title: Stem cell marker nestin is critical for TGF-β1-mediated tumor progression in pancreatic cancer.
abstract: The stem cell marker nestin is an intermediate filament protein that plays an important role in cell integrity, migration, and differentiation. Nestin expression occurs in approximately one third of pancreatic ductal adenocarcinoma (PDAC), and its expression strongly correlates with tumor staging and metastasis. Little is known about the mechanisms by which nestin influences PDAC progression. Here, nestin overexpression in PDAC cells increased cell motility and drove phenotypic changes associated with the epithelial-mesenchymal transition (EMT) in vitro; conversely, knockdown of endogenous nestin expression reduced the migration rate and reverted cells to a more epithelial phenotype. Mouse xenograft studies showed that knockdown of nestin significantly reduced tumor incidence and volume. Nestin protein expression was associated with Smad4 status in PDAC cells; hence, nestin expression might be regulated by the TGF-β1/Smad4 pathway in PDAC. We examined nestin expression after TGF-β1 treatment in human pancreatic cancer PANC-1 and PANC-1 shSmad4 cells. The TGF-β1/Smad4 pathway induced nestin protein expression in PDAC cells in a Smad4-dependent manner. Moreover, increased nestin expression caused a positive feedback regulator of the TGF-β1 signaling system. In addition, hypoxia was shown to induce nestin expression in PDAC cells, and the hypoxia-induced expression of nestin is mediated by the TGF-β1/Smad4 pathway. Finally, the antimicrotubule inhibitors, cytochalasin D and withaferin A, exhibited anti-nestin activity; these inhibitors might be potential antimetastatic drugs. Our findings uncovered a novel role of nestin in regulating TGF-β1-induced EMT. Anti-nestin therapeutics may serve as a potential treatment for PDAC metastasis.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 80424.
authors.forename: Huei-Ting
authors.initials: HT
authors.lastname: Su
authors.forename: Ching-Chieh
authors.initials: CC
authors.lastname: Weng
authors.forename: Pi-Jung
authors.initials: PJ
authors.lastname: Hsiao
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Chen
authors.forename: Tzu-Lei
authors.initials: TL
authors.lastname: Kuo
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Cheng
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D015638:Cytochalasin D / Q000494:pharmacology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009362:Neoplasm Metastasis; D064231:Nestin / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D051901:Smad4 Protein / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D054358:Withanolides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D064231:Nestin; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1; D054358:Withanolides; D015638:Cytochalasin D; C009684:withaferin A