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GSK-3? regulates the endothelial-to-mesenchymal transition via reciprocal crosstalk between NSCLC cells and HUVECs in multicellular tumor spheroid models.

ABSTRACT: BACKGROUND:Chemotherapy used for patients with unresectable lung tumors remains largely palliative due to chemoresistance, which may be due to tumor heterogeneity. Recently, multiple studies on the crosstalk between lung cancer cells and their tumor microenvironment (TME) have been conducted to understand and overcome chemoresistance in lung cancer. METHODS:In this study, we investigated the effect of reciprocal crosstalk between lung cancer cells and vascular endothelial cells using multicellular tumor spheroids (MCTSs) containing lung cancer cells and HUVECs. RESULTS:Secretomes from lung cancer spheroids significantly triggered the endothelial-to-mesenchymal transition (EndMT) process in HUVECs, compared to secretomes from monolayer-cultured lung cancer cells. Interestingly, expression of GSK-3?-targeted genes was altered in MCTSs and inhibition of this activity by a GSK-3? inhibitor induced reversion of EndMT in lung tumor microenvironments. Furthermore, we observed that HUVECs in MCTSs significantly increased the compactness of the spheroids and exhibited strong resistance against Gefitinib and Cisplatin, relative to fibroblasts, by facilitating the EndMT process in HUVECs. Subsequently, EndMT reversion contributed to control of chemoresistance, regardless of the levels of soluble transforming growth factor (TGF)-?. Using the MCTS xenograft mouse model, we demonstrated that inhibition of GSK-3? reduces lung cancer volume, and in combination with Gefitinib, has a synergistic effect on lung cancer therapy. CONCLUSION:In summary, these findings suggest that targeting EndMT through GSK-3? inhibition in HUVECs might represent a promising therapeutic strategy for lung cancer therapy.

SUBMITTER: Kim SH

PROVIDER: S-EPMC6359813 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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GSK-3β regulates the endothelial-to-mesenchymal transition via reciprocal crosstalk between NSCLC cells and HUVECs in multicellular tumor spheroid models.

Kim Se-Hyuk SH Song Yeonhwa Y Seo Haeng Ran HR

Journal of experimental & clinical cancer research : CR 20190201 1

<h4>Background</h4>Chemotherapy used for patients with unresectable lung tumors remains largely palliative due to chemoresistance, which may be due to tumor heterogeneity. Recently, multiple studies on the crosstalk between lung cancer cells and their tumor microenvironment (TME) have been conducted to understand and overcome chemoresistance in lung cancer.<h4>Methods</h4>In this study, we investigated the effect of reciprocal crosstalk between lung cancer cells and vascular endothelial cells us ...[more]

PMID: 30709379

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Project description:BackgroundMetastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial-mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified.MethodsThe expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting.ResultsCHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002.ConclusionThese results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.

Project description:Rationale: Glioblastoma (GBM) is the most common and aggressive brain tumor, characterized by its propensity to invade the surrounding brain parenchyma. The effect of extracellular high-mobility group box 1 (HMGB1) protein on glioblastoma (GBM) progression is still controversial. p62 is overexpressed in glioma cells, and has been associated with the malignant features and poor prognosis of GBM patients. Hence, this study aimed to clarify the role of p62 in HMGB1-induced epithelial-mesenchymal transition (EMT) of GBM both in vitro and in vivo. Methods: Immunoblotting, immunofluorescence and qRT-PCR were performed to evaluate EMT progression in both human GBM cell line and primary GBM cells. Transwell and wound healing assays were used to assess the invasion and migration of GBM cells. shRNA technique was used to investigate the role of p62 in HMGB1-induced EMT both in vitro and in vivo orthotopic tumor model. Co-immunoprecipitation assay was used to reveal the interaction between p62 and GSK-3β (glycogen synthase kinase 3 beta). Immunohistochemistry was performed to detect the expression levels of proteins in human GBM tissues. Results: In this study, GBM cells treated with recombinant human HMGB1 (rhHMGB1) underwent spontaneous EMT through GSK-3β/Snail signaling pathway. In addition, our study revealed that rhHMGB1-induced EMT of GBM cells was accompanied by p62 overexpression, which was mediated by the activation of TLR4-p38-Nrf2 signaling pathway. Moreover, the results demonstrated that p62 knockdown impaired rhHMGB1-induced EMT both in vitro and in vivo. Subsequent mechanistic investigations showed that p62 served as a shuttling factor for the interaction of GSK-3β with proteasome, and ultimately activated GSK-3β/Snail signaling pathway by augmenting the degradation of GSK-3β. Furthermore, immunohistochemistry analysis revealed a significant inverse correlation between p62 and GSK-3β, and a combination of the both might serve as a more powerful predictor of poor survival in GBM patients. Conclusions: This study suggests that p62 is an effector for HMGB1-induced EMT, and may represent a novel therapeutic target in GBM.

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GSK-3? regulates the endothelial-to-mesenchymal transition via reciprocal crosstalk between NSCLC cells and HUVECs in multicellular tumor spheroid models.

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GSK-3β regulates the endothelial-to-mesenchymal transition via reciprocal crosstalk between NSCLC cells and HUVECs in multicellular tumor spheroid models.

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