β-Catenin/POU5F1/SOX2 Transcription Factor Complex Mediates IGF-I Receptor Signaling and Predicts Poor Prognosis in Lung Adenocarcinoma

Xu, Chuan; Xie, Dan; Yu, Shi Cang; Yang, Xiao; Li, He; Yang, Jing; Ping, Yi; Wang, Bin; Yang, Lang; Xu, Sen Lin; Cui, Wei; Wang, Qing Liang; Fu, Wen; Liu, Qing; Qian, Cheng; Cui, Yinghui; Rich, Jeremy; Kung, Hsiang Fu; Zhang, Xia; Bian, Xiu Wu

doi:10.1158/0008-5472.can-12-4403

Cited by 86 publications

(70 citation statements)

References 52 publications

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“…CD133 expression is linked to a resistant phenotype in NSCLC and suggests that the detection of CD133 + cells may be useful to predict the efficacy of cytotoxic therapy for lung cancer (34). In addition, SOX2 expression maintained the self-renewal of lung cancer cells and was positively correlated with the metastatic progression of NSCLC (35,36), suggesting that CD133 and SOX2 expression plays an important role in studying the properties of cancer stem cells and the therapeutic response in lung cancer. Our study observed that SOX2 and CD133 expression were positively correlated with EGFR-TKI nonresponders and low expression levels of FOXO3a in lung cancer patients, and we found that NF-κB/miR-155 decreased FOXO3a expression to enhance CSC characteristics in vitro and in vivo, indicating that the NF-κB-driven suppression of FOXO3a plays a crucial role in CSC properties and EGFR-TKI resistance of lung cancer.…”

Section: Discussionmentioning

confidence: 99%

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3′UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

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Section: Discussionmentioning

confidence: 99%

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Several studies reported that SOX2 contributed to tumorigenesis and tumor progression of diverse cancers, including lung cancer [9], breast cancer [10], esophageal cancer [11].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR‐638 promotes invasion and proliferation by regulating SOX2 and induces EMT in NSCLC

Xia

Liu

et al. 2014

FEBS Letters

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Edited by Tamas DalmayKeywords: miR-638 SRY (sex determining region Y)-box 2 Proliferation Invasion Epithelial-to-mesenchymal transition Non-small-cell lung cancer a b s t r a c t Aberrant expression of microRNAs has been shown to regulate the biological processes of lung cancer cells. However, the role of miR-638 in the development of NSCLC is still unclear. In this study, low miR-638 and high SOX2 were shown to be associated with tumor size and metastasis of NSCLC patients. Downregulated miR-638 could promote cell invasion and proliferation, while high miR-638 expression reversed the effect. Furthermore, miR-638 could regulate SOX2 by directly binding to its 3 0 -UTR. Silencing of SOX2 by siRNA partially abolished the enhancement of cell invasion and proliferation induced by downregulated miR-638. Aberrant miR-638 expression could modulate the expression levels of markers of epithelial-to-mesenchymal transition. Our results indicate that miR-638 may play a pivotal role in the development of NSCLC.

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“…Recent studies have demonstrated that aberrant expression of IGF-1R was correlated with tumor growth and poor prognosis in several human cancers such as myeloma[13] and breast cancer[14]. On the other hand, IGF-1R, as a hallmark of cell carcinogenesis, could also be regulated by transcription factors(TFs)[15], methylation[16] and microRNAs(miRNAs)[6, 17]. …”

Section: Introductionmentioning

confidence: 99%

IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma

Gao

Wang

et al. 2014

Oncotarget

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Insulin-like growth factor (IGF) signaling is involved in oral squamous cell carcinoma (OSCC), but IGF-1 receptor (IGF-1R)-mediated intricate regulatory networks among molecular interactions and signalling path ways in OSCC remain unclear. Here, we found that overexpression of IGF-1R and insulin receptor substrate-2 (IRS-2) was negatively associated with histological differentiation. IGF signaling stimulated OSCC cell growth. Conversely, overexpression of let-7b inhibited proliferation and colony formation and triggered S/G2 cell cycle arrest by targeting IGF-1R and IRS-2 through the Akt pathway. Also, the inverse relationship between expression of let-7b and IGF-1R/IRS-2 was confirmed in OSCC tumor xenografts and clinical specimens. Furthermore, by activating ERK1/2, IGF-1R transcriptionally upregulated IRS-2. Our results indicate that let-7b/IGF-1R-mediated crosstalk between IRS-2/Akt and MAPK is involved in OSCC and is a potential therapeutic target for therapy.

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β-Catenin/POU5F1/SOX2 Transcription Factor Complex Mediates IGF-I Receptor Signaling and Predicts Poor Prognosis in Lung Adenocarcinoma

Cited by 86 publications

References 52 publications

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Downregulation of miR‐638 promotes invasion and proliferation by regulating SOX2 and induces EMT in NSCLC

IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma

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