Abstract
Background
Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis, a characteristic feature of pancreatic cancer. Although it is still controversial, previous studies have suggested that PSCs promote the progression of pancreatic cancer by regulating the cell functions of cancer cells. PSCs produce large amounts of IL-6, which promotes the accumulation of myeloid-derived suppressor cells via a signal transducers and activator of transcription 3 (STAT3)-dependent mechanism. But the role of IL-6/STAT3 pathway in the interaction between PSCs and pancreatic cancer cells remains largely unknown.
Aims
To clarify the role of IL-6/STAT3 in the interaction between PSCs and cancer cells.
Methods
Human pancreatic cancer cells (Panc-1 and SUIT-2 cells) were treated with conditioned medium of immortalized human PSCs (PSC-CM). The effects of PSC-CM and IL-6 neutralization on the mRNA expression profiles were examined using Agilent’s microarray. Activation of STAT3 was assessed by Western blotting using an anti-phospho-specific antibody. Cellular migration was examined by a two-chamber assay. The expression of markers related to epithelial–mesenchymal transition (EMT) was assessed by real-time reverse transcription PCR.
Results
PSC-CM induced the activation of STAT3 in pancreatic cancer cells. Neutralization of IL-6 suppressed the PSC-CM-induced upregulation of genes including complement factor B, lipocalin, and chemokine (C–C motif) ligand 20. Inhibition of IL-6/STAT3 pathway by anti-IL-6 antibody or a STAT3 inhibitor (NSC74859) inhibited the PSC-CM-induced migration and the expression of EMT-related markers (Snail and cadherin-2) in pancreatic cancer cells.
Conclusion
IL-6/STAT3 pathway regulates the PSC-induced EMT and alterations in gene expression in pancreatic cancer cells.
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Abbreviations
- CFB:
-
Complement factor B
- CCL20:
-
Chemokine (C–C motif) ligand 20
- CM:
-
Conditioned medium
- DAPI:
-
4′,6-diamidino-2-phenylindole
- EMT:
-
Epithelial–mesenchymal transition
- ERK:
-
Extracellular signal-regulated kinase
- GFAP:
-
Glial fibrillary acidic protein
- IκB:
-
Inhibitor of κB
- IPA:
-
Ingenuity Pathway Analysis
- JNK:
-
c-Jun N-terminal kinase
- LCN2:
-
Lipocalin
- MAPK:
-
Mitogen-activated protein kinase
- PSCs:
-
Pancreatic stellate cells
- RT:
-
Reverse transcription
- SMA:
-
Smooth muscle actin
- STAT:
-
Signal transducers and activator of transcription
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Acknowledgments
This study was supported in part by Grant-in-Aid from the Japan Society for the Promotion of Science (26293171, 26461029, 15H04804), the Mitsui Life Social Welfare Foundation (to A. Masamune), and the Pancreas Research Foundation of Japan (to T. Takikawa).
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Hamada, S., Masamune, A., Yoshida, N. et al. IL-6/STAT3 Plays a Regulatory Role in the Interaction Between Pancreatic Stellate Cells and Cancer Cells. Dig Dis Sci 61, 1561–1571 (2016). https://doi.org/10.1007/s10620-015-4001-5
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DOI: https://doi.org/10.1007/s10620-015-4001-5