integration of multilevel data, we identified aryl-hydrocarbon receptor (AHR), grainyhead-like-2 (GRHL2), and KIAA0101 as new pathogenic factors. GRHL2 expression was associated with higher chances for disease relapse and retained prognostic utility after controlling for grade and stage [hazard ratio (HR), 3.47, P = 0.012]. Patients with KIAA0101-positive expression suffered worse disease-free survival (HR, 3.64, P < 0.001), and in multivariate analysis KIAA0101 retained its independent prognostic significance. Survival analysis showed that GRHL2- and KIAA0101-positive patients had significantly lower disease-free survival (P = 0.002 and P < 0.001). We also found that KIAA0101 silencing decreased kidney cancer cell migration and invasion in vitro. CONCLUSIONS Using an integrative system biology approach, we identified 3 novel factors as potential biomarkers (AHR, GRHL2 and KIAA0101) involved in ccRCC pathogenesis and not linked to kidney cancer before.

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Section: Discussionmentioning

confidence: 99%

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

et al. 2014

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“…[19][20][21][22][23][24][25] Moreover, the overall response rate of women diagnosed with HER2-positive metastatic breast cancer and treated with trastuzumab as a single first-line agent is only 26%; that is, > 70% of HER2-overexpressing metastatic breast carcinomas show a resistance to trastuzumab ab initio. A variety of possible mechanisms of escape from trastuzumab appear to involve many of the same biomarkers that have been implicated in the biology of CS-like cells: e.g., the overexpression of the stem cell-related marker CD44, leading to a loss or blockage of the trastuzumab-binding site at the extracellular domain of HER2; 26,27 the upregulation of stem cell markers, such as CXCR4, β1 integrin or Notch-1, [28][29][30][31][32] leading to the activation of alternative pathways circumventing HER2 signaling and the upregulation of pro-survival mediators, such as the inhibitor of apoptosis survivin. 33 Accordingly, it has been suggested that, although trastuzumab effectively targets cancer-initiating cells, a clinical resistance to trastuzumab may counter-intuitively be driven by breast CSCs.…”

Section: Epithelial-to-mesenchymal Transition (Emt) Confers Primary Rmentioning

confidence: 99%

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

et al. 2012

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“…miR-200 has also been shown to increase metastatic potential of mammary carcinoma cell lines (Korpal et al 2011), while other studies have observed an inverse correlation between miR-200 expression and tumor invasion and metastasis (Gregory et al 2008;Korpal et al 2008). Overexpression of miR-139-5p was recently shown to correlate with reduced metastatic activity in hepatocellular carcinoma and gastric cancer cells (Bao et al 2011;Wong et al 2011;Li et al 2013) and downregulated in glioblastoma (Li et al 2013). Furthermore, in patients with invasive squamous cell carcinoma, loss of miR-139-5p expression is associated with increased metastatic disease (Mascaux et al 2009).…”

Section: Introductionmentioning

confidence: 99%

miR-139-5p is a regulator of metastatic pathways in breast cancer

Krishnan

Steptoe

Martin

et al. 2013

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Metastasis is a complex, multistep process involved in the progression of cancer from a localized primary tissue to distant sites, often characteristic of the more aggressive forms of this disease. Despite being studied in great detail in recent years, the mechanisms that govern this process remain poorly understood. In this study, we identify a novel role for miR-139-5p in the inhibition of breast cancer progression. We highlight its clinical relevance by reviewing miR-139-5p expression across a wide variety of breast cancer subtypes using in-house generated and online data sets to show that it is most frequently lost in invasive tumors. A biotin pull-down approach was then used to identify the mRNA targets of miR-139-5p in the breast cancer cell line MCF7. Functional enrichment analysis of the pulled-down targets showed significant enrichment of genes in pathways previously implicated in breast cancer metastasis (P < 0.05). Further bioinformatic analysis revealed a predicted disruption to the TGFβ, Wnt, Rho, and MAPK/PI3K signaling cascades, implying a potential role for miR-139-5p in regulating the ability of cells to invade and migrate. To corroborate this finding, using the MDA-MB-231 breast cancer cell line, we show that overexpression of miR-139-5p results in suppression of these cellular phenotypes. Furthermore, we validate the interaction between miR-139-5p and predicted targets involved in these pathways. Collectively, these results suggest a significant functional role for miR-139-5p in breast cancer cell motility and invasion and its potential to be used as a prognostic marker for the aggressive forms of breast cancer.

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HER2 Interacts With CD44 to Up-regulate CXCR4 via Epigenetic Silencing of microRNA-139 in Gastric Cancer Cells

Cited by 140 publications

References 37 publications

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin)

miR-139-5p is a regulator of metastatic pathways in breast cancer

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