APBB1 reinforces cancer stem cell and epithelial-to-mesenchymal transition by regulating the IGF1R signaling pathway in non-small-cell lung cancer cells

Lee, Jei Ha; Kim, Jung Yul; Kim, Seo Yeon; Choi, Soo Im; Kim, Kuk Chan; Cho, Eun Wie; Kim, In Gyu

doi:10.1016/j.bbrc.2016.11.030

Cited by 16 publications

(8 citation statements)

References 33 publications

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“…Among the NSCLC cells, A549 adenocarcinoma cells shows more metastatic abilities and resistance to γ-radiation than H460 large cell carcinoma cells. We previously showed that ALDH1 high cells sorted from A549 cells had extensive EMT properties and sphere-forming capacity in vitro 21 , 22 . In several other cancers, ALDH1 high cell subpopulations had been shown to be highly tumorigenic and more resistant to γ-radiation and drug treatments than ALDH1 low cell subpopulations 23 , 24 .…”

Section: Resultsmentioning

confidence: 99%

“…In previous studies, we have found that ALDH1 high and ALDH1 low cells sorted from NSCLC cells have very different gene profiles. Several significant genes were identified to be involved in the enhancement of ALDH1 high CSC-like properties through various signaling pathways, such as amyloid β A4 precursor protein-binding family B member 1 (APBB1), EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1), and transmembrane 4 superfamily member 4 (TM4SF4) 21 , 22 , 37 . For example, APBB1 regulates the expression of ALDH1 through activation of the IGF1R pathway, thereby regulating EMT-related, CSC-like characteristics and γ-radiation resistance in cells.…”

Section: Discussionmentioning

confidence: 99%

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Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1

Lee

Choi

Kim

et al. 2018

Sci Rep

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Tescalcin (TESC; also known as calcineurin B homologous protein 3, CHP3) has recently reported as a regulator of cancer progression. Here, we showed that the elevation of TESC in non-small cell lung cancer (NSCLC) intensifies epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties, consequently enhancing the cellular resistance to γ-radiation. TESC expression and the phosphorylation (consequent activation) of signal transducer and activator of transcription 3 (STAT3) were upregulated in CSC-like ALDH1high cells than in ALDH1low cells sorted from A549 NSCLC cells. Knockdown of TESC suppressed CSC-like properties as well as STAT3 activation through inhibition of insulin-like growth factor 1 receptor (IGF1R), a major signaling pathway of lung cancer stem cells. TESC activated IGF1R by the direct recruitment of proto-oncogene tyrosine kinase c-Src (c-Src) to IGF1Rβ complex. Treatment of IGF1R inhibitor, AG1024, also suppressed c-Src activation, implicating that TESC mediates the mutual activation of c-Src and IGF1R. STAT3 activation by TESC/c-Src/IGF1R signaling pathway subsequently upregulated ALDH1 expression, which enhanced EMT-associated CSC-like properties. Chromatin immunoprecipitation and luciferase assay demonstrated that STAT3 is a potential transcription activator of ALDH1 isozymes. Ultimately, targeting TESC can be a potential strategy to overcome therapeutic resistance in NSCLC caused by augmented EMT and self-renewal capacity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1

Lee

Choi

Kim

et al. 2018

Sci Rep

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“…In this study, we combined the use of pharmacological inhibitors and genetic manipulations to modulate the activity and expression of different FGFRs as well as the downstream mediators such as AKT and SOX2. We employed the sphereformation assay as a surrogate approach to evaluate the impact of such manipulations on self-renewal capabilities in vitro (Lee et al, 2017) and further used the xenograft model to evaluate their tumorigenic properties in vivo (Zhao et al, 2019). Though the regulation of FGF2 and FGFR2 on SOX2 has been already reported in the development phase (Mansukhani et al, 2005), we were the first to demonstrate that FGFR signaling regulates the protein stability of SOX2 through AKT and promotes its nuclear localization, thus enhancing stemness in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

An FGFR/AKT/SOX2 Signaling Axis Controls Pancreatic Cancer Stemness

Quan

Guo

Liu

et al. 2020

Front. Cell Dev. Biol.

