Ionizing Radiation Promotes Migration and Invasion of Cancer Cells Through Transforming Growth Factor-Beta–Mediated Epithelial–Mesenchymal Transition

Zhou, Yunyun; Liu, Jun-Ye; Li, Jing; Zhang, Jie; Xu, Yuan; Zhang, Huawei; Qiu, Lian-Bo; Ding, Gui‐Rong; Su, Xiaoming; Mei-Shi,; Guo, Guozhen

doi:10.1016/j.ijrobp.2011.06.1956

Cited by 133 publications

(137 citation statements)

References 17 publications

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“…It has been shown that IR can activate TGF-b signaling, 40 and EMT mediated by TGF-b/Smad signaling may be a mechanism in the IR-promoted migration and invasion of cancer cells. 18 Consistent with the results of Inhibition of TBK1 attenuates radiation-induced EMT of A549 cells W Liu et al previous researchers, we found an increase in TGF-b and phosphorylation of Smad3, but we did not detect such changes in TBK1 knockdown cells. This suggests the lack of cross-talk between TBK1 signaling and the TGF-b/Smad pathway.…”

Section: Discussionsupporting

confidence: 92%

“…27 Numerous studies have attempted to clarify the role of TGF-b in EMT 28 and the pathways involved in radiation-induced EMT. 18 Therefore, we studied the TGF-b signaling in response to radiation and identified that if TBK1 modulated it. We first investigated the level of TGF-b in cell lysate by real-time PCR.…”

Section: Tgf-b/smad Pathway Are Not Attenuated By Tbk1 Inhibitionmentioning

confidence: 99%

“…15 Previous findings indicate that ionizing radiation (IR) is able to affect abundance of proteases and transcription factors involving in multiple signaling pathways participating in this complex pathogenesis. [16][17][18] Thus, utilizing this knowledge and identifying novel pathways for therapeutic targets is the first goal in research on pulmonary neoplasms.…”

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confidence: 99%

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Inhibition of TBK1 attenuates radiation-induced epithelial–mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1

Huang

et al. 2014

Laboratory Investigation

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Radiotherapy is an effective treatment method for lung cancer, particularly when the disease is at an advanced stage. However, previous researchers have observed that the majority of patients with conventional radiation therapy develop distant metastases and succumb to the disease. Thus, identifying and understanding novel pathways for the development of new therapeutic targets is a major goal in research on pulmonary neoplasms. Recent studies suggest that epithelial-mesenchymal transition (EMT) is the most important contributor to cancer metastasis. Induction of this complex process requires endogenously produced microRNAs; specifically, downregulation of the miRNA-200c causes an induction of EMT. We recently identified the tank-binding kinase-1 (TBK1) as a downstream effector of the miR-200c-driven pathway, but the biological function of TBK1 in EMT remains unknown. In this study, we tested whether TBK1 has a role in radiation-induced EMT and identified associated potential mechanisms. Human alveolar type II epithelial carcinoma A549 cells were irradiated with 60 Co g-rays. Western blotting revealed a time-and dose-dependent decrease in E-cadherin with a concomitant increase in vimentin after radiation, suggesting that the epithelial cells acquired a mesenchymal-like morphology. TBK1 siRNA significantly inhibited radiationinduced suppression of the epithelial marker E-cadherin and upregulation of the mesenchymal marker vimentin. The invasion and migratory potential of lung cancer cells upon radiation treatment was also reduced by TBK1 knockdown. Furthermore, radiation-induced EMT attenuated by TBK1 depletion was partially dependent on transcriptional factor ZEB1 expression. Finally, we found glycogen synthase kinase-3b (GSK-3b) is involved in regulation of radiation-induced EMT by TBK1. Thus, our findings reveal that TBK1 signaling regulates radiation-induced EMT by controlling GSK-3b phosphorylation and ZEB1 expression. TBK1 may therefore constitute a useful target for treatment of radiotherapy-induced metastasis diseases.

