Loss of the Keratin Cytoskeleton Is Not Sufficient to Induce Epithelial Mesenchymal Transition in a Novel KRAS Driven Sporadic Lung Cancer Mouse Model

König, Katharina; Meder, Lydia; Kröger, Cornelia; Diehl, Linda; Florin, Alexandra; Rommerscheidt-Fuss, Ursula; Kahl, Philip; Wardelmann, Eva; Magin, Thomas M.; Buettner, Reinhard; Heukamp, Lukas C.

doi:10.1371/journal.pone.0057996

Cited by 27 publications

(21 citation statements)

References 25 publications

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“…In-vivo systems over comes the weakness of in-vitro experiments which fails to replicate the complex cellular and tissue interaction in an organism; hence, better suited for observing the overall effects of a target gene in a living system. KRT76 -KO mice displayed hyperplastic changes in buccal epithelium, however they do not spontaneously develop tumors similar to previous reports on other keratin knockout mice models [53], [54], [55]. Our current findings suggest that the loss of KRT76 may not be a sole molecular event leading to oral cancer development.…”

Section: Discussionsupporting

confidence: 90%

Downregulation of Keratin 76 Expression during Oral Carcinogenesis of Human, Hamster and Mouse

et al. 2013

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BackgroundKeratins are structural marker proteins with tissue specific expression; however, recent reports indicate their involvement in cancer progression. Previous study from our lab revealed deregulation of many genes related to structural molecular integrity including KRT76. Here we evaluate the role of KRT76 downregulation in oral precancer and cancer development.MethodsWe evaluated KRT76 expression by qRT-PCR in normal and tumor tissues of the oral cavity. We also analyzed K76 expression by immunohistochemistry in normal, oral precancerous lesion (OPL), oral squamous cell carcinoma (OSCC) and in hamster model of oral carcinogenesis. Further, functional implication of KRT76 loss was confirmed using KRT76-knockout (KO) mice.ResultsWe observed a strong association of reduced K76 expression with increased risk of OPL and OSCC development. The buccal epithelium of DMBA treated hamsters showed a similar trend. Oral cavity of KRT76-KO mice showed preneoplastic changes in the gingivobuccal epithelium while no pathological changes were observed in KRT76 negative tissues such as tongue.ConclusionThe present study demonstrates loss of KRT76 in oral carcinogenesis. The KRT76-KO mice data underlines the potential of KRT76 being an early event although this loss is not sufficient to drive the development of oral cancers. Thus, future studies to investigate the contributing role of KRT76 in light of other tumor driving events are warranted.

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Section: Discussionsupporting

confidence: 90%

Downregulation of Keratin 76 Expression during Oral Carcinogenesis of Human, Hamster and Mouse

et al. 2013

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“…The remodeling of the cytoskeleton has been suggested to be a hallmark of EMT. Loss of cytokeratins leads to alterations in cell-to-cell adhesions and changes in polarity and cell motility (27). The results of the present study showed that Oct4 upregulated the expression of the mesenchymal markers vimentin and N-cadherin, as well as downregulated the expression of the epithelial marker cytokeratin in A549 cells.…”

Section: Discussionsupporting

confidence: 52%

Octamer-binding protein 4 affects the cell biology and phenotypic transition of lung cancer cells involving β-catenin/E-cadherin complex degradation