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Cancer stemness is associated with high malignancy and low differentiation, as well as therapeutic resistance of tumors including pancreatic ductal adenocarcinoma (PDAC). Fibroblast growth factors (FGFs) exert pleiotropic effects on a variety of cellular processes and functions including embryonic stem cell pluripotency and cancer cell stemness via the activation of four tyrosine kinase FGF receptors (FGFRs). FGF ligands have been a major component of the cocktail of growth factors contained in the cancer stemness-inducing (CSI) and organoid culture medium. Although FGF/FGFR signaling has been hypothesized to maintain cancer stemness, its function in this process is still unclear. We report that inhibition of FGF/FGFR signaling impairs sphereforming ability of PDAC in vitro, and knocking down FGFR1 and FGFR2 decreased their tumorigenesis abilities in vivo. Mechanistically, we demonstrated that SOX2 is down-regulated upon loss of FGFR signaling. The overexpression of SOX2 in SOX2negative cells, which normally do not display stemness capabilities, is sufficient to induce spheroid formation. Additionally, we found that AKT phosphorylation was reduced upon FGFR signaling inhibition. The inhibition of AKT using specific pharmacological inhibitors in the context of CSI medium leads to the loss of spheroid formation associated with loss of SOX2 nuclear expression and increased degradation. We demonstrate that an FGFR/AKT/SOX2 axis controls cancer stemness in PDAC and therefore may represent an important therapeutic target in the fight against this very aggressive form of cancer.

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“…This result also suggested the feasibility of our present results. While other genes have not been reported to be associated with COAD/READ/CRC, their associations with other cancers have also been reported, such as APBB1, HHIP, and HOXA3 with lung cancer [30][31][32][33];TCF7L1, HOXB3, and ABCC2 with pancreatic cancer [34][35][36][37]; SALL1 with neck cancer [38,39];C2CD4A with breast cancer [40]. These results suggest both their relevance and their role as prognostic genes for corresponding cancers.Based on the results of our study and the relationship between those genes and other kind of cancers found in previous studies, it is suggested that those genes mentioned above may be used as prognostic genes for colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Combined Analysis of the Aberrant Epigenetic Alteration of Colorectal Cancer

Xing

Yao

Zhang

et al. 2020

Preprint

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BackgroundColorectal cancer (CRC) is the third most common cancer which could be classified as colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) mainly. Accumulating evidence indicatedmethylations are involved in multiple tumors.MethodsTo know the effect of abnormal methylation in COAD, READ and CRC, we downloaded methylation and mRNA data of COAD and READ from The Cancer Genome Atlas (TCGA) database. And then, we used DESeq2, ChAMP, DAVID 6.8, Cytoscape_3.7.2 and Correlation analysis to identify the potential biomarkers.ResultsWe obtain 12 potential biomarkers (APBB1, CDC42SE2, EIF4E3, FBXO17, FES, GNPNAT1, HSPA1A, OSBPL3, RORC, SALL1, SPEG, and TCF7L1) directly associated with the pathologic TNM of COAD maybe regulated by 28 differential methylations; 2 potential biomarkers (AQP1 and HOXA3) directly associated with pathologic NM maybe regulated by 8 differential methylations; and 15 potential biomarkers (ADAMTSL3, ANXA9, APBB1, AQP1, C2CD4A, CLIP3, DNAJC15, EIF4E3, FAM160A1, GNG4, HLX, HSPA1A, LAYN, NR3C2, and SYT1)directly associated with the pathologic TNM of COAD maybe regulated by 29 differential methylations. Furthermore, weconstruct the network of differential methylation and differential expression genes. In addition, we also obtain 1 methylation (cg18149207), 2 methylations (cg02000808 and cg21134232) and 2 methylations (cg04408595 and cg19413725) associated with the overall survival.ConclusionOur results provide an analysis of theoretical knowledge and clinical outcomes, but more researches are needed to confirm our findings.

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APBB1 reinforces cancer stem cell and epithelial-to-mesenchymal transition by regulating the IGF1R signaling pathway in non-small-cell lung cancer cells

Cited by 16 publications

References 33 publications

Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1

Tescalcin/c-Src/IGF1Rβ-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1

An FGFR/AKT/SOX2 Signaling Axis Controls Pancreatic Cancer Stemness

Combined Analysis of the Aberrant Epigenetic Alteration of Colorectal Cancer

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