1364

CLDN4

claudin 4;CLDN4;claudin 4

CPE-receptor|Clostridium perfringens enterotoxin receptor 1|Williams-Beuren syndrome chromosomal region 8 protein|claudin-4

7q11.23

protein-coding

In this study, we analyzed Claudin-1 and Claudin-4 expressions in colon carcinomas. We investigated the relationship between the expression of these tight junction proteins and clinicopathologic parameters. Claudin-1 and 4 expressions were determined by immunohistochemical methods, and the rate of cells expressing these tight junction proteins were calculated with stereologic methods. Fifty-nine colon cancer cases were enrolled in the study group. Claudin-1 and 4 expressions were found to be significantly lower in cases with lymph node metastasis. Mean staining rates of Claudin-1 and 4 in lymph node (+) cases were 36.1+/-20.1 and 58+/-28.9, while in lymph node (-) cases, these were 63.8+/-25.9 and 72.3+/-25.6, respectively (p=0.0005 for Claudin-1, p=0.049 for Claudin-4). The mean staining rate for Claudin-1 in adenomatous polyps was significantly higher than incarcinomas (77.13+/-23.4 and 50.6+/-26.93, respectively) (p=0.003), while it was quite similar for Claudin-4 (65.4+/-26.9 and 65.3+/-27.9, respectively). In this study, we demonstrated Claudin-1 and 4 expressions in colon cancer cases. Claudin-1 expression seems to be more prominent in adenomatous polyps as compared with cancer cases. expression of Claudin-1 decreases significantly in the presence of lymph node metastasis and diminishes in mucinous carcinoma cases, indicating a negative correlation between Claudin-1 expression and neoplastic progression.

Claudin-4 (CL-4) is a tight junction-associated protein that is expressed in most epithelial cells but absent in mesothelial cells. The purpose of this study is to evaluate the utility of CL-4 immunostaining for assisting in the differential diagnosis of mesothelioma. Sixty mesotheliomas (40 epithelioid, 10 biphasic, and 10 sarcomatoid), 185 carcinomas of different origins that can potentially be confused with mesotheliomas, 37 soft-tissue sarcomas, and 5 melanomas were investigated for CL-4 expression. All 60 mesotheliomas were CL-4 negative. In contrast, 169 (91%) of 185 carcinomas expressed this marker. Five of 8 desmoplastic small round cell tumors and the epithelial component of all 5 biphasic synovial sarcomas were CL-4 positive, whereas none of the remaining soft-tissue sarcomas or melanomas expressed this marker. It is concluded that CL-4 is a highly specific and sensitive immunohistochemical marker for assisting in distinguishing epithelioid mesotheliomas from metastatic carcinomas to the serosal membranes.

Claudin-4 has been identified as an integral constituent of tight junctions and has been found to be highly expressed in pancreatic cancer. The aim of the present study was to elucidate the effect of claudin-4 on growth and metastatic potential in pancreatic cancer cells, as well as the regulation of claudin-4 by oncogenic pathways. Claudin-4 was stably overexpressed in SUIT-2 pancreatic cancer cells, and its effect on invasion and growth in vitro was examined by using two-chamber invasion assays, soft agar assays, and fluorescence-activated cell sorter analysis. Claudin-4 localization was characterized by light and electron microscopy, and pulmonary colonization was analyzed in vivo after injection of claudin-4 overexpressing cells into the tail vein of nude mice. Overexpression of claudin-4 was associated with significantly reduced invasive potential in vitro and inhibited colony formation in soft agar assays. In vivo, tail vein-injected claudin-4 overexpressing cells formed significantly less pulmonary metastases in comparison with mock-transfected cells. These effects were not caused by changes in proliferation, cell cycle progression, or matrix metalloproteinase gelatinolytic activity, but were paralleled by increased cell contact formation. Moreover, proinvasive transforming growth factor beta was able to down-regulate claudin-4 in PANC-1 cells. Inhibition of Ras signaling by using dominant-negative Ras and specific inhibitors of both downstream effectors mitogen-activated protein/extracellular signal-regulated kinase kinase and phosphatidylinositol 3-kinase also decreased claudin-4 expression. Our findings identify claudin-4 as a potent inhibitor of the invasiveness and metastatic phenotype of pancreatic cancer cells, and as a target of the transforming growth factor beta and Ras/Raf/extracellular signal-regulated kinase pathways.

In the quest for markers of expression and progression for prostate cancer (PCa), the majority of studies have focussed on molecular data exclusively from primary tumours. Although expression in metastases is inferred, a lack of correlation with secondary tumours potentially limits their applicability diagnostically and therapeutically. Molecular targets were identified by examining expression profiles of prostate cell lines using cDNA microarrays. Those genes identified were verified on PCa cell lines and tumour samples from both primary and secondary tumours using real-time RT-PCR, western blotting and immunohistochemistry. Claudin-4, coding for an integral membrane cell-junction protein, was the most significantly (P<0.00001) upregulated marker in both primary and metastatic tumour specimens compared with benign prostatic hyperplasia at both RNA and protein levels. In primary tumours, claudin-4 was more highly expressed in lower grade (Gleason 6) lesions than in higher grade (Gleason >or=7) cancers. expression was prominent throughout metastases from a variety of secondary sites in fresh-frozen and formalin-fixed specimens from both androgen-intact and androgen-suppressed patients. As a result of its prominent expression in both primary and secondary PCas, together with its established role as a receptor for Clostridium perfringens enterotoxin, claudin-4 may be useful as a potential marker and therapeutic target for PCa metastases.