Wu, Yuan Seng and Chung, Ivy and Wong, Won Fen and Masamune, Atsushi and Sim, Maw Shin and Looi, Chung Yeng (2017) Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells. Biochimica et Biophysica Acta (BBA) - General Subjects, 1861 (2). pp. 296-306. ISSN 0304-4165, DOI https://doi.org/10.1016/j.bbagen.2016.10.006.
Full text not available from this repository.Abstract
Background We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process. Methods Gene expression of IL-6 and IL-6Rα in PSC and PDAC cells was measured with qRT-PCR. The role of PSC-secreted IL-6, JAK/Stat3 signaling, and Nrf2 mediation on EMT-related genes expression was also examined with qRT-PCR. EMT phenotypes were assessed with morphological change, wound healing, migration, and invasion. Results PSC expressed higher mRNA levels of IL-6 but lower IL-6Rα compared to PDAC cells. Neutralizing IL-6 in PSC secretion reduced mesenchymal-like morphology, migration and invasion capacity, and mesenchymal-like gene expression of N-cadherin, vimentin, fibronectin, collagen I, Sip1, Snail, Slug, and Twist2. Inhibition of JAK/Stat3 signaling induced by IL-6 repressed EMT and Nrf2 gene expression. Induction of Nrf2 activity by tert-butylhydroquinone (tBHQ) increased both EMT phenotypes and gene expression (N-cadherin, fibronectin, Twist2, Snail, and Slug) repressed by IL-6 neutralizing antibody. Simultaneous inhibition of Nrf2 expression with siRNA and Stat3 signaling further repressed EMT gene expression, indicating that Stat3/Nrf2 pathway mediates EMT induced by IL-6. Conclusions IL-6 from PSC promotes EMT in PDAC cells via Stat3/Nrf2 pathway. General significance Targeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC.
| Item Type: | Article |
|---|---|
| Funders: | University of Malaya RP027A-14HTM, Grant-in-Aid from the Japan Society for the Promotion of Science 15H04804, Malaysia Ministry of Education MyBrain 15 fellowship KPT (B) 860221145079 |
| Uncontrolled Keywords: | Tumor microenvironment; Cancer-associated fibroblasts; Cytokines; Metastasis; Mechanism; Pancreatic ductal adenocarcinoma |
| Subjects: | R Medicine |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 21 Oct 2019 03:55 |
| Last Modified: | 21 Oct 2019 03:55 |
| URI: | http://eprints.um.edu.my/id/eprint/22775 |
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