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Rb and P53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors

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Rb and P53 Execute Distinct Roles in the Development of Pancreatic Neuroendocrine Tumors Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Title: Rb and p53 execute distinct roles in the development of pancreatic neuroendocrine tumors 2 Running Title: Roles of Rb and p53 in pancreatic neuroendocrine tumors 3 4 1Yuki Yamauchi, 1,2Yuzo Kodama, 1Masahiro Shiokawa, 1Nobuyuki Kakiuchi, 1Saiko Marui, 5 1Takeshi Kuwada, 1Yuko Sogabe, 1Teruko Tomono, 1Atsushi Mima, 1Toshihiro Morita, 1Tomoaki 6 Matsumori, 1Tatsuki Ueda, 1Motoyuki Tsuda, 1Yoshihiro Nishikawa, 1Katsutoshi Kuriyama, 7 1Yojiro Sakuma, 1Yuji Ota, 1Takahisa Maruno, 1Norimitsu Uza, 2Atsuhiro Masuda, 3Hisato 8 Tatsuoka, 3Daisuke Yabe, 4Sachiko Minamiguchi, 5Toshihiko Masui, 3Nobuya Inagaki, 5Shinji 9 Uemoto, 1,6Tsutomu Chiba, and 1Hiroshi Seno 10 11 1Department of Gastroenterology and Hepatology, Kyoto University Graduate School of 12 Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. 13 2Department of Gastroenterology, Kobe University Graduate School of Medicine, 7-5-1 14 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. 15 3Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of 16 Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. 17 4Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, 54 18 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. 1 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 19 5Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, 20 Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507, Japan. 21 6Kansai Electric Power Hospital, 2-1-7 Fukushima, Fukushima-ku, Osaka, 553-0003, Japan. 22 23 Correspondence: Yuzo Kodama 24 Department of Gastroenterology, Kobe University Graduate School of Medicine, 7-5-1 25 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. 26 E-mail: [email protected] 27 Phone: +81-78-382-6308 28 Fax: +81-78-382-6309 29 30 Conflict-of-interest disclosure 31 The authors declare no competing financial interests. 32 33 Word counts: 4294 words 34 Total number of figures: 6 figures 35 2 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 36 Abstract 37 Pancreatic neuroendocrine tumors (PanNET) were classified into grades (G) 1-3 by the World 38 Health Organization in 2017, but the precise mechanisms of PanNET initiation and progression 39 have remained unclear. In this study, we used a genetically engineered mouse model to 40 investigate the mechanisms of PanNET formation. Although pancreas-specific deletion of the Rb 41 gene (Pdx1-Cre;Rbf/f) in mice did not affect pancreatic exocrine cells, the α-cell/β-cell ratio of 42 islet cells was decreased at 8 months of age. During long-term observation (18-20 months), mice 43 formed well-differentiated PanNET with a Ki67-labeling index of 2.7%. In contrast, 44 pancreas-specific induction of a p53 mutation (Pdx1-Cre;Trp53R172H) had no effect on pancreatic 45 exocrine and endocrine tissues, but simultaneous induction of a p53 mutation with Rb gene 46 deletion (Pdx1-Cre;Trp53R172H;Rb f/f) resulted in the formation of aggressive PanNET with a 47 Ki67-labeling index of 24.7% over the short-term (4 months). In Pdx1-Cre;Trp53R172H;Rb f/f mice, 48 mRNA expression of Pten and Tsc2, negative regulators of the mTOR pathway, significantly 49 decreased in the islet cells, and activation of the mTOR pathway was confirmed in subsequently 50 formed PanNET. Thus, by manipulating Rb and p53 genes, we established a multistep 51 progression model from dysplastic islet to indolent PanNET and aggressive metastatic PanNET 52 in mice. These observations suggest that Rb and p53 have distinct roles in the development of 53 PanNET. 3 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 54 55 Key words: Pancreatic neuroendocrine tumor, Rb, p53 56 57 4 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 58 Significance 59 Pancreas-specific manipulation of Rb and p53 genes induced malignant transformation of islet 60 cells, reproducing stepwise progression from microadenomas to indolent (Grade 1) and 61 subsequent aggressive PanNETs (Grade 2-3). 