Down-Regulation of Claudin-1 Expression in Gastric Cancer Mucosa Is Correlated with Poor Prognosis


Background: Cell adhesion molecule abnormalities are given as one reason for the occurrence of invasion and metastasis in various cancers. In this study, we conducted an immunohistochemical examination of cell adhesion molecule claudin-1 in mucosa and invasive front of gastric cancer, and investigated the correlation of claudin-1 expression and clinicopathological factors. Methods: Immunohistochemical examination was performed for 35 patients who underwent surgery be-tween January 2010 and October 2011, to assess the correlation of claudin-1 with primary gastric cancer. Results: The expression rate of claudin-1 was 48.6% (17/35) in 35 gastric carcinoma patients. The positive rates of claudin-1 were 42.9% (15/35) in mucosa and 28.6% (10/35) in invasive front of gastric cancer. The expression rate of claudin-1 in invasive front was lower than in mucosa. From comparing claudin-1 expression in mucosa, it was found that well-to moderately-differentiated adenocarcinoma had significantly more claudin-1 expression than poorly-differrentiated adenocarcinoma. Claudin-1 expression of well-to moderately-differentiated adenocar-cinoma decreased in the invasive front of gastric cancer. Expression of claudin-1 in mucosa was negative in many cases with advanced tumor invasion (T2, T3, T4) and positive in many cases with early tumor invasion (T1), with a significant difference between the two (p < 0.05). In mucosa, many cases at an advanced stage (Stage II, III, IV) were negative for claudin-1 expression and many cases at an early stage (Stage I) were positive for claudin-1 expression. A significant difference was seen between the two (p < 0.05). However, claudin-1 expression in the invasive front was not correlated with histological type, depth of tumor invasion and stage. Conclusion: From the above results, it is considered that decreased claudin-1expression in mucosa is related to histological type, gastric cancer invasion and stage, and this information may be useful when making a pathological diagnosis of advanced gastric cancer and estimating outcomes.

