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) cases, and its expression positively correlates with tumor stage and peripancreatic invasion. Little is known of the mechanisms by which Nestin influences PDAC progression. We showed that Nestin overexpression in PDAC cells increased cell motility and drove phenotypic changes associated with the epithelial-mesenchymal transition in vitro, conversely, knockdown of endogenous Nestin expression reduced the migration rate and cells reverted to a more epithelial phenotype. In vivo mice studies showed that knockdown of Nestin significantly reduced tumor incidence and volume in xenografts. Expression of the Nestin protein was associated with Smad4 status in PDAC cells, hence Nestin expression might be regulated by the TGF-b1/SMAD4 pathway in PDAC. We examined Nestin expression after TGF-b1 treatment in human pancreatic cancer PANC-1, and PANC-1 shSmad4 cells. The TGF-b/SMAD pathway induced Nestin protein expression in PDAC cells through Smad4 in a dependent manner. Moreover, increased Nestin expression caused a positive feedback loop in the TGFb/SMAD signaling system.
Finally, we demonstrated that 2 anti-microtubule inhibitors, Cytochalasin D (CD) and Withaferin A (WFA), exhibited anti-Nestin activity; these inhibitors might be potential anti-metastatic drugs. Our findings uncovered a novel role of Nestin in regulating TGF-b1-induced EMT. Anti-Nestin therapeutics are under development as a potential treatment for PDAC metastasis.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0625112-152043 |
| Date | 25 June 2012 |
| Creators | Su, Huei-Ting |
| Contributors | Wen-Chun Hung, Kuang-hung Cheng, Long-Sen Chang, Hurng-Wern Huang |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0625112-152043 |
| Rights | user_define, Copyright information available at source archive |
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