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APC haploinsufficiency coupled with p53 loss sufficiently induces mucinous cystic neoplasms and invasive pancreatic carcinoma in mice

Oncogene volume 35, pages 2223–2234 (2016)Cite this article

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Abstract

Adenomatous polyposis coli (APC), a tumor-suppressor gene critically involved in familial adenomatous polyposis, is integral in Wnt/β-catenin signaling and is implicated in the development of sporadic tumors of the distal gastrointestinal tract including pancreatic cancer (PC). Here we report for the first time that functional APC is required for the growth and maintenance of pancreatic islets and maturation. Subsequently, a non-Kras mutation-induced premalignancy mouse model was developed; in this model, APC haploinsufficiency coupled with p53 deletion resulted in the development of a distinct type of pancreatic premalignant precursors, mucinous cystic neoplasms (MCNs), exhibiting pathomechanisms identical to those observed in human MCNs, including accumulation of cystic fluid secreted by neoplastic and ovarian-like stromal cells, with 100% penetrance and the presence of hepatic and gastric metastases in >30% of the mice. The major clinical implications of this study suggest targeting the Wnt signaling pathway as a novel strategy for managing MCN.

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Acknowledgements

We gratefully thank Dr Sheau-Fang Yang, at Kaohsiung Medical University for helping us to confirm the histologic features and pathology of MCN mice. This work was supported by grants NSC 101-2314-B-110-001-MY2, 101-2628- B-110-001-MY2 (to KH Cheng) and MOST 103-2314-B-037-062 (to DC Wu and KH Cheng) from the National Science Council, Taiwan ROC, and grants KMU-TP103G00 and KMU-TP103G01 (to DC Wu and KH Cheng) from Kaohsiung Medical University, Kaohsiung, Taiwan.

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Microarray data are available in the Gene Expression Omnibus (GEO) with accession number GSE 61894.

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Authors and Affiliations

  1. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

    T-L Kuo, C-C Weng & K-H Cheng

  2. Division of Hepatobiliopancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan,

    K-K Kuo

  3. Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan

    K-K Kuo, C-Y Chen, D-C Wu & K-H Cheng

  4. Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan,

    C-Y Chen

  5. Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    D-C Wu

  6. Division of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    D-C Wu

  7. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    W-C Hung

  8. Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan

    K-H Cheng

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  1. T-L Kuo
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Correspondence to K-H Cheng.

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Kuo, TL., Weng, CC., Kuo, KK. et al. APC haploinsufficiency coupled with p53 loss sufficiently induces mucinous cystic neoplasms and invasive pancreatic carcinoma in mice. Oncogene 35, 2223–2234 (2016). https://doi.org/10.1038/onc.2015.284

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