Knockdown of EGFR inhibits growth and invasion of gastric cancer cells

Zhen, Yingwei; Guang-hui, Ling; Zhang, Xiefu

doi:10.1038/cgt.2014.55

Cited by 27 publications

(16 citation statements)

References 38 publications

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“…It was reported that upregulation of EGFR expression is associated with lymph node metastases of gastric cancer, and blockade of EGFR signaling suppresses growth and invasion of gastric cancer cells through AKT pathway. 14 We hypothesed that overexpression of Rab11-FIP2 promotes the sustained AKT activation in gastric cancer. Overexpression of Rab11-FIP2 may result in suppression of the internalization of EGFR in COS-7 cells.…”

Section: Overexpression Of Rab11-fip2 Results In Suppression Of the Imentioning

confidence: 99%

Rab11‐FIP2 promotes the metastasis of gastric cancer cells

Qin

Shen

2015

Intl Journal of Cancer

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Rab11-FIP2 can interact with MYO5B and plays an important role in regulating plasma membrane recycling. Our previous study has shown that MYO5B is epigenetically silenced and associated with c-Met signaling in human gastric cancer. However, little is known of the function of Rab11-FIP2 in gastric cancer. In this study, we investigated Rab11-FIP2 expression by immunohistochemistry in 86 patients with gastric cancer. We found that the expression level of Rab11-FIP2 was significantly increased in gastric cancer tissues and high expression of Rab11-FIP2 was closely correlated with nodal metastasis in gastric cancer patients. Rab11-FIP2 overexpression promoted epithelial-mesenchymal transition (EMT) in a manner associated with gastric cancer metastasis in vitro and in vivo. We also found that hypoxia could enhance the expression of Rab11-FIP2 through HIF-1a. Inactivation of Rab11-FIP2 dramatically decreased hypoxia-induced migration of gastric cancer cells. Suppression of the internalization of EGFR, at least in part, plays an important role in EMT induced by overexpression of Rab11-FIP2 in gastric cancer cells. Finally, we demonstrated that Rab11-FIP2 could regulate actin cytoskeleton dynamics. In conclusion, our findings reveal a novel mechanism underlying the role of Rab11-FIP2 in gastric cancer dissemination, suggesting that Rab11-FIP2 may be a promising candidate target for gastric cancer treatment.Rab11-FIP2 is a member of a family of Rab11-binding proteins (Rab11-FIPs) that have been implicated in the function of plasma membrane recycling. 1,2 Rab11-FIPs, which are effectors of Rab11, are categorized into two subfamilies according to their domain structures. The three identified class I FIPs including Rab11-FIP2 possess an amino terminal C2 domain, whereas the two class II FIPs included Rab11-FIP3 and Rab11-FIP4. 2,3 The two class II FIPs were involved in cell motility. Invasive cell migration is a crucial process that is aberrantly upregulated in tumor cells, promoting cancer metastasis. For instance, hypoxia can upregulate Rab11-FIP4 through HIF-1a to promote the metastasis of hepatocellular carcinoma. 4 Rab11-FIP3 affects cell motility by regulating Arf6 localization to the plasma membrane of the leading edge, thus regulating polarized Rac1 activation and actin dynamics. 5 Among the Rab11-FIP proteins, only Rab11-FIP2 can interact with MYO5B. 6 The interaction of Rab11-FIP2 with both Rab11a and MYO5B regulates recycling endosome trafficking. 6,7 Endocytic membrane trafficking plays an important role in regulating cell motility. 8 For example, Rab11 controls recycling of integrin in breast cancer cells in a way that may contribute to hypoxia-induced invasive migration. 9 Our previous study has shown that MYO5B is epigenetically silenced in human gastric cancer and associated with the motility of gastric cancer. 10 However, little is known of the function of Rab11-FIP2 in gastric cancer. In this study, we found that the expression level of Rab11-FIP2 was significantly increased in gastric cancer tissues. Rab1...

