Upregulation of REG Ia accelerates tumor progression in pancreatic cancer with diabetes Lin Zhou 1 , Ruifeng Zhang 2 , Lishun Wang 3 , Shaoming Shen 3 , Hiroshi Okamoto 4 , Akira Sugawara 4 , Li Xia 3 , Xiaoling Wang 3 , Naoya Noguchi 4 , Takeo Yoshikawa 4 , Akira Uruno 4 , Weiyan Yao 1 and Yaozong Yuan 1 1 Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 2 Department of Respiratory medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 3 Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiaotong University School of Medicine, Shanghai, China 4 Department of Advanced Biological Sciences for Regeneration, Tohoku University Graduate School of Medicine, Sendai, Japan Diabetes is now generally accepted as a crucial event in the process of pancreatic cancer (PaC). However, molecular mechanisms underlying the relationship between diabetes and PaC are not fully understood. Regenerating gene (REG)Ia is a growth factor affecting pancreatic islet beta cells, and it has been shown to be involved in the carcinogenesis in gastrointestinal tract. It is rational to speculate that REG Ia plays a potential role in the pathogenesis of PaC with diabetes. The aim of this study was to evaluate the REG Ia protein expression profile in PaC with and without diabetes, and define the contribution of REG Ia on PaC development. We found that REG Ia protein preferentially expressed in cancerous tissues of PaC patients with diabetes by Western blot. REG Ia positive cancer cells in PaC with diabetes (n 5 38) was significantly higher than that in subjects without diabetes (n 5 42, p < 0.05) by immunohistochemical analysis. Furthermore, we found that overexpression of REG Ia protein in PaC cell lines resulted in accelerated cell proliferation and consequently tumor growth, both in vitro and in vivo. The findings suggest that REG Ia may act as one of the tumor promoter and contribute to the aggressive nature of PaC, especially in the subpopulation with diabetes. This study would shed new insights for understanding the molecular mechanisms underlying the link between diabetes and PaC. Pancreatic cancer (PaC), one of the most aggressive human cancers, with the 5-year survival rate of 5%. 1 The disease is characterized by rapid tumor spread and dismal prognosis. Most PaC patients are diagnosed at an advanced stage, and only up to 9% of patients undergo a potentially curative pro- cedure. 2 Based on human epidemiologic and animal studies, diabetes is now generally accepted as a crucial event in the development of PaC. A recent population-based study showed that diabetes has a high (40%) prevalence in PaC and frequently is new onset. 3 Another observation showed that PaC patients with diabetes tend to present a more advanced stage of the disease and a shorter survival period than their nondiabetic counterparts. 4 Therefore, it is impera- tive to better understand the biological influence of diabetes on PaC. Previous studies have shown that several kinds of growth factors, such as insulin and insulin-like growth fac- tors, have been found to stimulate the PaC cells prolifera- tion 5,6 ; however, more molecular mechanisms underlying the relationship between diabetes and PaC remain to be elucidated. The Regenerating gene (REG), an epithelial growth factor, 7 was originally isolated from a complementary DNA (cDNA) library derived from regenerating rat pancreatic islets, and its human homologue was named REG Ia. 8 REG Ia is a known growth factor affecting pancreatic islet beta cells, which enco- des a 166-amino acid protein with a 22-amino acid signal sequence. 8 Reg I gene has been previously associated with di- abetes. For examples, overexpression of Reg I in the pancreas of nonobese diabetic mice at various degrees of diabetogene- sis has been found. 9,10 Recently, REG Ia was suggested to be involved not only in inflammatory diseases but also in carci- nogenesis in various gastroenterological tissues, such as the stomach, 11,12 colon 13 and bile duct. 14 Therefore, it is rational to speculate that pancreatic REG Ia level may be different in PaC patients with and without diabetes, and REG Ia may play an important role in the development of PaC. Key words: REG Ia, pancreatic cancer, diabetes Abbreviations: IFN: interferon; IL: interleukin; PaC: pancreatic cancer; PCNA: proliferating cell nuclear antigen; REG: regenerating gene; WST-8: 2-methoxy-4-nitrophenyl-3-(4-nitrophenyl)-5-(2,4- disulfophenyl)-2H-tetrazolium, monosodium salt. Additional Supporting Information may be found in the online version of this article. Grant sponsor: Key Program of Science and Technology Committee of Shanghai, China; Grant number: 06JC14055 DOI: 10.1002/ijc.25188 History: Received 14 Apr 2009; Accepted 28 Dec 2009; Online 22 Jan 2010 Correspondence to: Yaozong Yuan, Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China, Tel/Fax: þ[86-21-64150773], E-mail: yyz28@medmail.com.cn Cancer Cell Biology Int. J. Cancer: 127, 1795–1803 (2010) V C 2010 UICC International Journal of Cancer IJC