TBX2 overexpression promotes proliferation and invasion through epithelial‑mesenchymal transition and ERK signaling pathway

Liu, Xingyu; Zhang, Miao; Wang, Zhenning; Zhao, Tingting; Xu, Yingying; Song, Yongxi; Huang, Jinyu; Zhang, Junyan; Xu, Hao; Wu, Jianhua; Xu, Hui

doi:10.3892/etm.2018.7028

Cited by 14 publications

(16 citation statements)

References 45 publications

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“…Moreover, IPA analysis shows that OU and Digo could reduce the activity of many transcription factors in which overexpression is required for sustained proliferation and cancer progression (e.g., NRF2, SOX11, TBX2) [ 48 , 49 , 50 , 51 ]. This implies that these CGs could generally impact the transcriptional networks required for sustained cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Busonero

Leone

Bianchi

et al. 2020

Cancers

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Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.

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Section: Discussionmentioning

confidence: 99%

Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Busonero

Leone

Bianchi

et al. 2020

Cancers

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“…We proved that TBX2 driving LAC oncogenesis and metastasis through epithelial mesenchymal transition (EMT) by western blot. And consistently the role of TBX2 in EMT has already been reported as well as ERK signaling pathway, triggering cell proliferation and invasion 53. Besides, there are also other pathways TBX2 involved that might promote bone metastasis.…”

Section: Discussionmentioning

confidence: 88%

TBX2 Identified as a Potential Predictor of Bone Metastasis in Lung Adenocarcinoma via Integrated Bioinformatics Analyses and Verification of Functional Assay

Yu¹,

Zhao²,

Li³

et al. 2020

J. Cancer

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Objective: Bone metastasis from patients with advanced lung adenocarcinoma (LAC) is a very serious complication. To better understand the molecular mechanism, our current study sheds light on identification of hub genes mediating bone metastatic spread by combining bioinformatic analysis with functional verification. Methods: First, we downloaded a lung adenocarcinoma dataset (GSE76194) from Gene Expression Omnibus, analyzed differentially expressed genes (DEGs) through Limma package in R software and constructed a protein-protein interaction network. Based on that preliminary data, we further performed modular and topological analysis using Cystoscope to obtain biological connected genes. Through literature searching and performing mRNA expression analysis on the other independent public dataset (GSE10799), we finally focused on TBX2. Functional effects of TBX2 were performed in tumorigenicity assays including migration and invasion assays, cell proliferation assay, and cell cycle assay. In addition, mechanically, we found enriched pathways related to bone metastasis using Gene Set Enrichment Analysis (GSEA) and validated our results by western blot. Result: A total of 1132 significant genes were sorted initially. We selected common significant genes (log FC>2; p<0.01) from both the biological network data and microarray data. In total, 44 such genes were identified. we found TBX2, along with 10 other genes, to be reported with relevance to bone metastasis in other cancer types. Moreover, TBX2 showed significantly higher expression levels in patients that were found positive for metastasis to bone marrow compared to patients that did not exhibit this type of metastasis in the other separated cohort (GSE10799). Thus, we finally focused on TBX2. We found that TBX2 had detectable expression in LAC cell lines and silencing endogenous TBX2 expression in A549 and H1299 cell lines markedly suppressed migration and invasion, cell proliferation and arrested cell-cycle. Pathway enrichment analyses suggested that TBX2 drove LAC oncogenesis and metastasis through various pathways with epithelial mesenchymal transition (EMT) figuring prominently in the bone metastatic group, which was evidenced by western blot. Conclusion: Collectively, TBX2 plays as a potential predictor of bone metastasis from LAC, yielding a better promise view towards "driver" gene responsible for bone metastasis.

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“…These results suggest involvement of the processes regulated by KLF6 in response to BTZ treatment and bridging of those process may result in a treatment resistant phenotype. Apart from this top hit, a number of genes shown to be involved in proliferation of cancer cells were statistically significantly associated with BTZ induced methylation changes, including: ARHGAP26 38 , TBX2 39 , 40 , MAML3 41 , DCLK1 42 , 43 . The “GO cellular components” (Fig.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

Łuczkowska

Sokołowska

Taryma-Leśniak

et al. 2021

Sci Rep

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The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.

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TBX2 overexpression promotes proliferation and invasion through epithelial‑mesenchymal transition and ERK signaling pathway

Cited by 14 publications

References 45 publications

Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

TBX2 Identified as a Potential Predictor of Bone Metastasis in Lung Adenocarcinoma via Integrated Bioinformatics Analyses and Verification of Functional Assay

Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound

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