EpEX/EpCAM and Oct4 or Klf4 alone are sufficient to generate induced pluripotent stem cells through STAT3 and HIF2α

Kuan, I.-I.; Liang, Kang-Hao; Wang, Yi Ping; Kuo, Ting-Wen; Meir, Yaa‐Jyuhn James; Wu, Sareina Chiung‐Yuan; Yang, Shan-Yi; Lu, Jean; Wu, Han‐Chung

doi:10.1038/srep41852

Cited by 45 publications

(43 citation statements)

References 48 publications

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“…Furthermore, we provide evidence that the soluble ectodomain EpEX, which is produced upon RIP of EpCAM [ 39 , 48 , 110 ] including HNSCC cell lines ( Fig 3 ), is a regulatory ligand of EGFR that induces ERK1/2 and AKT signaling ( Fig 9 ). The definition of EpEX as a ligand for EGFR is in line with recent reports on the activation of EGFR signaling after treatment with EpEX in mouse embryonic fibroblasts and in colon carcinoma cell lines [ 71 , 111 ]. In colon carcinoma cells, EpEX induced mild proliferation and regulated proteolysis of intact EpCAM molecules through the activation of ADAM17 and γ-secretase [ 111 ].…”

Section: Discussionmentioning

confidence: 58%

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

et al. 2018

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Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhigh HNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal–regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs.

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Section: Discussionmentioning

confidence: 58%

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

et al. 2018

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“…Since Yamanaka's factors (Sox2, Oct3/4, Klf4, and c‐Myc) were discovered for cell reprogramming, many studies have been conducted to establish more effective methods for inserting the glis family zinc finger 1 (Maekawa et al, ). The STAT3 signal regulates the expression of HIF‐2α, and this STAT3‐HIF‐2α pathway has been examined for its involvement in reprogramming and stemness processes in human iPS cells (Kuan et al, ). In this study, the relationship between STAT3 and the regulation of the pluripotency in human iPS cells was investigated using two specific inhibitors that suppressed the dimer formation and nuclear translocation of STAT3 (Schust, Sperl, Hollis, Mayer, & Berg, ; Siddiquee et al, ).…”

Section: Discussionmentioning

confidence: 99%

Effects of hypoxia inducible factors on pluripotency in human iPS cells

Sugimoto

Mizutani

Nakazono

et al. 2018

Microscopy Res & Technique

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A hypoxic condition is known to contribute to pluripotency. In the present article, the effects of transcription factors were first assessed regarding the proliferation and differentiation of human induced pluripotent stem (iPS) cells under hypoxic conditions using cell morphology and real-time polymerase chain reaction (RT-PCR). Morphology evaluations and RT-PCR revealed that the colony formation was promoted and the expression of pluripotent markers was increased under hypoxic conditions. In addition, the function of hypoxia inducible factors (HIFs) in human iPS cells under hypoxic conditions was evaluated in relation to the morphology and the expression of pluripotency markers by siRNA and RT-PCR. The HIF-2α silencing group showed a reduction in the colony size of human iPS cells and a statistically significant reduction in the expression of undifferentiation markers compared to the control group. Furthermore, the expression of HIF-2α was decreased when signal transducer and activator of transcription 3 (STAT3) was suppressed by its inhibitor, Stattic or S31 201. The inhibition using Stattic did not produce colony formation. The expression of pluripotent markers was also decreased using Stattic or S31 201. This study indicates that the HIF-2α expression in human iPS cells was activated under hypoxic conditions, similarly to that in murine iPS cells, and that HIF-2α among HIFs is the most effective compound for maintaining the pluripotency of human iPS cells. Furthermore, the STAT3 signal pathway regulates the expression of HIF-2α.

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“…It is unknown either how these factors, used in the present study, enhance stat3 expression or which one of them plays a crucial role in the activation. However, recent study has shown that Oct4 or Klf4 alone, but not Sox2, can successfully reprogram fibroblasts into induced pluripotent stem cells with the help of epithelial cell adhesion molecule (a trans-membrane protein) and its extracellular domain (a soluble protein), via activation of Stat3, which leads to the nuclear-translocation of HIF2α 30 . This study provides an evidence to show that Oct4 and Klf4 of the four factors may play a crucial role in activation of Stat3 and again supports our above argument.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming Factors Remodel Melanoma Cell Phenotype by Changing Stat3 Expression

et al. 2017

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The limited availability of melanoma stem cells is a major challenge for therapeutic reagent screening and study of molecular mechanisms. It has been shown that induced expression of four stem cell factors (Oct4, Sox2, Klf4, and c-Myc) changes the phenotype of osteosarcoma and breast cancer cells to osteosarcoma stem cells and breast cancer stem cells, respectively. The present study aimed to explore whether these four factors might change the phenotype of melanoma cells to melanoma stem cells and, if so, to examine the possible molecular signal involved. Melanoma B16-F10 cells were transfected with the plasmid TetO-FUW-OSKM which contains cDNA expressing four factors, driven by the Tet-On element. We found that expression of the four transcription factors was highly induced by DOX in the stable melanoma cell clones. Further studies confirmed that induced expression of these factors remodeled the phenotype of the melanoma cells to melanoma stem cells (MSCs). This conclusion was supported by the evidence that induced expression of these factors increased the numbers of tumor-initiating cells, (namely MSCs), both in an in vitro cell culture system and in a mouse in vivo model. The conclusion was further supported by the observation that the induction of these factors exclusively increased the mRNA of signal transducer and activator of transcription 3 which has been reported to play a crucial role in stem cell maintenance. Thus, phenotypic remodeling of melanoma cells following the induction of these four factors provided a simple and optimal means to constantly obtain MSCs for screening new therapeutic reagents. The result also reveals that Stat3 may be a crucial link between the induction of the four factors and the cell remodeling, suggesting its potential role as a target to fight melanoma.

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EpEX/EpCAM and Oct4 or Klf4 alone are sufficient to generate induced pluripotent stem cells through STAT3 and HIF2α

Cited by 45 publications

References 48 publications

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers

Effects of hypoxia inducible factors on pluripotency in human iPS cells

Reprogramming Factors Remodel Melanoma Cell Phenotype by Changing Stat3 Expression

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