Little evidence for epithelial-mesenchymal transition in a murine model of airway fibrosis induced by repeated naphthalene exposure

AbstractKrüppel-like factor 10 (KLF10) is a tumor suppressor in multiple cancers. In a murine model of spontaneous pancreatic adenocarcinoma (PDAC), additional KLF10 depletion accelerated distant metastasis. However, Klf10 knockout mice, which suffer from metabolic disorders, do not develop malignancy. The mechanisms of KLF10 in PDAC progression deserve further exploration. KLF10-depleted and KLF10-overexpressing PDAC cells were established to measure epithelial-mesenchymal transition (EMT), glycolysis, and migration ability. A murine model was established to evaluate the benefit of genetic or pharmacological manipulation in KLF10-depleted PDAC cells (PDACshKLF10). Correlations of KLF10 deficiency with rapid metastasis, elevated EMT, and glycolysis were demonstrated in resected PDAC tissues, in vitro assays, and murine models. We identified sirtuin 6 (SIRT6) as an essential mediator of KLF10 that modulates EMT and glucose homeostasis. Overexpressing SIRT6 reversed the migratory and glycolytic phenotypes of PDACshKLF10 cells. Linoleic acid, a polyunsaturated essential fatty acid, upregulated SIRT6 and prolonged the survival of mice injected with PDACshKLF10. Modulating HIF1α and NFκB revealed that EMT and glycolysis in PDAC cells were coordinately regulated upstream by KLF10/SIRT6 signaling. Our study demonstrated a novel KLF10/SIRT6 pathway that modulated EMT and glycolysis coordinately via NFκB and HIF1α. Activation of KLF10/SIRT6 signaling ameliorated the distant progression of PDAC.Clinical Trial Registration: ClinicalTrials.gov. identifier: NCT01666184.

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O12‐3: Epithelial mesenchymal transition (EMT) is an active process in smokers, patients with small airway disease and COPD: Implications for small airway fibrosis and obliteration

Respirology ◽

10.1111/resp.14149_70 ◽

2021 ◽

Vol 26 (S3) ◽

pp. 33-33

Keyword(s):

Epithelial Mesenchymal Transition ◽

Airway Disease ◽

Small Airway ◽

Active Process ◽

Mesenchymal Transition ◽

Small Airway Disease ◽

Airway Fibrosis

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Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer

Clinical and Translational Medicine ◽

10.1186/s40169-014-0033-2 ◽

2014 ◽

Vol 3 (1) ◽

Cited By ~ 29

Author(s):

Sukhwinder Singh Sohal ◽

Malik Quasir Mahmood ◽

Eugene Haydn Walters

Keyword(s):

Lung Cancer ◽

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Clinical Significance ◽

Epithelial Mesenchymal Transition ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Mesenchymal Transition ◽

Potential Target ◽

Airway Fibrosis

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Heparin-binding epidermal growth factor contributes to COPD disease severity by modulating airway fibrosis and pulmonary epithelial–mesenchymal transition

Laboratory Investigation ◽

10.1038/s41374-018-0049-0 ◽

2018 ◽

Vol 98 (9) ◽

pp. 1159-1169 ◽

Cited By ~ 6

Author(s):

Tianwen Lai ◽

Yanyu Li ◽

Min Chen ◽

Guihai Pan ◽

Xiaoxia Wen ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Disease Severity ◽

Epithelial Mesenchymal Transition ◽

Heparin Binding ◽

Mesenchymal Transition ◽

Epidermal Growth ◽

Airway Fibrosis

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Fucoxanthin Prevents Pancreatic Tumorigenesis in C57BL/6J Mice That Received Allogenic and Orthotopic Transplants of Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms222413620 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13620

Author(s):

Wataru Murase ◽

Yukino Kamakura ◽

Serina Kawakami ◽

Ayaka Yasuda ◽

Momoka Wagatsuma ◽

...

Keyword(s):

Pancreatic Cancer ◽

Animal Models ◽

Cancer Cells ◽

Murine Model ◽

Epithelial Mesenchymal Transition ◽

Cancer Chemoprevention ◽

Pancreatic Tumors ◽

Mesenchymal Transition ◽

Anti Cancer ◽

Protein Expressions

Fucoxanthin (Fx) is a marine carotenoid with anti-inflammatory and anti-cancer properties in various animal models of carcinogenesis. However, there is currently no information on the effects of Fx in animal models of pancreatic cancer. We investigated the chemopreventive effects of Fx in C57BL/6J mice that received allogenic and orthotopic transplantations of cancer cells (KMPC44) derived from a pancreatic cancer murine model (Ptf1aCre/+; LSL-krasG12D/+). Using microarray, immunofluorescence, western blot, and siRNA analyses, alterations in cancer-related genes and protein expression were evaluated in pancreatic tumors of Fx-administered mice. Fx administration prevented the adenocarcinoma (ADC) development of pancreatic and parietal peritoneum tissues in a pancreatic cancer murine model, but not the incidence of ADC. Gene and protein expressions showed that the suppression of chemokine (C-C motif) ligand 21 (CCL21)/chemokine receptor 7 (CCR7) axis, its downstream of Rho A, B- and T-lymphocyte attenuator (BTLA), N-cadherin, αSMA, pFAK(Tyr397), and pPaxillin(Tyr31) were significantly suppressed in the pancreatic tumors of mice treated with Fx. In addition, Ccr7 knockdown significantly attenuated the growth of KMPC44 cells. These results suggest that Fx is a promising candidate for pancreatic cancer chemoprevention that mediates the suppression of the CCL21/CCR7 axis, BTLA, tumor microenvironment, epithelial mesenchymal transition, and adhesion.

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