Expression of REG III and prognosis in head and neck cancer

Masui,Takashi; Ota,Ichiro; Itaya-Hironaka,Asako; Takeda,Maiko; Kasai,Takahiko; Yamauchi,Akiyo; Sakuramoto-Tsuchida,Sumiyo; Mikami,Shinji; Yane,Katsunari; Takasawa,Shin; Hosoi,Hiroshi

doi:10.3892/or.2013.2521

Expression of REG III and prognosis in head and neck cancer

Authors:
- Takashi Masui
- Ichiro Ota
- Asako Itaya-Hironaka
- Maiko Takeda
- Takahiko Kasai
- Akiyo Yamauchi
- Sumiyo Sakuramoto-Tsuchida
- Shinji Mikami
- Katsunari Yane
- Shin Takasawa
- Hiroshi Hosoi
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Affiliations: Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashihara, Nara 634-8522, Japan, Department of Biochemistry, Nara Medical University, Kashihara, Nara 634-8522, Japan, Department of Diagnostic Pathology, Nara Medical University, Kashihara, Nara 634-8522, Japan, Department of Otolaryngology, Kinki University School of Medicine, Nara Hospital, Ikoma, Nara 630-0293, Japan
Published online on: June 5, 2013 https://doi.org/10.3892/or.2013.2521
Pages: 573-578

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Abstract

Identification of a reliable biomarker for predicting prognosis in head and neck cancers is highly desirable and has long been sought. There have been several reports that members of the regenerating gene (REG) family are highly expressed in chronic inflammation and in tumors of the digestive organs. In addition, it has been described in several reports that REG expression is associated with the progression of digestive cancers. In the present study, we evaluated the effect of REG expression on the prognosis of hypopharyngeal cancer. We investigated 37 cases with hypopharyngeal squamous cell carcinoma, determined REG mRNA expression, which is easily detected in formalin-fixed paraffin-embedded tissues using the real-time reverse transcriptase-polymerase chain reaction method, and evaluated the survival rate using the Kaplan-Meier method. According to these results, REG III mRNA expression was significantly associated with prolonged survival. Therefore, we constructed hypopharyngeal cancer cell lines transfected with REG III and assessed the cell proliferation and chemosensitivity and/or radiosensitivity in vitro. Cells transfected with REG III exhibited significantly lower cell proliferation and higher chemosensitivity and/or radiosensitivity compared with the control cells. These data suggest that REG III may be a reliable biomarker of prognosis in hypopharyngeal cancer. This is the first report concerning the association of REG III expression and the prognosis of head and neck squamous cell carcinoma including hypopharyngeal cancer.

