RegIV在胃癌及胃非癌组织中的表达及意义
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摘要
目的检测再生基因4 (regenerating islet-derived family member 4,RegIV)在各种胃癌(gastric carcinoma,GC)及胃非癌组织中的表达情况,并探讨其可能临床意义。
方法运用免疫组织化学方法半定量检测73例我院胃癌手术切除标本和90例胃癌、癌旁非癌组织芯片中RegIV蛋白的表达情况。
结果RegIV选择性表达于胃黏膜的壁细胞中,胃小凹上皮细胞为RegIV阴性。RegIV在胃黏膜肠化生杯状细胞呈固定强胞浆染色(阳性率100%)。肠型胃癌(杯状细胞可见)、胃印戒细胞癌、粘液腺癌的癌细胞中呈RegIV的频繁免疫反应性(分别为100%(3/3)、93.3%(14/15)和90.9%(10/11))。RegIV强核周染色在肠化生基础上的神经内分泌细胞中见到,6例胃神经内分泌癌无1例见RegIV表达。RegIV的表达与胃癌的侵袭参数(包括浸润深度、转移或TNM分期)无明显相关性(P>0.05),RegIV的表达与胃癌的组织分型相关(P<0.05),其在肠型和弥漫浸润型胃癌中的表达差异有统计学意义。组织芯片免疫组化染色形态同我院石蜡组织切片。但30例胃管状腺癌无1例出现RegIV阳性表达(阳性率0%)。RegIV在胃粘液腺癌和印戒细胞癌中的表达阳性率分别为43.3%(13/30)和40.0%(12/30),与我院组织标本的阳性率有较大差异。
结论RegIV在胃黏膜肠化生杯状细胞、胃印戒细胞癌、粘液腺癌中显示频繁免疫反应性,RegIV可能参与从肠上皮化生、杯状异型增生发展成胃腺癌的癌变过程。RegIV的表达是否与胃癌的神经内分泌分化有关需进一步证实。RegIV的表达与胃癌患者的临床病理学特征无明显相关,但不能完全排除其可能参与肿瘤细胞的侵袭浸润行为。我院石蜡包埋胃癌手术标本与组织芯片的免疫组化结果并未显示严格一致性,考虑与地域差异等因素有关。
OBJECTIVE To investigate the expression and significance of RegIV( regenerating islet-derived family member 4) protein in gastric neoplastic and nonneoplastic tissues.
METHOD RegIV protein was detected with immunohistochemiscal (IHC) methods in 73 GC specimens that were collected from surgical resection in our hospital and a tissue microarray(TMA) of 90 GC specimens with adjacent non-neoplastic mucosa.
RESULTS RegIV was selectively expressed in the parietal cells of gastric mucosa, and was absent in foveolar epithelial cells. In intestinal metaplasia (IM) of the stomach, goblet cells were strongly positive for RegIV (positive rate 100%). Intestinal gastric carcinomas (with goblet cells present), gastric signet ring cell carcinomas (SRCCs) and mucinous adenocarcinomas showed frequently immunoreactivity (100%(3/3)、93.3%(14/15)and 90.9%(10/11)respectively). Neuroendocrine cells at the base of intestinal metaplasia were strongly perinuclear positive for Reg IV, none of the 6 cases of gastric neuroendocrine neoplasm showed RegIV staining. No association of Reg IV expression with aggressive parameters of gastric carcinoma, including invasion, metastasis, or TNM staging was found ( P>0.05 ) .However, RegIV expression was associated with histopathological subtype(sP<0.05). The expressive difference of RegIV in intestinal and diffusetype gastric carcinoma was of statistical significance. The staining pattern of tissue microarray of the stomach was similar to that of paraffin tissue sections collected from our hospital. None of 30 cases of gastric tubular adenocarcinoma was positive for RegIV(positive rate 0%).The positive rate of RegIV expression in gastric mucinous adenocarcinomas and SRCCs were 43.3%(13/30)and 40.0%(12/30)respectively, which were apparently different from that of specimens supported by our hospital.
