Epigenetic Switch between <i>SOX2</i> and <i>SOX9</i> Regulates Cancer Cell Plasticity

Lin, Sheng-Chieh; Chou, Yu‐Ting; Jiang, Shih Sheng; Chang, Junn-Liang; Chung, Chih‐Hung; Kao, Yu-Rung; Chang, I–Shou; Wu, Cheng‐Wen

doi:10.1158/0008-5472.can-15-3178

Cited by 55 publications

(56 citation statements)

References 47 publications

(56 reference statements)

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“…HCC827 cells were kindly provided by Dr. Jeff Wang (Development Center for Biotechnology, Taiwan) and further certified via short tandem repeat-PCR DNA profiling in 2013 (37). H1975 cells were obtained from Dr. Wayne Chang (National Health Research Institutes, Taiwan) and further authenticated via EGFR sequencing analysis in 2015 (38). HCC827GR cells were established in our laboratory, as described in Supplementary Materials and Methods, and tested positive for human origin carrying specific EGFR mutations by EGFR sequencing analysis (Supplementary Fig.…”

Section: Cell Culturementioning

confidence: 99%

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Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition

et al. 2017

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Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. .

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Section: Cell Culturementioning

confidence: 99%

“…Approval for this study was granted by the Institutional Review Board protocol number CRC-04-11-05. The public gene expression profiling datasets used in this study were analyzed as described previously (38). The sources of these gene expression profiling datasets are listed in Supplementary Table S5.…”

Section: Tissue Samples and Public Domain Data Analysismentioning

confidence: 99%

Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition

et al. 2017

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“…These findings support the notion that CEA expression patterns in patients can be altered by TKI treatment, and patients with changes in expression patterns of CEA In and CEA Pd may exhibit different responses toward subsequent chemotherapies after the EGFR-TKI treatment. We have previously reported that tumor heterogeneity is in part regulated by epigenetic control to generate lung cancer cells with distinct dissemination and chemoresistant properties 35 . Whether heterogeneous CEA expression patterns and related oncogenic properties in lung cancer cells are under epigenetic control requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Association of Divergent Carcinoembryonic Antigen Patterns and Lung Cancer Progression

Kuo

Zheng

Huang

et al. 2020

Sci Rep

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changes in expression patterns of serum carcinoembryonic antigen at initial diagnosis (ceA in) and disease progression (ceA pd) in lung cancer patients under eGfR-tyrosine kinase inhibitors (tKi) treatment may reflect different tumor progression profiles. Of the 1736 lung cancer patients identified from the cancer registry group between 2011 to 2016, we selected 517 patients with advanced stage adenocarcinoma, data on eGfR mutation status and ceA in , among whom were 288 patients with data on ceA pd , eligible for inclusion in the correlation analysis of clinical characteristics and survival. Multivariable analysis revealed that ceA in expression was associated with poor progression-free survival in patients harboring mutant EGFR. Moreover, CEA in and ceA pd were associated with the good and poor post-progression survival, respectively, in the EGFR-mutant group. Cell line experiments revealed that CEA expression and cancer dissemination can be affected by EGFR-TKI selection. EGFR-mutant patients, exhibiting high ceA in (≥5 ng/mL) and low CEA pd (<5 ng/mL), showed a potential toward displaying new metastasis. Taken together, these findings support the conclusion that EGFR mutation status is a critical factor in determining prognostic potential of ceA in and ceA pd in patients under eGfR-tKi treatment, and ceA in and ceA pd are associated with distinct cancer progression profiles. Carcinoembryonic antigen (CEA) is one of the most commonly used tumor markers whose overexpression was first discovered in colorectal cancer and followed by cancers in the aerodigestive tract and other organs 1,2. Serum CEA is used as a marker along with imaging for monitoring tumor progression and predicting survival outcomes in colorectal cancer 3,4. Although the suitability of CEA as an effective marker for lung cancer remains debatable, characteristics such as lower cost, noninvasiveness, and lack of other reliable markers, make CEA an attractive option in lung cancer 5,6. Additionally, CEA measurements before and after surgery have been suggested to provide valuable information for predicting disease progression and for determining the need for adjuvant treatment during early stage lung cancer 7,8. As proven by several large-scale clinical trials, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) are highly effective in lung cancer patients harboring EGFR activating mutations, mainly, deletions in exon 19 (Del19) and a L858R mutation in exon 21 9-13. However, despite an initial positive response, patients harboring the activating EGFR mutations ultimately develop resistance to EGFR-TKI by different mechanisms 14-18. Thus, the utility of CEA as a predictive or prognostic marker of EGFR-TKI treatment response remains controversial. Several studies have reported that serum CEA levels are closely associated with EGFR-TKI treatment outcomes, and that high CEA expression after EGFR-TKI treatment predicts poor survival in patients with EGFR-mutant lung cancer 19,20. In contrast, some reports have shown that CEA levels...

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“…Interestingly, SOX2 was expressed in highly proliferative but minimally invasive lung cancer cells; in contrast, cells with highly invasiveness capacity exhibited increased SOX9 expression but reduced SOX2 expression. The switch between SOX2 and SOX9 expression is epigenetically controlled and is important for determining cancer cell plasticity and metastatic progression [78]. Ectopic expression of SOX9 enhanced growth, invasion, and angiogenesis, whereas silencing of endogenous SOX9 markedly impaired tumor growth in prostate cancer.…”

Section: Sox9 and Cancermentioning

confidence: 99%

SOX Genes and Cancer

Cui¹,

Zhao²,

Hu³

2018

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

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Transcription factors play a critical role in regulating the gene expression programs that establish and maintain specific cell states in humans. Deregulation of these gene expression programs can lead to a broad range of diseases including cancer. SOX transcription factors are a conserved group of transcriptional regulators that mediates DNA binding by a highly conserved high-mobility group (HMG) domain. Numerous evidence has recently demonstrated that SOX transcription factors critically control cell fate and differentiation in major developmental processes, and that their upregulation may be important for cancer progression. In this review, we discuss recent advances in our understanding of the role of SOX genes in cancer.

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Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity

Cited by 55 publications

References 47 publications

Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition

Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition

Association of Divergent Carcinoembryonic Antigen Patterns and Lung Cancer Progression

SOX Genes and Cancer

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