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1	Ang KK, Trotti A, Brown BW, et al: Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 51:571–578. 2001. View Article : Google Scholar : PubMed/NCBI
2	Ozer E, Grecula JC, Agrawal A, Rhoades CA, Young DC and Schuller DE: Long-term results of a multimodal intensification regimen for previously untreated advanced resectable squamous cell cancer of the oral cavity, oropharynx, or hypopharynx. Laryngoscope. 116:607–612. 2006. View Article : Google Scholar
3	Kumar B, Cordell KG, Lee JS, et al: EGFR, p16, HPV titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol. 26:3128–3137. 2008. View Article : Google Scholar : PubMed/NCBI
4	Worden FP, Kumar B, Lee JS, et al: Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol. 26:3138–3146. 2008. View Article : Google Scholar : PubMed/NCBI
5	Watanabe T, Yonekura H, Terazono K, Yamamoto H and Okamoto H: Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues. The reg protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene. J Biol Chem. 265:7432–7439. 1990.PubMed/NCBI
6	Fukui H, Kinoshita Y, Maekawa T, et al: Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology. 115:1483–1493. 1998. View Article : Google Scholar : PubMed/NCBI
7	Higham AD, Bishop LA, Dimaline R, et al: Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia. Gastroenterology. 116:1310–1318. 1999. View Article : Google Scholar : PubMed/NCBI
8	Shinozaki S, Nakamura T, Iimura M, et al: Upregulation of Reg 1α and GW112 in the epithelium of inflamed colonic mucosa. Gut. 48:623–629. 2001.
9	Ose T, Kadowaki Y, Fukuhara H, et al: Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine. Oncogene. 26:349–359. 2007. View Article : Google Scholar : PubMed/NCBI
10	Macadam RC, Sarela AI, Farmery SM, Robinson PA, Markham AF and Guillou PJ: Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family. Br J Cancer. 83:188–195. 2000.PubMed/NCBI
11	Violette S, Festor E, Pandrea-Vasile I, et al: Reg IV, a new member of the regenerating gene family, is overexpressed in colorectal carcinomas. Int J Cancer. 103:185–193. 2003. View Article : Google Scholar
12	Yonemura Y, Sakurai S, Yamamoto H, et al: REG gene expression is associated with the infiltrating growth of gastric carcinoma. Cancer. 98:1394–1400. 2003. View Article : Google Scholar : PubMed/NCBI
13	Dhar DK, Udagawa J, Ishihara S, et al: Expression of regenerating gene I in gastric adenocarcinomas: correlation with tumor differentiation status and patient survival. Cancer. 100:1130–1136. 2004. View Article : Google Scholar
14	Bishnupuri KS, Luo Q, Murmu N, Houchen CW, Anant S and Dieckgraefe BK: Reg IV activates the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon adenocarcinomas. Gastroenterology. 130:137–149. 2006. View Article : Google Scholar : PubMed/NCBI
15	Hayashi K, Motoyama S, Koyota S, et al: REG I enhances chemo- and radiosensitivity in squamous cell esophageal cancer cells. Cancer Sci. 99:2491–2495. 2008. View Article : Google Scholar : PubMed/NCBI
16	Zhou L, Zhang R, Wang L, et al: Upregulation of REG Iα accelerates tumor progression in pancreatic cancer with diabetes. Int J Cancer. 127:1795–1803. 2010.
17	Terazono K, Yamamoto H, Takasawa S, et al: A novel gene activated in regenerating islets. J Biol Chem. 263:2111–2114. 1988.PubMed/NCBI
18	Watanabe T, Yonemura Y, Yonekura H, et al: Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proc Natl Acad Sci USA. 91:3589–3592. 1994. View Article : Google Scholar : PubMed/NCBI
19	Unno M, Nata K, Noguchi N, et al: Production and characterization of Reg knockout mice: reduced proliferation of pancreatic beta-cells in Reg knockout mice. Diabetes. 51(Suppl 3): S478–S483. 2002. View Article : Google Scholar : PubMed/NCBI
20	Takasawa S, Ikeda T, Akiyama T, et al: Cyclin D1 activation through ATF-2 in Reg-induced pancreatic beta-cell regeneration. FEBS Lett. 580:585–591. 2006. View Article : Google Scholar : PubMed/NCBI
21	Sanchez D, Figarella C, Marchand-Pinatel S, Bruneau N and Guy-Crotte O: Preferential expression of reg Iβ gene in human adult pancreas. Biochem Biophys Res Commun. 284:729–737. 2001.
22	Hervieu V, Christa L, Gouysse G, et al: HIP/PAP, a member of the reg family, is expressed in glucagon-producing enteropancreatic endocrine cells and tumors. Hum Pathol. 37:1066–1075. 2006. View Article : Google Scholar : PubMed/NCBI
23	Okamoto H and Takasawa S: Recent advances in the Okamoto model: the CD38-cyclic ADP-ribose signal system and the regenerating gene protein (Reg)-Reg receptor system in beta-cells. Diabetes. 51(Suppl 3): S462–S473. 2002. View Article : Google Scholar : PubMed/NCBI