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Section: Overexpression Of Rab11-fip2 Results In Suppression Of the Imentioning

confidence: 99%

Rab11‐FIP2 promotes the metastasis of gastric cancer cells

Qin

Shen

2015

Intl Journal of Cancer

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“…This is in line with observation of Zuo et al who showed that pharmacologic inhibition of EGFR activity reduced the production of MMP‐9, as well as squamous carcinoma cell migration and invasion. Zhen et al also indicated that knockdown of EGFR reduced cell invasion of gastric cancer and led to decreased expression of MMP‐9. Interestingly, reduced activity of MMP‐9 was induced by the overexpression of EGFR in A375 cells.…”

Section: Discussionmentioning

confidence: 98%

Expression level of EGFR and MET receptors regulates invasiveness of melanoma cells

Pietraszek-Gremplewicz

Simiczyjew

Dratkiewicz

et al. 2019

J Cellular Molecular Medi

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Epidermal and hepatocyte growth factors can stimulate invasive abilities of melanoma cells, while treatment with combination of their receptors' (EGFR and MET, respectively) inhibitors reduces viability of these cells, as we have previously shown. Proposed therapy has potential; however, used drugs block more than one goal effectively, what raises the question about the real target of analysed inhibitors. For this reason, we analysed direct involvement of these receptors in the invasion of melanoma cells inducing EGFR and MET up‐ and down‐regulations in examined cells. Results were acquired with assays evaluating cell migration and invasion (scratch wound assay, Transwell filter‐based method and single‐cell tracking). We revealed that cells' motile abilities are increased after EGFR overexpression and decreased following EGFR and MET silencing. This outcome correlates with elevated (EGFR up‐regulation) or reduced (EGFR/MET down‐regulation) number of formed invadopodia, visualized with immunofluorescence, and their rate of proteolytic abilities, evaluated by fluorescent gelatin degradation assay, and gelatin zymography, compared to control cells. Above‐mentioned data indicate that both—EGFR and MET signalling is directly connected with melanoma cells invasion, what establishes these receptors as promising targets for anti‐cancer treatment.

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“…For example, CD24 was shown to support the expression of HER2 and contribute to decrease the sensitivity of HER2-positive breast cancer cells to lapatinib (HER2-targeted therapy) [21]. EGFR, a homodimer of ErbB1, is of particular importance in gastric cancer, as its level of expression is increased during the progression of tumor progression and is correlated with reduced overall survival [22]. In the present study, we investigated the relevance of EGFR expression in CD24 positive gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

CD24 associates with EGFR and supports EGF/EGFR signaling via RhoA in gastric cancer cells

Deng

et al. 2016

J Transl Med

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BackgroundCD24, a mucin-like membrane glycoprotein, plays a critical role in carcinogenesis, but its role in human gastric cancer and the underlying mechanism remains undefined.MethodsThe contents of CD24 and epidermal growth factor receptor (EGFR) in gastric cancer cells (SGC-7901 and BGC-823) and non-malignant gastric epithelial cells (GES-1) were evaluated by Western blotting assay. Cellular EGFR staining was examined by immunofluorescence assay. Cell migration rate was measured by wound healing assay. The effects of depletion/overexperssion of CD24 on EGFR expression and activation of EGF/EGFR singaling pathways were evaluated by immunofluorescence, qPCR, Western blotting and flow cytometry techniques. RhoA activity was assessed by pulldown assay. CD24 and EGFR expression patterns in human gastric tumor samples were also investigated by immunohistochemistry staining.ResultsCD24 was overexpressed in human gastric cancer cells. Ectopic expression of CD24 in gastric epithelial cells augmented the expression of EGFR, while knockdown of CD24 in gastric cancer cells decreased the level of EGFR and cell migration velocity. To further explore the mechanisms, we investigated the effect of CD24 expression on EGF/EGFR signaling. We noticed that this effect of CD24 on EGFR expression was dependent on promoting EGFR internalization and degradation. Lower ERK and Akt phosphorylations in response to EGF stimulation were observed in CD24-depleted cells. In addition, we noticed that the effect of CD24 on EGFR stability was mediated by RhoA activity in SGC-7901 gastric cancer cells. Analysis of gastric cancer specimens revealed a positive correlation between CD24 and EGFR levels and an association between CD24 expression and worse prognosis.ConclusionThus, these findings suggest for the first time that CD24 regulates EGFR signaling by inhibiting EGFR internalization and degradation in a RhoA-dependent manner in gastric cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0787-y) contains supplementary material, which is available to authorized users.

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Knockdown of EGFR inhibits growth and invasion of gastric cancer cells

Cited by 27 publications

References 38 publications

Rab11‐FIP2 promotes the metastasis of gastric cancer cells

Rab11‐FIP2 promotes the metastasis of gastric cancer cells

Expression level of EGFR and MET receptors regulates invasiveness of melanoma cells

CD24 associates with EGFR and supports EGF/EGFR signaling via RhoA in gastric cancer cells

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