Abstract
Simple SummaryThe claudin (CLDN) family, the backbone of tight junctions, consists of more than 20 members in humans, and exhibits distinct expression patterns in tissue- and cell-type-specific manners. Among the CLDN members, CLDN6 is primarily expressed in diverse embryonic epithelial cells. It is also aberrantly expressed in various types of cancers, but its significance remains obscure. In the present study, we generated a highly specific anti-human CLDN6 monoclonal antibody, and assessed the prognostic significance of aberrant CLDN6 expression in endometrial cancer tissues. This study indicates that high CLDN6 expression in endometrial cancer relates to several clinicopathological factors and is an independent prognostic factor. The established monoclonal antibody could be a valuable tool to evaluate CLDN6-expressing tumors.Background: Among the claudin (CLDN) family, CLDN6 exhibits aberrant expression in various cancers, but its biological relevance has not yet been established. We generated a monoclonal antibody (mAb) against human CLDN6 and verified its specificity. By immunohistochemical staining and semi-quantification, we evaluated the relationship between CLDN6 expression and clinicopathological parameters in tissues from 173 cases of endometrial cancer. Results: The established mAb selectively recognized CLDN6 protein. Ten of the 173 cases (5.8%) showed high CLDN6 expression (score 3+), whereas 19 (11.0%), 18 (10.4%) and 126 (72.4%) cases revealed low CLDN6 expression (score 2+, 1+ and 0, respectively). In addition, intratumor heterogeneity of CLDN6 expression was observed even in the cases with high CLDN6 expression. The 5-year survival rates in the high and low CLDN6 groups was approximately 30% and 90%, respectively. Among the clinicopathological factors, the high CLDN6 expression was significantly associated with surgical stage III/IV, histological type, histological grade 3, lymphovascular space involvement, lymph node metastasis and distant metastasis. Furthermore, the high CLDN6 expression was an independent prognostic marker for overall survival of endometrial cancer patients (hazard ratio 3.50, p = 0.014). Conclusions: It can be concluded that aberrant CLDN6 expression is useful to predict poor outcome for endometrial cancer and might be a promising therapeutic target.
Highlights
Endometrial cancer is the most common gynecological malignancy in developed countries, with an increased prevalence worldwide [1]
Using this specific monoclonal antibody (mAb), we show that the high CLDN6 expression in endometrial cancer is significantly associated with several clinicopathological factors
We first generated a novel mAb against the C-terminal cytoplasmic region of human CLDN6 (Figure 1A) using the iliac lymph node method [24]
Summary
Endometrial cancer is the most common gynecological malignancy in developed countries, with an increased prevalence worldwide [1]. Up to 20% of cases recur after primary surgery, and the 5-year overall survival rates for International Federation of Gynecology and Obstetrics (FIGO) stages III and IV cancer are 57–66% and 20–26%, respectively [7]. By immunohistochemical staining and semi-quantification, we evaluated the relationship between CLDN6 expression and clinicopathological parameters in tissues from 173 cases of endometrial cancer. The 5-year survival rates in the high and low CLDN6 groups was approximately 30% and 90%, respectively. The high CLDN6 expression was significantly associated with surgical stage III/IV, histological type, histological grade 3, lymphovascular space involvement, lymph node metastasis and distant metastasis. The high CLDN6 expression was an independent prognostic marker for overall survival of endometrial cancer patients (hazard ratio 3.50, p = 0.014)
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