Chen

Ling

Yang-de

et al. 2014

Molecular Medicine Reports

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Abstract. Clinical studies have reported evidence for the involvement of octamer-binding protein 4 (Oct4) in the tumorigenicity and progression of lung cancer; however, the role of Oct4 in lung cancer cell biology in vitro and its mechanism of action remain to be elucidated. Mortality among lung cancer patients is more frequently due to metastasis rather than their primary tumors. Epithelial-mesenchymal transition (EMT) is a prominent biological event for the induction of epithelial cancer metastasis. The aim of the present study was to investigate whether Oct4 had the capacity to induce lung cancer cell metastasis via the promoting the EMT in vitro. Moreover, the effect of Oct4 on the β-catenin/E-cadherin complex, associated with EMT, was examined using immunofluorescence and immunoprecipitation assays as well as western blot analysis. The results demonstrated that Oct4 enhanced cell invasion and adhesion accompanied by the downregulation of epithelial marker cytokeratin, and upregulation of the mesenchymal markers vimentin and N-cadherin. Furthermore, Oct4 induced EMT of lung cancer cells by promoting β-catenin/E-cadherin complex degradation and regulating nuclear localization of β-catenin. In conclusion, the present study indicated that Oct4 affected the cell biology of lung cancer cells in vitro through promoting lung cancer cell metastasis via EMT; in addition, the results suggested that the association and degradation of the β-catenin/E-cadherin complex was regulated by Oct4 during the process of EMT. IntroductionLung cancer is one of the most prevalent types of malignant tumor worldwide, with a five-year survival rate of ~16% (1). Mortality among lung cancer patients is more frequently due to metastasis rather than their primary tumors. Therefore, it is necessary to elucidate the molecular mechanisms of lung cancer metastasis in order to develop effective treatment options.Epithelial-mesenchymal transition (EMT) is a process characterized by downregulation of epithelial markers and upregulation of mesenchymal markers (2,3). Previous studies have proposed that EMT may be a key step in the progression of tumor cell metastasis (4-6).Octamer-binding protein 4 (Oct4), a transcription factor that belongs to the Pit-Oct-Unc (POU) family, has been reported to be a master regulator of maintenance and differentiation in pluripotent cells. It has been suggested that Oct4 may be a key component of the regulation of self-renewal and differentiation in stem cells (7-9); in addition, Oct4 may also have a crucial role in cancer development (10). Chen et al (11) demonstrated that Oct4 expression was involved in the tumorigenesis and malignancy of lung cancer. The aims of the present study were to investigate the effect of Oct4 on the cell biology of lung cancer cells in vitro, elucidate the underlying mechanisms associated with lung cancer metastasis and examine the effect of Oct4 on the degradation of the β-catenin/E-cadherin complex degradation, a process strongly associated with EMT. Materials and methods Cell

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“…The epithelial tissue type specific regulation of type I and type II keratin genes leads to different compositions of cytoplasmic keratin filaments for cells found within various tissues [Coulombe and Omary, ]. Keratins bind to desmosomes and promote strong intercellular adhesion which is necessary to maintain epithelial tissue architecture thereby providing a barrier against EMT [Simpson et al, ; König et al, ]. Overexpression of Snail, a transcription factor that mediates TGFβ‐induced EMT, results in reduced expression levels of a variety of keratins in colorectal and breast cancer cells [De Craene et al, ; McGrail et al, ].…”

Section: Regulation Of Cytoskeletal Components and Organization Durinmentioning

confidence: 99%

Cytoskeletal signaling in TGFβ‐induced epithelial–mesenchymal transition

2015

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Epithelial-mesenchymal transition (EMT) is a physiological process that plays an important role in embryonic development and wound healing and is appropriated during pathological conditions including fibrosis and cancer metastasis. EMT can be initiated by a variety of factors, including transforming growth factor (TGF)-b, and is characterized by loss of epithelial features including cell-cell contacts and apicobasal polarity and acquisition of a motile, mesenchymal phenotype. A key feature of EMT is reorganization of the cytoskeleton and recent studies have elucidated regulation mechanisms governing this process. This review describes changes in gene expression patterns of cytoskeletal associated proteins during TGFb-induced EMT. It further reports TGFbinduced intracellular signaling cascades that regulate cytoskeletal reorganization during EMT. Finally, it highlights how changes in cytoskeletal architecture during EMT can regulate gene expression, thus further promoting EMT progression. V C 2015 Wiley Periodicals, Inc.

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Loss of the Keratin Cytoskeleton Is Not Sufficient to Induce Epithelial Mesenchymal Transition in a Novel KRAS Driven Sporadic Lung Cancer Mouse Model

Cited by 27 publications

References 25 publications

Downregulation of Keratin 76 Expression during Oral Carcinogenesis of Human, Hamster and Mouse

Downregulation of Keratin 76 Expression during Oral Carcinogenesis of Human, Hamster and Mouse

Octamer-binding protein 4 affects the cell biology and phenotypic transition of lung cancer cells involving β-catenin/E-cadherin complex degradation

Cytoskeletal signaling in TGFβ‐induced epithelial–mesenchymal transition

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