CONCLUSION Goblet cells of intestinal metaplasia of the stomach,gastric SRCCs and mucinous adenocarcinomas expressed Reg IV more frequently than other histologic subtypes, indicating that Reg IV might be involved in the molecular mechanisms of gastric carcinogenesis from IM and globoid dysplasia to adenocarcinoma. Whether Reg IV expression is associated with the neuroendocrine differentiation in gastric carcinoma needs to be confirmed. No association of Reg IV expression with clinicopathological features of patients with gastric cancer was found, however, the potential role of RegIV in invasive behavior of malignant cells could not be excluded completely. The inconsistent IHC results detected in 2 sources of tissues were considered to be associated with many factors such as arealvariation.
方法运用免疫组织化学方法半定量检测73例我院胃癌手术切除标本和90例胃癌、癌旁非癌组织芯片中RegIV蛋白的表达情况。
结果RegIV选择性表达于胃黏膜的壁细胞中,胃小凹上皮细胞为RegIV阴性。RegIV在胃黏膜肠化生杯状细胞呈固定强胞浆染色(阳性率100%)。肠型胃癌(杯状细胞可见)、胃印戒细胞癌、粘液腺癌的癌细胞中呈RegIV的频繁免疫反应性(分别为100%(3/3)、93.3%(14/15)和90.9%(10/11))。RegIV强核周染色在肠化生基础上的神经内分泌细胞中见到,6例胃神经内分泌癌无1例见RegIV表达。RegIV的表达与胃癌的侵袭参数(包括浸润深度、转移或TNM分期)无明显相关性(P>0.05),RegIV的表达与胃癌的组织分型相关(P<0.05),其在肠型和弥漫浸润型胃癌中的表达差异有统计学意义。组织芯片免疫组化染色形态同我院石蜡组织切片。但30例胃管状腺癌无1例出现RegIV阳性表达(阳性率0%)。RegIV在胃粘液腺癌和印戒细胞癌中的表达阳性率分别为43.3%(13/30)和40.0%(12/30),与我院组织标本的阳性率有较大差异。
结论RegIV在胃黏膜肠化生杯状细胞、胃印戒细胞癌、粘液腺癌中显示频繁免疫反应性,RegIV可能参与从肠上皮化生、杯状异型增生发展成胃腺癌的癌变过程。RegIV的表达是否与胃癌的神经内分泌分化有关需进一步证实。RegIV的表达与胃癌患者的临床病理学特征无明显相关,但不能完全排除其可能参与肿瘤细胞的侵袭浸润行为。我院石蜡包埋胃癌手术标本与组织芯片的免疫组化结果并未显示严格一致性,考虑与地域差异等因素有关。
OBJECTIVE To investigate the expression and significance of RegIV( regenerating islet-derived family member 4) protein in gastric neoplastic and nonneoplastic tissues.
METHOD RegIV protein was detected with immunohistochemiscal (IHC) methods in 73 GC specimens that were collected from surgical resection in our hospital and a tissue microarray(TMA) of 90 GC specimens with adjacent non-neoplastic mucosa.
RESULTS RegIV was selectively expressed in the parietal cells of gastric mucosa, and was absent in foveolar epithelial cells. In intestinal metaplasia (IM) of the stomach, goblet cells were strongly positive for RegIV (positive rate 100%). Intestinal gastric carcinomas (with goblet cells present), gastric signet ring cell carcinomas (SRCCs) and mucinous adenocarcinomas showed frequently immunoreactivity (100%(3/3)、93.3%(14/15)and 90.9%(10/11)respectively). Neuroendocrine cells at the base of intestinal metaplasia were strongly perinuclear positive for Reg IV, none of the 6 cases of gastric neuroendocrine neoplasm showed RegIV staining. No association of Reg IV expression with aggressive parameters of gastric carcinoma, including invasion, metastasis, or TNM staging was found ( P>0.05 ) .However, RegIV expression was associated with histopathological subtype(sP<0.05). The expressive difference of RegIV in intestinal and diffusetype gastric carcinoma was of statistical significance. The staining pattern of tissue microarray of the stomach was similar to that of paraffin tissue sections collected from our hospital. None of 30 cases of gastric tubular adenocarcinoma was positive for RegIV(positive rate 0%).The positive rate of RegIV expression in gastric mucinous adenocarcinomas and SRCCs were 43.3%(13/30)and 40.0%(12/30)respectively, which were apparently different from that of specimens supported by our hospital.