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Hirakawa, E. , Tokuhara, Y. , Morinishi, T. , Ohsaki, H. , Uemura, E. , Miki, Y. , Matsunaga, T. , Kushida, Y. and Haba, R. (2014) Down-Regulation of Claudin-1 Expression in Gastric Cancer Mucosa Is Correlated with Poor Prognosis. Open Journal of Pathology, 4, 206-212. doi: 10.4236/ojpathology.2014.44026.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Kang, C., Song, J., Lee, K. and Kim, M.Y. (2014) Epigenetics: An Emerging Player in Gastric Cancer. World Journal of Gastroenterology, 20, 6433-6447.
[2] Yamamoto, S. (2001) Stomach Cancer Incidence in the World. Japanese Journal of Clinical Oncology, 31, 471.
[3] Ferlay, J., Shin, H.R., Bray, F., et al. (2010) Estimates of Worldwide Burden of Cancer in 2008: GLOBOCAN 2008. International Journal of Cancer, 127, 2893-2917.
[4] Matter, K. and Balda, M.S. (2003) Signalling to and from Tight Junctions. Nature Reviews Molecular Cell Biology, 4, 225-236.
[5] Mitic, L.L., Van Itallie, C.M. and Anderson, J.M. (2000) Molecular Physiology and Pathophysiology of Tight junctions I. Tight Junction Structure and Function: Lessons from Mutant Animals and Proteins. American Journal of Physiology-Gastrointestinal and Liver Physiology, 279, 250-254.
[6] Tsukita, S., Furuse, M. and Itoh, M. (2001) Multifunctional Strands in Tight Junctions. Nature Reviews Molecular Cell Biology, 2, 285-293.
[7] Martin, T.A. and Jiang, W.G. (2001) Tight Junctions and Their Role in Cancer Metastasis. Histology and Histopathology, 16, 1183-1195.
[8] Langbein, L., Pape, U.F., Grund, C., et al. (2003) Tight Junction-Related Structures in the Absence of a Lumen: Occludin, Claudins and Tight Junction Plaque Proteins in Densely Packed Cell Formations of Stratified Epithelia and Squamous Cell Carcinomas. European Journal of Cell Biology, 82, 385-400.
[9] Jawhari, A., Jordan, S., Poole, S., Browne, P., Pignatelli, M. and Farthing, M.J. (1997) Abnormal Immunoreactivity of the E-Cadherin-Catenin Complex in Gastric Carcinoma: Relationship with Patient Survival. Gastroenterology, 112, 46-54.
[10] Mimata, A., Fukamachi, H., Eishi, Y. and Yuasa Y. (2011) Loss of E-Cadherin in Mouse Gastric Epithelial Cells Induces Signet Ring-Like Cells, a Possible Precursor Lesion of Diffuse Gastric Cancer. Cancer Science, 102, 942-950.
[11] Soini, Y., Tommola, S., Helin, H. and Martikainen, P. (2006) Claudins 1,3,4 and 5 in Gastric Carcinoma, Loss of Clau- din Expression Associates with the Diffuse Subtype. Virchows Archiv, 448, 52-58.
[12] Hewitt, K.J., Agareal, R. and Morin, P.J. (2006) The Claudin Gene Family: Expression in Normal and Neoplastic Tissues. BMC Cancer, 6, 186.
[13] Jung, H., Jun, K.H., Jung, J.H., Chin, H.M. and Park, W.B. (2011) The Expression of Claudin-1, Claudin-2, Claudin-3, and Claudin-4 in Gastric Cancer Tissue. Journal of Surgical Research, 167, 185-191.
[14] Wu, Y.L., Zhang, S., Wang, G.R. and Chen, Y.P. (2008) Expression Tranformation of Claudin-1 in the Process of Ga- stric Adenocarcinoma Invasion. World Journal of Gastroenterology, 14, 4943-4948.
[15] Japanese Gastric Cancer Association (2011) Japanese Classification of Gastric Gastric Carcinoma: 3rd English Edition. Gastric Cancer, 14, 101-112.
[16] Sano, T. and Aiko, T. (2011) New Japanese Classifications and Treatment Guidelines for Gastric Cancer: Revision Concepts and Major Revised Points. Gastric Cancer, 14, 97-100.
[17] Sobin, L.H., Gospodarowicz, M.K. and Wittekind, C., Eds. (2007) TNM Classification of Malignant Tumours. 7th Edi- tion, John Wiley & Sons, New York.
[18] Jechlinger, M., Grunert, S. Tamir, I.H., Janda, E., Lüdemann, S., Waerner, T., et al. (2003) Expression Profiling of Epithelial Plasticity in Tumor Progression. Oncogene, 22, 7155-7169.
[19] Tsukita, S. and Furuse, M. (2000) Pores in the Wall: Claudins Constitute Tight Junction Strands Containing Aqueous Pores. The Journal of Cell Biology, 149, 13-16.
[20] Resnick, M.B., Konkin, T., Routhier, J., Sabo, E. and Pricolo, V.E. (2005) Claudin-1 is a Strong Prognostic Indicator in Stage II Colonic Cancer: A Tissue Microarray Study. Modern Pathology, 18, 511-518.
[21] Krämer, F., White, K., Kubbies, M., Swisshelm, K. and Weber, B.H.F. (2000) Genomic Organization of Claudin-1 and Its Assessment in Hereditary and Sporadic Breast Cancer. Human Genetics, 107, 249-256.
[22] Tökés, A.M., Kulka, J., Paku, S., Szik, á., Páska, C., Novák, P.K., et al. (2005) Claudin-1, -3 and -4 Proteins and mRNA Expression in Benign and Malignant Breast Lesions: A Research Study. Breast Cancer Research, 7, R296- R305.
[23] Resnick, M.B., Gavilannez, M., Newton, E., Konkin, T., Bhattachrya, B., Britt, D., et al. (2005) Claudin Expression in Gastric Adenocarcinomas: A Tissue Microarray Study with Prognostic Correlation. Human Pathology, 36, 886-892.
[24] Lauren, P. (1965) The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Car- cinoma. An Attempt at a Histo-Clinical Classification. Acta Pathologica et Microbiologica Scandinavica, 64, 31-49.
[25] Ming, S.C. (1997) Gastric Carcinoma. A Pathobiological Classification. Cancer, 39, 2475-2485.
[26] Huang, J., Li, J., Qu, Y., Zhang, J., Zhang, L., Chen, X., et al. (2014) The Expression of Claudin 1 Correlates with β- Catenin and Is a Prognostic Factor of Poor Outcome in Gastric Cancer. International Journal of Oncology, 44, 1293- 1301.
[27] Eftang, L.L., Esbensen, Y., Tannes, T.M., Blom, G.P., Bunkholm, I.R. and Bunkholm, G. (2013) Up-Regulation of CLDN1 in Gastric Cancer is Correlated with Reduced Survival. BMC Cancer, 13, 586.
[28] Ohtani, S., Terajiima, M., Satoh, J., Soeta, N., Saze, Z., Kashimura, S., et al. (2009) Expression of Tight-Junction-As- sociated Proteins in Human Gastric Cancer: Downregulation of Claudin-4 Correlates with Tumor Aggressiveness and Survival. Gastric Cancer, 12, 43-51.
[29] Gao, M., Li, W., Wang, H. and Wang, G. (2013) The Distinct Expression Patterns of Claudin-10, -14, -17 and E-Ca- dherin between Adjacent Non-Neoplastic Tissues and Gastric Cancer Tissues. Diagnostic Pathology, 8, 205.

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