62 5 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 63 Introduction 64 Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common epithelial 65 neoplasms in the pancreas, and the number of people affected is gradually increasing (1). In 2017, 66 the World Health Organization classified human PanNENs into two groups: well-differentiated 67 PanNENs, called PanNETs, and poorly differentiated PanNENs, called PanNECs. PanNECs, 68 which include small and large cell carcinomas, have an extremely poor prognosis and are thought 69 to be biologically distinct from PanNETs (2-5). PanNETs are further subclassified into grades 70 (G) 1–3 on the basis of their proliferative activity assessed by the Ki67 labeling index and 71 mitotic rate. Although the prognosis of patients with PanNETs correlates with the tumor grade, 72 the underlying mechanisms of PanNET formation and grade progression are unclear. 73 Previous gene analyses of PanNETs revealed major mutations in MEN1, DAXX, ATRX, and 74 genes in the mTOR pathway, but extremely rare mutations in the retinoblastoma (RB) gene or 75 TP53 gene (6-8). In contrast, a recent report analyzed by immunohistochemistry revealed a loss 76 of Rb expression in 54.5% of G3 PanNEC but not in G3 PanNET cases (5). However, in various 77 human neoplasms, the RB gene is functionally inactivated not only by mutations, but also by 78 altered expression of upstream regulators (9). Indeed, a recent study demonstrated that increased 79 expression of CDK4/6 via copy number abnormalities leads to Rb phosphorylation in 46-68% of 80 human PanNETs, resulting in inactivation of the Rb pathway (10,11). Likewise, aberrant 6 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 81 activation of MDM2, MDM4, and WIP1 suppresses the p53 signaling pathway in approximately 82 70% of PanNETs (12). The involvement of Rb and p53 in the tumorigenic process in PanNETs is 83 further suggested by findings from genetically engineered mouse models. For example, the 84 RIP1-Tag2 mouse, in which transgenic expression of the simian virus 40 (SV40) large T antigen 85 is under control of the rat insulin promoter (RIP), develops aggressive insulinomas through 86 suppression of both the Rb and p53 pathways (13). Similarly, preproglucagon promoter-driven 87 expression of SV40 large T antigen results in moderate to aggressive glucagonomas (14,15), and 88 homozygous deletion of Rb and p53 in renin-expressing cells leads to the development of 89 aggressive glucagonomas in the pancreas (16). These models highlight the importance of 90 simultaneous inactivation of both the Rb and p53 pathways in the development of aggressive 91 PanNETs in mice. Whether these aggressive tumors develop from indolent tumors, however, 92 remains unknown. Furthermore, no studies have investigated the individual roles of Rb and p53 93 in PanNET formation from pancreatic cells. 94 In the present study, we investigated the roles of Rb and p53 in the development of PanNETs 95 utilizing a genetically engineered mouse model. We provide the first reported evidence that 96 pancreas duodenum homeobox protein 1 (Pdx1) Cre-dependent pancreas-specific deletion of Rb 97 gene per se induces indolent PanNETs in islet cells. Whereas pancreas-specific induction of a 98 p53 mutation alone had no effect on pancreatic tissue, it markedly accelerated the progression of 7 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 99 PanNETs in combination with Rb deletion. These data suggest that Rb and p53 have distinctive 100 roles in the development of PanNETs. 101 8 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2020; DOI: 10.1158/0008-5472.CAN-19-2232 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 102 Materials and Methods 103 Mice 104 We used Pdx1-Cre mice (17), Rosa26R mice (18), Rb flox mice (19), and LSL-Trp53R172H mice 105 (20,21), which were previously described. Non-recombinant littermates were used as controls.
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