CONCLUSION Goblet cells of intestinal metaplasia of the stomach,gastric SRCCs and mucinous adenocarcinomas expressed Reg IV more frequently than other histologic subtypes, indicating that Reg IV might be involved in the molecular mechanisms of gastric carcinogenesis from IM and globoid dysplasia to adenocarcinoma. Whether Reg IV expression is associated with the neuroendocrine differentiation in gastric carcinoma needs to be confirmed. No association of Reg IV expression with clinicopathological features of patients with gastric cancer was found, however, the potential role of RegIV in invasive behavior of malignant cells could not be excluded completely. The inconsistent IHC results detected in 2 sources of tissues were considered to be associated with many factors such as arealvariation.
引文
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[1] Broekaert D, Eyckerman S, Lavens D, Verhee A, Waelput W, Vandekerckhove J, Tavernier J. Comparison of leptin? and interleukin?6?regulated expression of the rPAP gene family: evidence for differential co?regulatory signals. Eur Cytokine Netw. 2002; 13:78?85.
[2] Zhang YW, Ding LS, Lai MD. Reg gene family and human diseases. World J Gastroenterol ogy.2003; 9:2635-2641.
[3] Bluth MH, Patel SA, Dieckgraefe BK, Okamoto H, Zenilman ME. Pancreatic regenerating protein (regI) and reg I receptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis. World J Gastroenterol 2006; 12: 4511-4516.
[4] Ose T, Kadowaki Y, Fukuhara H, Kazumori H, Ishihara S, Udagawa J, Otani H, Takasawa S,Okamoto H, Kinoshita Y. 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 2007;26: 349-359.
[5] Hervieu V, Christa L, Gouysse G, Bouvier R, Chayvialle JA, Bréchot C, Scoazec JY.HIP/PAP, a member of the reg family, is expressed in glucagonproducing enteropancreatic endocrine cells and tumors. Hum Pathol 2006; 37: 1066-1075.
[6] Hartupee JC, Zhang H, Bonaldo MF, Soares MB, Dieckgraefe BK. Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. Biochim Biophys Acta. 2001; 1518(3):287-93.
[7] K?m?r?inen M, Heiskala K, Knuutila S, Heiskala M,Winqvist O, Andersson LC. RELP, a novel human REG-like protein with up-regulated expression in inflammatory and metaplastic gastrointestinal mucosa. Am J Pathol 2003; 163: 11-20.
[8] Oue N, Mitani Y, Aung PP, Sakakura C, Takeshima Y, Kaneko M, Noguchi T, Nakayama H, Yasui W. Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma. J Pathol. 2005 ;207(2):185-98.
[9] Violette S,Festor E,Pandrea Vasile I,et al.RegIV,a new member of the regenerating gene family,is over expressed in colorectal carcinomas[J].Int J Cancer.2003;103(2):185-193.
[10] Oue N, Hamai Y, Mitani Y, Matsumura S, Oshimo Y, Aung PP, Kuraoka K, Nakayama H, Yasui W. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res. 2004;64(7):2397-405.
[11]Sasahira T, Oue N, Kirita T, Luo Y, Bhawal UK, Fujii K, Yasui W, Kuniyasu H. Reg IV expression is associated with cell growth and prognosis of adenoid cystic carcinoma in the salivary gland. Histopathology. 2008;53(6):667-75.
[12] Sentani K, Oue N, Tashiro T, Sakamoto N, Nishisaka T, Fukuhara T, Taniyama K, Matsuura H, Arihiro K, Ochiai A, Yasui W. Immunohistochemical staining of Reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma. Am J Surg Pathol. 2008;32(8):1182-9.
[13] Mitani Y, Oue N, Matsumura S, Yoshida K, Noguchi T, Ito M, Tanaka S, Kuniyasu H, Kamata N, Yasui W. Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy.Oncogene. 2007;26(30):4383-93.
[14]刘兵,项明,于颖彦,杨秋蒙,蔡劬,陈雪华,李建芳,刘炳亚,朱正纲.体外RNA干扰抑制RegⅣ基因表达对胃癌细胞增殖及凋亡的影响.世界华人消化杂志.2009:17(6):549-553.
