REG IV overexpression in an early stage of colorectal carcinogenesis: An immunohistochemical study
Xiao-Han Li1,2, Yang Zheng1, Hua-Chuan Zheng1,3, Hiroyuki Takahashi1, Xiang-Hong Yang2, Shinji Masuda4 and Yasuo Takano1
1Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan, 2Division of Pathology, Affiliated Shengjing Hospital of China Medical University, Shenyang, China, 3Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, China and 4Division of Pathology, Kouseiren Takaoka Hospital, Takaoka, Japan.
Offprint requests to: Yasuo Takano, Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan. e-mail: firstname.lastname@example.org
Summary. To clarify the role of REG IV, a new member of the regenerating gene (REG) family, in tumorigenesis and progression of colorectal carcinoma (CRC), 320 CRC specimens, 123 corresponding adjacent non-cancerous mucosa (ANCMs), 46 corresponding non-adjacent non-cancerous mucosa (NANCMs) and 86 adenomas were investigated immunohistochemically to compare REG IV expression with clinicopathological features. In addition, double immunofluorescence labeling was performed to analyze the localization of REG IV and the intestinal mucin, MUC2. The expression of REG IV in CRCs was significantly lower than in NANCMs, ANCMs or adenomas, and inversely correlated with poor differentiation and venous invasion. In cases of ANCM, REG IV expression was positively correlated with the depth of invasion, lymph node metastasis and Duke’s staging of corresponding cases. The expression of REG IV in CRC was significantly linked to that of MUC2 and the EGFR phosphorylated on Tyr1068, but not to that of MUC5AC, EGFR, Akt, or Akt phosphorylated on Ser473 or Thr308. The double immunofluorescence revealed coexpression, but independent localization, of REG IV and MUC2 in NANCMs, ANCMs, adenomas and CRCs, except for mucinous carcinomas. Univariate analysis using the Kaplan-Meier method indicated no correlation between REG IV expression and the cumulative survival rate of CRC patients. In conclusion, REG IV expression was upregulated in ANCMs and adenomas, then decreased in CRCs. This indicated that REG IV overexpression may be an early event in CRC carcinogenesis. Its expression in CRCs was positively linked to MUC2 and phosphorylation of the EGFR on Tyr1068, suggesting that REG IV may be a useful marker for intestinal type mucinous carcinoma and a good candidate as a molecular therapeutic target for CRCs. Histol Histopathol 25, 473-484 (2010)
Key words: Colorectal carcinoma, REG IV, Biological behavior