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      MUC4 and MUC1 Expression in Adenocarcinoma of the Stomach Correlates with Vessel Invasion and Lymph Node Metastasis: An Immunohistochemical Study of Early Gastric Cancer

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          We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by Western blotting and IHC of two MUC4 mRNA expressing gastric cancer cell lines. MAb 8G7 reacted clearly, whereas MAb 1G8 did not show any reactivity, in either Western blotting or IHC. In the IHC of the gastric cancers, the expression rates of MUC4/8G7 detected by MAb 8G7, MUC4/1G8 detected by MAb 1G8 and MUC1/DF3 detected by MAb DF3 in well differentiated types (70%, 38/54; 67%, 36/54; 52%, 28/54) were significantly higher than those in poorly differentiated types (18%, 10/55; 36%, 20/55; 13%, 7/55) ( P<0.0001; P = 0.0021; P<0.0001), respectively. The MUC4/8G7 expression was related with lymphatic invasion (r = 0.304, P = 0.033). On the other hand, the MUC4/1G8 expression was related with lymphatic invasion (r = 0.395, P = 0.001) and lymph node metastasis (r = 0.296, P = 0.045). The MUC1/DF3 expression was related with lymphatic invasion (r = 0.357, P = 0.032) and venous invasion (r = 0.377, P = 0.024). In conclusion, the expression of MUC4 as well as MUC1 in early gastric cancers is a useful marker to predict poor prognostic factors related with vessel invasion.

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          Most cited references 32

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          Japanese classification of gastric carcinoma: 3rd English edition.

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            Japanese gastric cancer treatment guidelines 2010 (ver. 3).

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              Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer.

              Mucins are a large family of glycoproteins expressed by many epithelial cells and their malignant counterparts. Much interest has been focused on expression of its members in breast cancer because of their potential role as prognostic indicators and their involvement in cancer therapy. We have examined 1447 cases of invasive breast carcinoma with a long-term follow-up, using tissue microarray (TMA) technology and immunohistochemistry to evaluate the expression profiles of several mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and to assess their prognostic value. We detected MUC1 expression in 91% of tumours. MUC1 overexpression was associated with a lower grade, smaller tumour size, a higher oestrogen receptor (ER)-positive phenotype and absence of both regional recurrence and distance metastasis. The subcellular localization but not the level of expression had a prognostic value in predicting outcome. The aberrant cytoplasmic and membranous localization of MUC1 was associated with poor outcome compared with apical localization, which is the normal physiological site of expression. MUC2 expression was noticed in only 8.3% of all cases and was restricted to the cytoplasm of the tumour cells. An inverse trend was identified between MUC2 expression and lymph node stage and vascular invasion status. On excluding cases of mucinous carcinoma from the analysis, the inverse association with vascular invasion was still defined and in addition an inverse association with ER status emerged. MUC3 expression was detected in 91% of cases and its expression was associated with increased local recurrence, and lymph node stage. The membranous expression of MUC3 was found to be a potentially poor prognostic feature, with higher grade and poorer Nottingham Prognostic Index (NPI), and negative ER expression. MUC4, MUC5AC and MUC6 were expressed in 95, 37 and 20% of cases, respectively. Apart from an association between MUC4 expression and tumour grade and between MUC6 and ER-negative tumours, no other associations with any clinicopathological variables were found. Apart from the higher expression of MUC2 and MUC6 in mucinous carcinomas, no association was found between the expression of different mucins and tumour type. No association between the level of expression of any of the studied mucins and patient outcomes has been identified. In conclusion, most breast carcinomas express MUC1, MUC3 and MUC4. Among the various mucins expressed in breast cancer, MUC1 and MUC3 are potential prognostic indicators, MUC1 having the strongest relationship with patient outcome.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                13 November 2012
                : 7
                : 11
                [1 ]Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan
                [2 ]Department of Internal Medicine, Ohsumi-Kanoya Hospital, Kanoya, Kagoshima, Japan
                [3 ]Department of Surgery, Kagoshima-shi Medical Association Hospital, Kagoshima, Japan
                [4 ]Department of Pathology, Kagoshima-shi Medical Association Hospital, Kagoshima, Japan
                [5 ]Departments of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
                [6 ]National Sanatorium Hoshizuka-Keiaien, Kanoya, Kagoshima, Japan
                Wayne State University School of Medicine, United States of America
                Author notes

                Competing Interests: The authors declare that they have no conflict of interest regarding the work in the study.

                Conceived and designed the experiments: YT M. Higashi S. Yonezawa. Performed the experiments: YT M. Higashi SK S. Yokoyama S. Yonezawa. Analyzed the data: YT M. Higashi MG S. Yonezawa. Contributed reagents/materials/analysis tools: MO M. Horinouchi TS MT SKB. Wrote the paper: YT M. Higashi.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Pages: 9
                This study was supported in part by Princes Takamatsu Cancer Research Fund to S. Yonezawa; Grants-in-Aid for Scientific Research on Scientific Research (B) 23390085 to S. Yonezawa; Scientific Research (C) 21590399 to M. Higashi; Young Scientists (B) 24701008 to S. Yokoyama; Scientific Research on Priority Areas 239349 to S. Kitamoto (JSPS Fellowship) from the Ministry of Education, Science, Sports, Culture and Technology, Japan; a Pancreas Research Foundation of Japan to S. Yokoyama; and the Kodama Memorial Foundation, Japan to M. Higashi. S. Batra is supported in part by the National Institutes of Health grants (CA78590, CA163120, CA133944 and CA111294). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.
                Research Article
                Cell Membrane
                Membrane Proteins
                Immunologic Techniques
                Immunohistochemical Analysis
                Anatomy and Physiology
                Immune Physiology
                Lymphatic System
                Diagnostic Medicine
                Anatomical Pathology
                Surgical Pathology
                Basic Cancer Research
                Cancers and Neoplasms
                Gastrointestinal Tumors
                Gastric Cancer



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