Many factors are involved in the development, advancement, and metastasis of malignant tumors. Recently, there has been increasing attention paid to the interaction between cancer cells and the adjacent normal cells. Cell binding among normal cells connects the cells to each other and induces a stable interrelation, and zonula adherens, desmosomes, zonula occludens, and the tight junction are involved [1]. The tight junction consists of three integral transmembrane proteins: occludins, claudins, and junctional adhesion molecules [1-3]. Claudin, one of the main proteins that form epithelial tight junctions, was first discovered in 1998, and 24 types have been reported to date [4]. The up-regulation or down-regulation of claudin is known to be related to the carcinogenesis and metastasis of various cancers, such as stomach cancer, colon cancer, and pancreatic cancer [5-7]. However, studies of the clinical correlation between various cancers and the expression of claudin have shown different results. Thus, studies are actively being conducted to confirm a clear correlation.

In this study, we verified the immunohistochemical expression level of claudin-1 and claudin-7 with clear cell RCC and compared the clinicopathologic prognostic factors (sex, age, BMI, tumor size, TNM stage, Fuhrman nuclear grade, postoperative distant metastasis, and cancer-specific survival) to investigate the significance of claudin-1 and claudin-7 expression.

RCC is the most common primary malignant tumor in kidneys. The World Health Organization (WHO) classifies the malignant tumors in kidneys into 10 types, among which clear cell RCC, papillary RCC, and chromophobe RCC are the most common subtypes, accounting for about 85% to 90% of the total RCC cases [8,9].

Pathologic classification, TNM stage, and clinical opinion of RCC are known as important factors in the patient's prognosis [10]. Additionally, various factors in prognosis have been studied recently, such as the expression of claudin and its value as a prognostic factor. The loss of intercellular adhesion in tumor cells is known to be an important process in the intrusion and metastasis of tumor cells to the peripheral matrix [11]. Cell binding induces cells to interconnect with each other and have stable interrelations, and zonula adherens, desmosomes, zonula occludens, and tight junction are involved in this interaction [1]. Tight junctional proteins are located in the apical and basolateral sections of cells, which play an important part in the maintenance of polarity of cells, control of paracellular transportation, and barrier functions. As a result, cell binding represses the diffusion of the water and ions surrounding the cells as well as the internal macromolecules [12], controls the osmotic force, affects cell movement [1,13], and maintains homeostasis and cell polarity [2]. Moreover, cell binding is known to be involved in cell growth, differentiation, and control of other cellular functions.

Claudin, one of the integral transmembrane proteins that constitute tight junctions, is the main protein that forms the epithelial tight junction, and 24 types have been reported to date [4]. The expression of claudins is known to be related to the carcinogenesis of various cancers: the low expression of claudin-1 and claudin-5 was associated with a Gleason score of 7 or higher and a high prostate-specific antigen value in prostate cancer [14]. Claudin-1 was shown to be under- expressed in the tissues of prostate cancer, breast cancer, and thyroid cancer [15-17], and claudin-1 expression was lost in hepatocellular carcinoma [18].

Although claudin expression varies depending on the tumor, RCC has not been studied much, and only a few articles are available about its clinical prognosis in particular. Osunkoya et al and Hornsby et al reported that claudin-7 expression was enhanced in chromophobe RCC [19,20], and Fritzsche et al reported that claudin-1 expression was found in a small number of clear cell RCC patients but that cancer-specific survival was reduced in those patients [21]. In our study, claudin-1 expression was found in 15.1% of clear cell RCC cases, and it was higher with higher age, larger tumor size, higher T stage, preoperative distant metastasis, higher Fuhrman grade, and recent postoperative distant metastasis. By contrast, claudin-7 expression was found in 26.1% of clear cell RCC, and it was higher only with higher Fuhrman grade.

Because claudin exists at the tight junction between the cells and it maintains cellular polarity, serving as a wall, a reduction in claudin expression is anticipated as a tumor develops. However, according to various clinical results, claudin expression varies depending on the subtypes and the kinds of cancer [14-21]. Regarding the cause of such a contradiction among results, the protein level might have been increased as a response to the lost cellular cohesion during the malignant degeneration process or by the amplification due to mutation of the claudin gene [22]. Also, in our study, high stage and Fuhrman grade as well as distant metastasis were found in the cases in which the claudin expression was increased. The accurate role played by claudin in malignant cells should be investigated in future studies.

In the present study, we found that the correlation between the expression of claudin-1 and claudin-7 and cancer-specific survival was insignificant (p=0.110 and p=0.662, respectively). However, because there is a report that cancer-specific survival was reduced in patients in whom claudin-1 was expressed [21], and only a limited number of studies have been conducted on the relationship between claudin and cancer-specific survival until now, more studies should be carried out in the future to assess the correlation between claudin and cancer-specific survival.

A limitation of this study is that we had a small number of cases of other subtypes except clear cell RCC, such as papillary RCC and chromophobe RCC, and thus the expression and clinical characteristics of claudin-1 and claudin-7 were not investigated with respect to the other subtypes. Comparison of the claudin-1 and claudin-7 expression among different RCC subtypes needs to be carried out in the future with a larger number of cases.

In clear cell RCC, the claudin-1 expression was higher with higher age, larger tumor size, higher T stage, preoperative distant metastasis, and higher Fuhrman nuclear grade. When the claudin-1 expression was positive, the risk of postoperative distant metastasis was increased. The expression of claudin-7 was higher in relation to only a higher Fuhrman nuclear grade. Claudin-1 and claudin-7 were not correlated with cancer-specific survival. In clear cell RCC, the claudin-1 expression may be valuable as a clinically meaningful prognostic factor of postoperative distant metastasis.