Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer and the 5-year survival rate is only 5%. Several studies have suggested that cancer stem cells (CSCs) are thought to be involved in recurrence and metastasis and so it is essential to establish an approach targeting CSCs. Here we have demonstrated that cyclic guanosine monophosphate (cGMP) suppressed CD44 expression and the properties of CSCs in PDAC. Microarray analysis suggested that cGMP inhibited Forkhead box O3 (FOXO3), which is known as a tumor suppressor. Surprisingly, our data demonstrated that FOXO3 is essential for CD44 expression and the properties of CSCs. Our data also indicated that patients with high FOXO3 activation signatures had poor prognoses. This evidence suggested that cGMP induction and FOXO3 inhibition could be ideal candidates for pancreatic CSC.
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This work was supported in part by JSPS KAKENHI grant 22228002 and 15H02448 to H Tachibana. This work was also supported in part by a Grant-in-Aid for JSPS Fellows to MK (PD) and JSPS KAKENHI grant 15K18821. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We appreciate the technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University, and the Center for Accelerator and Beam Applied Science, Kyushu University. We thank Takeshi Iwasaki (Kyushu University, Faculty of Medicine) for helpful advice on bioinformatics analysis. The authors would like to thank Enago (www.enago.jp) for the English language review.
MK and MT planned the studies. MK and MT contributed equally to this work. MK, MT, BJ, SH, YH, KT, YW, MY, SH, SY, SY, MM and ST performed the experiments. MK held the responsibility for all data integrity and data analysis. HT conducted the whole research. HT had primary responsibility for the final content. All authors have reviewed the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Kumazoe, M., Takai, M., Bae, J. et al. FOXO3 is essential for CD44 expression in pancreatic cancer cells. Oncogene 36, 2643–2654 (2017). https://doi.org/10.1038/onc.2016.426
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