Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells

Black, Peter C.; Brown, Gordon A.; Inamoto, Teruo; Shrader, Marissa; Arora, Ameeta; Siefker-Radtke, Arlene; Adam, Liana; Theodorescu, Dan; Wu, Xifeng; Munsell, Mark F.; Bar‐Eli, Menashe; McConkey, David J.; Dinney, Colin P.

doi:10.1158/1078-0432.ccr-07-1593

Cited by 95 publications

(92 citation statements)

References 39 publications

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“…Specifically, the combined inhibition of PI3K/Akt and b-catenin signaling may block the transformed growth of such E-cadherindeficient cells. Recent studies have shown that E-cadherin-deficient tumors are more resistant to treatment with epidermal growth factor receptor inhibitors (Yauch et al, 2005;Witta et al, 2006;Black et al, 2008). One possible explanation is that specific epidermal growth factor receptor inhibitors may fail to inhibit the growth of E-cadherin-deficient cells because b-catenin signaling could still promote the constitutive activation of PI3K/Akt signaling by inhibition of PTEN expression, thus promoting transformed growth.…”

Section: Regulation Of Pten Levels By Cell Density and E-cadherin-cadmentioning

confidence: 99%

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

2011

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E-cadherin is a cell-cell adhesion protein and tumor suppressor that is silenced in many malignancies. E-cadherin is thought to suppress tumor cell growth by antagonizing b-catenin signaling. However, the role of E-cadherin in ovarian cancer progression is still controversial. In this study, we showed that loss of E-cadherin induced ovarian cancer cell growth and constitutive activation of phosphoinositide 3-kinase (PI3K)/Akt signaling by the inhibition of phosphatase and tensin homolog (PTEN) transcription through the downregulation of early growth response gene 1 (Egr1). In addition, immunofluorescence microscopy and T-cell factor promoter/luciferase reporter assays showed that E-cadherin loss was associated with enhanced nuclear b-catenin signaling. Constitutive activation of PI3K/Akt signaling reinforced nuclear b-catenin signaling by inactivating glycogen synthase kinase-3b indicating cross-talk between the PI3K/Akt and b-catenin signaling pathways. Finally, we found that E-cadherin negatively regulates tumor cell growth, in part, by positively regulating PTEN expression via b-catenin-mediated Egr1 regulation, thus influencing PI3K/Akt signaling. In summary, endogenous E-cadherin inhibits PI3K/Akt signaling by antagonizing b-catenin-Egr1-mediated repression of PTEN expression. Thus, the loss of E-cadherin itself may contribute to dysregulated PI3K/Akt signaling through its effects on PTEN, or it may exacerbate the frequent activation of PI3K/Akt signaling that occurs as a result of overexpression, mutation and/or amplification.

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Section: Regulation Of Pten Levels By Cell Density and E-cadherin-cadmentioning

confidence: 99%

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

2011

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“…One potential mechanism underlying this observation is that high Tβ4 expression mainly accelerates the deteriorative process via specific EMTinducing signals in advanced BTCC, thereby inducing local invasion and distant metastasis; however, the precise details of how this process directly affects recurrence in early-stage carcinoma remains unknown. In addition, E-cadherin is not only the first and most important regulator of the EMT but also is clearly associated with the clinical outcomes of BTCC, such as recurrence [24]. However, several factors (e.g., microRNA-205, Twist) or pathways (e.g., epidermal growth factor receptor, tumor necrosis factor-related apoptosisinducing ligand) might interact with Tβ4 or influence the biological features of BTCC through acting on E-cadherin expression [25]; as a result, our findings demonstrated that Tβ4 was likely not an independent prognostic factor for recurrence.…”

Section: Discussionmentioning

confidence: 99%

Association of thymosin β4 expression with clinicopathological parameters and clinical outcomes of bladder cancer patients

Wang¹,

Zhang²,

Yang³

et al. 2016

neo

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The clinical significance of thymosin β4 (Tβ4) expression in bladder transitional cell carcinoma (BTCC) remains unclear. The present study assessed the relationship between the expression of Tβ4 protein and the clinicopathological features, as well as the prognosis of bladder cancer patients. Tβ4 protein expression in 24 normal bladder and 138 primary BTCC tissue specimens was detected by immunohistochemistry, and the association of this expression with BTCC clinicopathological features and recurrence as well as patient survival was analyzed. Tβ4 expression was significantly stronger in BTCC patients than in normal volunteers. The expression of Tβ4 was significantly associated with differentiation capability, tumor stage and lymph node metastasis (P = 0.025, 0.043, and 0.039, respectively). Moreover, Tβ4 expression was positively correlated with integrin-linked kinase (ILK) and β-catenin expression (P = 0.042, 0.031, respectively) and inversely correlated with Ecadherin expression (P = 0.022). In the present cohort of bladder cancer patients, Tβ4 expression was found to be a predictor of poor survival (P < 0.05); however, high Tβ4 expression exhibited unfavorable prognostic value for recurrence. These data suggested that Tβ4 is correlated with the pathogenesis of BTCC. In addition, the patients with higher Tβ4 expression had a shorter survival.

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“…Several groups reported that sensitivity to EGFR directed therapy is associated with expression of E-cadherin and other characteristics of a typical "epithelial" tumor phenotype [35][36][37][38][39]. Loss of E-cadherin expression is a hallmark of the EMT process, which is implicated in tumor invasion, migration and metastasis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo

Cho¹,

Kim²,

Lee³

et al. 2014

Tumor Microenvironment and Therapy

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MicroRNA-21 (miR-21) plays important roles in carcinogenesis and is highly expressed in diverse human cancers. We evaluated the potential of targeting miRNA-21 to overcome the radioresistance of human cancer cells having an activated EGFR2-associated signaling and also aimed to elucidate the mechanisms of radiosensitization, and the effect on epithelial- mesenchymal transition (EMT). Ectopic overexpression of miR-21 up-regulated EGFR/HER2-associated signaling and increased radioresistance of a panel of human cancer cells (U251, U87, and A549 cells). In contrast, a specific inhibitor of miR-21 attenuated this signaling and radiosensitized a panel of human cancer cells. Inhibition of miR-21 was associated with persistent γH2AX foci formation. Inhibition of miR-21 decreased the typical features of EMT, such as invasion and migration and vascular tube formation. Treatment with anti-miR-21 decreased tumor burden in nude mice bearing intracranial U251 xenografts compared to controls. Combined treatment of anti-miR-21 and radiation further decreased tumor burden compared to each treatment alone. In summary, miR-21 is an important onco-miR, which confers radioresistance and diverse features of EMT. Inhibition of miR-21 could be a potential strategy for improving the efficacy of radiation therapy via unique modulation of pro-survival signaling implicated in radiation response and EMT.

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Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells

Cited by 95 publications

References 39 publications

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

Association of thymosin β4 expression with clinicopathological parameters and clinical outcomes of bladder cancer patients

MicroRNA-21 inhibitor potentiates anti-tumor effect of radiation therapy in vitro and in vivo

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