[15] Miyagawa K, Sakakura C, Kin S, Nakase Y, Fukuda K, Hagiwara A, Okazaki Y, Hayashizaki Y, Yamagishi H. Over expression of Reg IV in peritoneal dissemination of gastric cancer. Gan To Kagaku Ryoho. 2004;31(11):1909-11.
[16] Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Fukuda K, Hagiwara A, Okazaki Y, Hayashizaki Y, Yamagishi H. Analysis of Reg IV expression in peritoneal dissemination of gastric cancer using real-time RT-PCR.Gan To Kagaku Ryoho.2005;32(11):1707-8.
[17] Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Fukuda K, Kin S, Nakase Y,Shimomura K, Oue N, Yasui W, Hayasizaki H, Okazaki Y, Yamagishi H, Hagiwara A, Otsuji E.Over expression of RegIV in peritoneal dissemination of gastric cancer and its potential as A novel marker for the detection of peritoneal micrometastasis.Anticancer Res.2008 ;28(2B):1169-79.
[18] Kuniyasu H, Oue N, Sasahira T, Yi L, Moriwaka Y, Shimomoto T, Fujii K, Ohmori H, Yasui W.Reg IV enhances peritoneal metastasis in gastric carcinomas.Cell Prolif.2009;42(1):110-21.
[19] Glebov OK, Rodriguez LM, Soballe P, DeNobile J, Cliatt J, Nakahara K, Kirsch IR.Gene expression patterns distinguish colonoscopically isolated human aberrant crypt foci from normal colonic mucosa.Cancer Epidemiol Biomarkers Prev. 2006;15(11):2253-62.
[20] Zhang Y, Lai M, Gu X, Luo M, Shao L. Reg IV, a differentially expressed gene in colorectal adenoma. Chin Med J. 2003 ;116(6):918-22.
[21] Zhang Y, Lai M, Lv B, Gu X, Wang H, Zhu Y, Zhu Y, Shao L, Wang G. Overexpression of Reg IV in colorectal adenoma.Cancer Lett. 2003 ;200(1):69-76.
[22] LüBJ,Cui J,Xu J,Zhang H,Luo MJ,Zhu YM,Lai MD.Bioinformatic analysis of adenoma-normal mucosa SSH library of colon.Yi Chuan. 2006;28(4):385-92.
[23] L BJ, Xu J, Zhu Y, Zhang H, Lai M.Systemic analysis of the differential gene expression profile in a colonic adenoma-normal SSH library. Clin Chim Acta. 2007 ;378(1-2):42-7.
[24] Pankova-Kholmyansky I, Arber N. Reg IV can serve for early diagnosis and therapy. Cancer Biol Ther. 2007;6(1):123-4.
[25] Yeh CS, Wang JY, Wu CH, Chong IW, Chung FY, Wang YH, Yu YP, Lin SR. Molecular detection of circulating cancer cells in the peripheral blood of patients with colorectal cancer by using membrane array with a multiple mRNA marker panel. Int J Oncol. 2006;28(2):411-20.
[26] Oue N, Kuniyasu H, Noguchi T, Sentani K, Ito M, Tanaka S, Setoyama T, Sakakura C, Natsugoe S, Yasui W. Serum concentration of Reg IV in patients with colorectal cancer: overexpression and high serum levels of Reg IV are associated with liver metastasis. Oncology. 2007;72(5-6):371-80.
[27] Takehara A, Eguchi H, Ohigashi H, Ishikawa O, Kasugai T, Hosokawa M, Katagiri T, Nakamura Y, Nakagawa H. Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4.Cancer Sci. 2006;97(11):1191-7.
[28] Heiskala K, Giles-Komar J, Heiskala M, Andersson LC. High expression of RELP (Reg IV) in neoplastic goblet cells of appendiceal mucinous cystadenoma and pseudomyxoma peritonei. Virchows Arch. 2006;448(3):295-300.
[29]Ohara S, Oue N, Matsubara A, Mita K, Hasegawa Y, Hayashi T, Usui T, Amatya VJ,Takeshima Y, Kuniyasu H, Yasui W Reg IV is an independent prognostic factor for relapse in patients withclinically localized prostate cancer..Cancer Sci. 2008;99(8):1570-7.
