Expression Of Claudin-4 In Human Clear-cell Renal Cell Carcinoma And Its Relationship With Clinical Pathology And Prognosis

Background: The incidence and mortality of renal cell carcinoma is still in high level because of unkonw causes and recurance after surgery, which hightlights the urgency and importance of post-surgery risk assessment. Currently, UISS, SSIGN and Leibovich staging system are widely used to predict the prognosis of cc RCC patients and have significant implications for cancer treatment. However, the classification criterion these systems based on is published by American Joint Committee(AJCC) in2002, still nedds further improvement. The claudins are crucial structural components of tight junctions,which play important roles in regulating cell physiology, and will cause many diseases including cancers when in disfunction and structure abnormlity.As a major member of claudins, claudin-4 is upregulated in many maligancy and associated with prognosis of some tumors. Unfortunately, our knowledge about the role of claudin-4 in cc RCC is still limited and controversial, more investigations are needed into its mechanism.Objective: To investgate the expressions of claudin-4 in cc RCC and its relationship with clinical pathology, prognosis in order to explore the possible function of claudin-4 in cc RCC.Methods: Tissue specimens were collected from patients with cc RCC underwent surgery in 307 hospital,PLA. The expression of cludin-4 in 50 cases of cc RCC and 10 normal kidney tissues were detected by IHC, analyzing the relationship between the expression level of claudin-4 and clinicopathological characteristics. Western blot was employed to confirm the expression of claudin-4 in 4 cases of cc RCC and 4 normal kidney tissues. The relationship of claudin-4 expression level and disease-free survival(DFS) was analyzed to predict the prognosis of cc RCC.Results:1. Claudin-4 was expressed in both tissues and mostly located in cell membrane,the mediam value of IOD in normal kidney tissues and cc RCC was(11391.383(8698.632,14292.705) and 15616.762(10266.791,24221.539), separately.There was a signficant difference between the expression level of claudin-4 in cc RCC and that in normal kidney tissues(P=0.028).2. The expression level of claudin-4 was markedly associated with tumor diameters, T stages, clinical stages and lymph node metastasis. Upregulation of claudin-4 expression can be found in cc RCC with diameters>7cm, T3-T4 and lymph node metastasis.3. The result of Western blot also confirmed that the expression of claudin-4 was much higher in cc RCC than normal kidney tissues. There was a positive association between the results of WB and IHC.4. Kaplan-Meier analysis showed DFS of elevating group was 20.7 months, which was significantly less than downregulating group, 30.8 months. Cox proportional-hazards regression model analysis indicated that clinical stage and lymph node metastasis were independent prognostic factor for cc RCC patients after surgery,while claduin-4 not(RR=1.686,95% CI 0.174~16.311,P=0.652).Conclusion: Claudin-4 might play a positive role in carcinogenesis and progression of cc RCC, which might become a potential therapeutic target and adverse prognostic factor.