EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation

Lanaya, Hanane; Natarajan, Arunkumar; Komposch, Karin; Li, Liang; Amberg, Nicole; Chen, Lei; Wculek, Stefanie K.; Hammer, Martina; Zenz, Rainer; Peck‐Radosavljevic, Markus; Sieghart, Wolfgang; Trauner, Michael; Wang, Hongyang; Sibilia, Maria

doi:10.1038/ncb3031

Cited by 210 publications

(216 citation statements)

References 39 publications

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“…EGFR is vitally involved in regulating cell survival and proliferation [24, 25]. And in model systems of autocrine stimulation of EGFR, or EGFR overexpression and mutation, consequent transformation has been observed [26, 27].…”

Section: Discussionmentioning

confidence: 99%

LINC00037 Inhibits Proliferation of Renal Cell Carcinoma Cells in an Epidermal Growth Factor Receptor-Dependent Way

Gong

et al. 2018

Cell Physiol Biochem

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Background/Aims: LINC00037 has previously been reported to be up-regulated in clear cell renal cell carcinoma (ccRCC), however, the underlying mechanism remained unknown. In this study, we designed to investigate the functional role of LINC00037 in ccRCC Methods: LINC00037 knockdown and re-expressing 786-O and A498 cells were established. CCK8 assay and EdU assay were performed to evaluate the proliferation rates of ccRCC cells. Flow cytometry assay was performed to detect the cell apoptosis and cell cycle. Subcutaneous injection xenotransplantation mouse model was used to observe the role of LINC00037 in tumor growth in vivo. Mass spectrometry (MS) was performed to find the interacting partner of LINC00037 and RNA immunoprecipitation (RIP) was carried out to validate their interaction. Results: We found that knockdown of LINC00037 resulted in inhibited cell proliferation with activated apoptosis and cell cycle arrest in vitro. Over-expression of LINC00037 in LINC00037 knockdown cells restored and enhanced cell proliferation. In vivo mouse model indicated reduced tumor progression by LINC00037 depletion and promoted tumor progression by LINC00037 overexpression. LINC00037 could bind to epidermal growth factor receptor (EGFR) and increase the protein level of EGFR. Conclusion: LINC00037 could inhibit proliferation of ccRCC in an epidermal growth factor receptor-dependent way.

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Section: Discussionmentioning

confidence: 99%

LINC00037 Inhibits Proliferation of Renal Cell Carcinoma Cells in an Epidermal Growth Factor Receptor-Dependent Way

Gong

et al. 2018

Cell Physiol Biochem

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“…could be more efficiently generated after breeding to Nes‐Cre or GFAP‐Cre mice. Genotyping was performed by PCR as previously described 19, 72. Primer sequences can be obtained upon request.…”

Section: Methodsmentioning

confidence: 99%

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain

et al. 2018

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Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR−/− mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFR‐deficient neural stem cells are impaired in their self‐renewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFRΔbrain) show low penetrance of cortical degeneration compared to EGFR−/− mice despite genetic recombination of the conditional allele. Adult EGFRΔ mice establish a proper blood–brain barrier and perform reactive astrogliosis in response to mechanical and infectious brain injury, but are more sensitive to Kainic acid‐induced epileptic seizures. EGFR‐deficient cortical astrocytes, but not midbrain astrocytes, have reduced expression of glutamate transporters Glt1 and Glast, and show reduced glutamate uptake in vitro, illustrating an excitotoxic mechanism to explain the hypersensitivity to Kainic acid and region‐specific neurodegeneration observed in EGFR‐deficient brains.

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“…Therefore, it should be noted that more studies are needed to elucidate the roles of EGFR activation in macrophages in inflammation-associated tumorigenesis. In fact, EGFR in macrophages in liver has shown tumor-promoting effects on hepatocellular carcinoma formation induced by diethylnitrosamine/phenobarbital (39). In this model, IL-1␤, released by DEN-damaged hepatocytes, stimulates Kupffer cells to produce IL-6.…”

Section: Journal Of Biological Chemistry 20467mentioning

confidence: 99%

Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth

Zhao

Liu

Peek

et al. 2016

Journal of Biological Chemistry

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EGF receptor (EGFR) in tumor cellsMacrophages contribute to immune responses through possessing phenotypic plasticity. Classically activated macrophages (M1 polarization) are driven by IFN-␥ and pathogenderived signals, such as LPS-activated canonical interferon-regulatory factor-3 (IRF-3) and STAT1 pathways. Macrophages with M1 polarization are characterized by production of proinflammatory cytokines and NOS2 (1). Alternatively activated macrophages (M2 polarization) are elicited by IL-4-and IL-13-activated STAT6 and IL-10-activated STAT3 signals. M2-polarized macrophages exhibit increased transcription of genes, including arginase 1 (Arg1), 4 mannose receptor 1 (Mrc1), resistin-like ␣ (Retnla, Fizz1), and chitinase 3-like 3 factor (Chi3l3, YM1) (1) and possess functions of antiinflammation, angiogenesis, and tissue repair, thus having tumor-promoting properties (1, 2). In addition, other transcriptional factors, such as NF-B (3) and IL-4-induced epigenetic changes (4) have been found to participate in directing polarization in macrophages.Tumor-associated macrophages (TAMs) in the tumor microenvironment usually exhibit M2 polarization in human and mouse models of cancers (5, 6) and possess pro-tumorigenic activities in most cancers, including promoting tumor cell proliferation, migration, and invasion, increasing angiogenesis, and suppressing immunity through secretion of growth factors such as HB-EGF, EGF, CSF-1, VEGF, and PDGF, enzymes, including metalloproteinases (MMPs), and cytokines, such as IL-6, IL-10, and TNF (7). Clinical studies have revealed that * This work was supported, in whole or in part, by National Institutes of Health Grants R01DK081134 (to F. Y.) and R01DK56008 and R01DK54993 (to D. B. P.), and core services were performed through Vanderbilt University Medical Center's Digestive Disease Research Center supported by National Institutes of Health Grant P30DK058404. This work was also supported by National Natural Science Foundation of China Grant 31471341 (to H. L.)The authors declare no conflict of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 4 The abbreviations used are: Arg1, arginase 1; TAM, tumor-associated macrophage; MMP, metalloproteinase; EGFR, EGF receptor; EMT, epithelial-mesenchymal transition; SOCS1, suppressor of cytokine signaling 1; IMCE, Immorto-Min colonic epithelial.

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EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation

Cited by 210 publications

References 39 publications

LINC00037 Inhibits Proliferation of Renal Cell Carcinoma Cells in an Epidermal Growth Factor Receptor-Dependent Way

LINC00037 Inhibits Proliferation of Renal Cell Carcinoma Cells in an Epidermal Growth Factor Receptor-Dependent Way

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain

Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth

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