[30] Hayashi T, Matsubara A, Ohara S, Mita K, Hasegawa Y, Usui T, Arihiro K, Norimura S, Sentani K, Oue N, Yasui W. Immunohistochemical analysis of Reg IV in urogenital organs: Frequent expression of Reg IV in prostate cancer and potential utility as serum tumor marker. Oncol Rep. 2009;21(1):95-100.
[31] Nakata K, Nagai E, Ohuchida K, Aishima S, Hayashi A, Miyasaka Y, Yu J, Mizumoto K, Tanaka M, Tsuneyoshi M. REG4 is associated with carcinogenesis in the 'intestinal' pathway of intraductal papillary mucinous neoplasms. Mod Pathol. 2009;22(3):460-8.
[32] Bishnupuri KS, Luo Q, Murmu N, Houchen CW, Anant S, Dieckgraefe BK. Reg IV activates the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon adenocarcinomas.Gastroenterology. 2006;130(1):137-49.
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9. Ose T, Kadowaki Y, Fukuhara H, Kazumori H, Ishihara S, Udagawa J, Otani H, Takasawa S,Okamoto H, Kinoshita Y. 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 2007; 26: 349-359.
10. Hervieu V, Christa L, Gouysse G, Bouvier R, Chayvialle JA, Bréchot C, Scoazec JY. HIP/PAP, a member of the reg family, is expressed in glucagonproducing enteropancreatic endocrine cells and tumors. Hum Pathol 2006; 37: 1066-1075.
11. Hartupee JC, Zhang H, Bonaldo MF, Soares MB,Dieckgraefe BK. Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. Biochim Biophys Acta.2001; 1518: 287-293.
12. K?m?r?inen M, Heiskala K, Knuutila S, Heiskala M, Winqvist O, Andersson LC. RELP, a novel human REG-like protein with up-regulated expression in inflammatory and metaplastic gastrointestinal mucosa. Am J Pathol 2003; 163: 11-20.
13. Oue N, Mitani Y, Aung PP, Sakakura C, Takeshima Y, Kaneko M, Noguchi T, Nakayama H, Yasui W. Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma. J Pathol 2005; 207: 185-198.
14. Mitani Y, Oue N, Matsumura S, et al. Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil–based chemotherapy. Oncogene 2007; 26:4383-93.
15. Miyagawa K, Sakakura C, Kin S, Nakase Y, Fukuda K, Hagiwara A, Okazaki Y, Hayashizaki Y, Yamagishi H. Over expression of Reg IV in peritoneal dissemination of gastric cancer.Gan To Kagaku Ryoho 2004; 31: 1909-1911.
16. Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Fukuda K, Hagiwara A, Okazaki Y, Hayashizaki Y, Yamagishi H. Analysis of Reg IV expression in peritoneal dissemination of gastric cancer using real-time RT-PCR.Gan To Kagaku Ryoho 2005; 32: 1707-1708.
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18. Kuniyasu H, Oue N, Sasahira T, Yi L, Moriwaka Y, Shimomoto T, Fujii K, Ohmori H, Yasui W. Reg IV enhances peritoneal metastasis in gastric carcinomas. Cell Prolif 2009; 42: 110-121.
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48. Sentani K, Oue N, Tashiro T, Sakamoto N, Nishisaka T, Fukuhara T, Taniyama K, Matsuura H, Arihiro K, Ochiai A, Yasui W. Immunohistochemical staining of Reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma. Am J Surg Pathol 2008; 32: 1182-1189.
49. Heiskala K, Giles-Komar J, Heiskala M, Andersson LC. High expression of RELP (Reg IV) in neoplastic goblet cells of appendiceal mucinous cystadenoma and pseudomyxoma peritonei. Virchows Arch 2006;448:295-300.
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52. Hidetsugu Yamagishi1, Hirokazu Fukui1, Akira Sekikawa1 et al.Expression profile of REG family proteins REG Ia and REG IV in advanced gastric cancer: comparison with mucin phenotype and prognostic markers. Modern Pathology 2009; 22:906–913.
[1] Broekaert D, Eyckerman S, Lavens D, Verhee A, Waelput W, Vandekerckhove J, Tavernier J. Comparison of leptin? and interleukin?6?regulated expression of the rPAP gene family: evidence for differential co?regulatory signals. Eur Cytokine Netw. 2002; 13:78?85.