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Section: Discussionsupporting

confidence: 92%

Section: Tgf-b/smad Pathway Are Not Attenuated By Tbk1 Inhibitionmentioning

confidence: 99%

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confidence: 99%

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Inhibition of TBK1 attenuates radiation-induced epithelial–mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1

Huang

et al. 2014

Laboratory Investigation

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“…Despite the response of HCC to stereotactic body radiation therapy (SBRT) has been described for the past few years, and the fact that radiation can be delivered to tumors while avoiding damage to normal sensitive organs (5), the existence of radioresistant cells in HCC is remains an important reason for the local failure of radiotherapy (6,7). Thus, understanding the mechanisms underlying radioresistance may provide an opportunity to develop more effective therapies.…”

Section: Introductionmentioning

confidence: 99%

HAb18G/CD147 Promotes Radioresistance in Hepatocellular Carcinoma Cells: A Potential Role for Integrin β1 Signaling

Dang³

et al. 2015

Molecular Cancer Therapeutics

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Radiotherapy has played a limited role in the treatment of hepatocellular carcinoma (HCC) due to the risk of tumor radioresistance. A previous study in our laboratory confirmed that CD147 interacts with integrin b1 and plays an important role in modulating the malignant properties of HCC cells. In this study, we further evaluated the role of CD147 in the radioresistance of HCC and as a potential target for improving radiosensitivity. Upon irradiation, the colony formation, apoptosis, cell-cycle distribution, migration, and invasion of SMMC-7721, CD147-knockout SMMC-7721, HepG2, and CD147-knockdown HepG2 cells were determined. A nude mouse xenograft model and a metastatic model of HCC were used to detect the role of CD147 in radioresistance in vivo. Deletion of HAb18G/CD147 significantly enhanced the radiosensitivity of SMMC-7721 and HepG2 cells, and knocking out HAb18G/CD147 in SMMC-7721 cells attenuated irradiation-enhanced migration and invasion. The knockout and antibody blockade of CD147 decreased the tumor growth and metastatic potentials of HCC cells under irradiation. CD147-deleted SMMC-7721 cells showed diminished levels of calpain, cleaved talin, active integrin b1, and decreased p-FAK (Tyr397) and p-Akt (Ser473) levels. FAK and PI3K inhibitors, as well as integrin b1 antibodies, increased the radiation-induced apoptosis of SMMC-7721 cells. Our data provide evidence for CD147 as an important determinant of radioresistance via the regulation of integrin b1 signaling. Inhibition of the HAb18G/CD147 integrin interaction may improve the efficiency of radiosensitivity and provide a potential new approach for HCC therapy.

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“…However, the effect was significantly enhanced with an addition of exogenous TGF-β. Moreover, the radiation-induced secretion of TGF-β from the surrounding stroma may increase the invasive abilities of the neighbouring epithelial cells via EMT which could be one of the early stages in the radiation-activated tumourigenic changes (Barcellos-Hoff and Nguyen, 2009;Bouquet et al, 2011;Zhou et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Lack of epithelial-to-mesenchymal transition induction in two bronchial epithelial cell lines after alpha and gamma irradiation

Acheva

Eklund

Lemola

et al. 2015

IJLR

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Abstract:The induction of epithelial-to-mesenchymal transition (EMT) in human lung epithelial cell lines was investigated after α-particle and γ-radiation exposures. We applied TGF-β treatment of cells as positive EMT-controls and tested in parallel if radiation has a potentiating effect on the EMT induction. BEAS-2B and HBEC-3KT cells were irradiated with 5.4 MeV α-particles or γ-rays ( 60 Co, 1.13-1.15 Gy/min) with or without of TGF-β. The cells were harvested three days post treatment and the EMT markers vimentin, fibronectin and E-cadherin were analysed by immunofluorescence staining and Western blotting. The TGF-β treatment-induced EMT in both cell lines in the applied concentrations. We could not prove any clear EMT induction with low or moderate doses of α-particles and γ-rays. No significant additive effect with radiation and TGF-β was observed. We suggest that there might be a different mechanism induced by radiation in bronchial cells after radon and medical exposures that does not involve direct EMT changes.

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Ionizing Radiation Promotes Migration and Invasion of Cancer Cells Through Transforming Growth Factor-Beta–Mediated Epithelial–Mesenchymal Transition

Cited by 133 publications

References 17 publications

Inhibition of TBK1 attenuates radiation-induced epithelial–mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1

Inhibition of TBK1 attenuates radiation-induced epithelial–mesenchymal transition of A549 human lung cancer cells via activation of GSK-3β and repression of ZEB1

HAb18G/CD147 Promotes Radioresistance in Hepatocellular Carcinoma Cells: A Potential Role for Integrin β1 Signaling

Lack of epithelial-to-mesenchymal transition induction in two bronchial epithelial cell lines after alpha and gamma irradiation

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