24	Dusetti NJ, Frigerio JM, Fox MF, Swallow DM, Dagorn JC and Iovanna JL: Molecular cloning, genomic organization, and chromosomal localization of the human pancreatitis-associated protein (PAP) gene. Genomics. 19:108–114. 1994. View Article : Google Scholar : PubMed/NCBI
25	Moriizumi S, Watanabe T, Unno M, et al: Isolation, structural determination and expression of a novel reg gene, human regI beta. Biochim Biophys Acta. 1217:199–202. 1994. View Article : Google Scholar : PubMed/NCBI
26	Lasserre C, Simon MT, Ishikawa H, et al: Structural organization and chromosomal localization of a human gene (HIP/PAP) encoding a C-type lectin overexpressed in primary liver cancer. Eur J Biochem. 224:29–38. 1994. View Article : Google Scholar : PubMed/NCBI
27	Miyashita H, Nakagawara K, Mori M, et al: Human REG family genes are tandemly ordered in a 95-kilobase region of chromosome 2p12. FEBS Lett. 377:429–433. 1995. View Article : Google Scholar : PubMed/NCBI
28	Hartupee JC, Zhang H, Bonaldo MF, Soares MB and Dieckgraefe BK: Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. Biochim Biophys Acta. 1518:287–293. 2001. View Article : Google Scholar : PubMed/NCBI
29	Nata K, Liu Y, Xu L, et al: Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III. Gene. 340:161–170. 2004. View Article : Google Scholar : PubMed/NCBI
30	Asahara M, Mushiake S, Shimada S, et al: Reg gene expression is increased in rat gastric enterochromaffin-like cells following water immersion stress. Gastroenterology. 111:45–55. 1996. View Article : Google Scholar : PubMed/NCBI
31	Ogawa H, Fukushima K, Naito H, et al: Increased expression of HIP/PAP and regenerating gene III in human inflammatory bowel disease and a murine bacterial reconstitution model. Inflamm Bowel Dis. 9:162–170. 2003. View Article : Google Scholar
32	Takasawa S, Kuroki M, Nata K, et al: A novel ryanodine receptor expressed in pancreatic islets by alternative splicing from type 2 ryanodine receptor gene. Biochem Biophys Res Commun. 397:140–145. 2010. View Article : Google Scholar : PubMed/NCBI
33	Ota H, Tamaki S, Itaya-Hironaka A, et al: Attenuation of glucose-induced insulin secretion by intermittent hypoxia via down-regulation of CD38. Life Sci. 90:206–211. 2012. View Article : Google Scholar : PubMed/NCBI
34	Akiyama T, Takasawa S, Nata K, et al: Activation of Reg gene, a gene for insulin-producing beta-cell regeneration: poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. Proc Natl Acad Sci USA. 98:48–53. 2001.PubMed/NCBI
35	Livesey FJ, O’Brien JA, Li M, Smith AG, Murphy LJ and Hunt SP: A Schwann cell mitogen accompanying regeneration of motor neurons. Nature. 390:614–618. 1997. View Article : Google Scholar : PubMed/NCBI
36	Namikawa K, Fukushima M, Murakami K, et al: Expression of Reg/PAP family members during motor nerve regeneration in rat. Biochem Biophys Res Commun. 332:126–134. 2005. View Article : Google Scholar : PubMed/NCBI
37	Iovanna J, Orelle B, Keim V and Dagorn JC: Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis. J Biol Chem. 266:24664–24669. 1991.
38	Dieckgraefe BK, Stenson WF, Korzenik JR, Swanson PE and Harrington CA: Analysis of mucosal gene expression in inflammatory bowel disease by parallel oligonucleotide arrays. Physiol Genomics. 4:1–11. 2000.PubMed/NCBI
39	Lawrance IC, Fiocchi C and Chakravarti S: Ulcerative colitis and Crohn’s disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet. 10:445–456. 2001.
40	Nishimune H, Vasseur S, Wiese S, et al: Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway. Nat Cell Biol. 2:906–914. 2000. View Article : Google Scholar : PubMed/NCBI
41	Dusetti NJ, Ortiz EM, Mallo GV, Dagorn JC and Iovanna JL: Pancreatitis-associated protein I (PAP I), an acute phase protein induced by cytokines. Identification of two functional interleukin-6 response elements in the rat PAP I promoter region. J Biol Chem. 270:22417–22421. 1995. View Article : Google Scholar
42	Ortiz EM, Dusetti NJ, Vasseur S, et al: The pancreatitis-associated protein is induced by free radicals in AR4–2J cells and confers cell resistance to apoptosis. Gastroenterology. 114:808–816. 1998.PubMed/NCBI
43	Rouquier S, Verdier JM, Iovanna J, Dagorn JC and Giorgi D: Rat pancreatic stone protein messenger RNA. Abundant expression in mature exocrine cells, regulation by food content, and sequence identity with the endocrine reg transcript. J Biol Chem. 266:786–791. 1991.
44	Bluth MH, Patel SA, Dieckgraefe BK, Okamoto H and Zenilman ME: Pancreatic regenerating protein (reg I) and reg I receptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis. World J Gastroenterol. 12:4511–4516. 2006.PubMed/NCBI