[2] Zhang YW, Ding LS, Lai MD. Reg gene family and human diseases. World J Gastroenterol ogy.2003; 9:2635-2641.
[3] Bluth MH, Patel SA, Dieckgraefe BK, Okamoto H, Zenilman ME. Pancreatic regenerating protein (regI) and reg I receptor mRNA are upregulated in rat pancreas after induction of acute pancreatitis. World J Gastroenterol 2006; 12: 4511-4516.
[4] Ose T, Kadowaki Y, Fukuhara H, Kazumori H, Ishihara S, Udagawa J, Otani H, Takasawa S,Okamoto H, Kinoshita Y. 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 2007;26: 349-359.
[5] Hervieu V, Christa L, Gouysse G, Bouvier R, Chayvialle JA, Bréchot C, Scoazec JY.HIP/PAP, a member of the reg family, is expressed in glucagonproducing enteropancreatic endocrine cells and tumors. Hum Pathol 2006; 37: 1066-1075.
[6] Hartupee JC, Zhang H, Bonaldo MF, Soares MB, Dieckgraefe BK. Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. Biochim Biophys Acta. 2001; 1518(3):287-93.
[7] K?m?r?inen M, Heiskala K, Knuutila S, Heiskala M,Winqvist O, Andersson LC. RELP, a novel human REG-like protein with up-regulated expression in inflammatory and metaplastic gastrointestinal mucosa. Am J Pathol 2003; 163: 11-20.
[8] Oue N, Mitani Y, Aung PP, Sakakura C, Takeshima Y, Kaneko M, Noguchi T, Nakayama H, Yasui W. Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma. J Pathol. 2005 ;207(2):185-98.
[9] Violette S,Festor E,Pandrea Vasile I,et al.RegIV,a new member of the regenerating gene family,is over expressed in colorectal carcinomas[J].Int J Cancer.2003;103(2):185-193.
[10] Oue N, Hamai Y, Mitani Y, Matsumura S, Oshimo Y, Aung PP, Kuraoka K, Nakayama H, Yasui W. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res. 2004;64(7):2397-405.
[11]Sasahira T, Oue N, Kirita T, Luo Y, Bhawal UK, Fujii K, Yasui W, Kuniyasu H. Reg IV expression is associated with cell growth and prognosis of adenoid cystic carcinoma in the salivary gland. Histopathology. 2008;53(6):667-75.
[12] Sentani K, Oue N, Tashiro T, Sakamoto N, Nishisaka T, Fukuhara T, Taniyama K, Matsuura H, Arihiro K, Ochiai A, Yasui W. Immunohistochemical staining of Reg IV and claudin-18 is useful in the diagnosis of gastrointestinal signet ring cell carcinoma. Am J Surg Pathol. 2008;32(8):1182-9.
[13] Mitani Y, Oue N, Matsumura S, Yoshida K, Noguchi T, Ito M, Tanaka S, Kuniyasu H, Kamata N, Yasui W. Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy.Oncogene. 2007;26(30):4383-93.
[14]刘兵,项明,于颖彦,杨秋蒙,蔡劬,陈雪华,李建芳,刘炳亚,朱正纲.体外RNA干扰抑制RegⅣ基因表达对胃癌细胞增殖及凋亡的影响.世界华人消化杂志.2009:17(6):549-553.
[15] Miyagawa K, Sakakura C, Kin S, Nakase Y, Fukuda K, Hagiwara A, Okazaki Y, Hayashizaki Y, Yamagishi H. Over expression of Reg IV in peritoneal dissemination of gastric cancer. Gan To Kagaku Ryoho. 2004;31(11):1909-11.
[16] Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Kin S, Nakase Y, Fukuda K, Hagiwara A, Okazaki Y, Hayashizaki Y, Yamagishi H. Analysis of Reg IV expression in peritoneal dissemination of gastric cancer using real-time RT-PCR.Gan To Kagaku Ryoho.2005;32(11):1707-8.
[17] Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Fukuda K, Kin S, Nakase Y,Shimomura K, Oue N, Yasui W, Hayasizaki H, Okazaki Y, Yamagishi H, Hagiwara A, Otsuji E.Over expression of RegIV in peritoneal dissemination of gastric cancer and its potential as A novel marker for the detection of peritoneal micrometastasis.Anticancer Res.2008 ;28(2B):1169-79.
[18] Kuniyasu H, Oue N, Sasahira T, Yi L, Moriwaka Y, Shimomoto T, Fujii K, Ohmori H, Yasui W.Reg IV enhances peritoneal metastasis in gastric carcinomas.Cell Prolif.2009;42(1):110-21.
[19] Glebov OK, Rodriguez LM, Soballe P, DeNobile J, Cliatt J, Nakahara K, Kirsch IR.Gene expression patterns distinguish colonoscopically isolated human aberrant crypt foci from normal colonic mucosa.Cancer Epidemiol Biomarkers Prev. 2006;15(11):2253-62.
[20] Zhang Y, Lai M, Gu X, Luo M, Shao L. Reg IV, a differentially expressed gene in colorectal adenoma. Chin Med J. 2003 ;116(6):918-22.
[21] Zhang Y, Lai M, Lv B, Gu X, Wang H, Zhu Y, Zhu Y, Shao L, Wang G. Overexpression of Reg IV in colorectal adenoma.Cancer Lett. 2003 ;200(1):69-76.
[22] LüBJ,Cui J,Xu J,Zhang H,Luo MJ,Zhu YM,Lai MD.Bioinformatic analysis of adenoma-normal mucosa SSH library of colon.Yi Chuan. 2006;28(4):385-92.
[23] L BJ, Xu J, Zhu Y, Zhang H, Lai M.Systemic analysis of the differential gene expression profile in a colonic adenoma-normal SSH library. Clin Chim Acta. 2007 ;378(1-2):42-7.
[24] Pankova-Kholmyansky I, Arber N. Reg IV can serve for early diagnosis and therapy. Cancer Biol Ther. 2007;6(1):123-4.
[25] Yeh CS, Wang JY, Wu CH, Chong IW, Chung FY, Wang YH, Yu YP, Lin SR. Molecular detection of circulating cancer cells in the peripheral blood of patients with colorectal cancer by using membrane array with a multiple mRNA marker panel. Int J Oncol. 2006;28(2):411-20.
[26] Oue N, Kuniyasu H, Noguchi T, Sentani K, Ito M, Tanaka S, Setoyama T, Sakakura C, Natsugoe S, Yasui W. Serum concentration of Reg IV in patients with colorectal cancer: overexpression and high serum levels of Reg IV are associated with liver metastasis. Oncology. 2007;72(5-6):371-80.
[27] Takehara A, Eguchi H, Ohigashi H, Ishikawa O, Kasugai T, Hosokawa M, Katagiri T, Nakamura Y, Nakagawa H. Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4.Cancer Sci. 2006;97(11):1191-7.
[28] Heiskala K, Giles-Komar J, Heiskala M, Andersson LC. High expression of RELP (Reg IV) in neoplastic goblet cells of appendiceal mucinous cystadenoma and pseudomyxoma peritonei. Virchows Arch. 2006;448(3):295-300.
[29]Ohara S, Oue N, Matsubara A, Mita K, Hasegawa Y, Hayashi T, Usui T, Amatya VJ,Takeshima Y, Kuniyasu H, Yasui W Reg IV is an independent prognostic factor for relapse in patients withclinically localized prostate cancer..Cancer Sci. 2008;99(8):1570-7.
[30] Hayashi T, Matsubara A, Ohara S, Mita K, Hasegawa Y, Usui T, Arihiro K, Norimura S, Sentani K, Oue N, Yasui W. Immunohistochemical analysis of Reg IV in urogenital organs: Frequent expression of Reg IV in prostate cancer and potential utility as serum tumor marker. Oncol Rep. 2009;21(1):95-100.
[31] Nakata K, Nagai E, Ohuchida K, Aishima S, Hayashi A, Miyasaka Y, Yu J, Mizumoto K, Tanaka M, Tsuneyoshi M. REG4 is associated with carcinogenesis in the 'intestinal' pathway of intraductal papillary mucinous neoplasms. Mod Pathol. 2009;22(3):460-8.
[32] Bishnupuri KS, Luo Q, Murmu N, Houchen CW, Anant S, Dieckgraefe BK. Reg IV activates the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon adenocarcinomas.Gastroenterology. 2006;130(1):137-49.