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Forkhead Box J1 Expression Is Upregulated and Correlated with Prognosis in Patients with Clear Cell Renal Cell Carcinoma

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Forkhead Box J1 Expression Is Upregulated and Correlated with Prognosis in Patients with Clear Cell Renal Cell Carcinoma ONCOLOGY LETTERS 10: 1487-1494, 2015 Forkhead box J1 expression is upregulated and correlated with prognosis in patients with clear cell renal cell carcinoma PINGYU ZHU1, YONGRUI PIAO2, XIUZHE DONG2 and ZHEHU JIN3 1Department of Urology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637200; Departments of 2Urology, and 3Dermatology and Venereology, Affiliated Hospital of Yanbian University, Yanji, Jilin 133000, P.R. China Received July 7, 2014; Accepted March 20, 2015 DOI: 10.3892/ol.2015.3376 Abstract. The forkhead box (FOX) family of transcription Introduction factors are considered to have a role in tumorigenesis. FOXJ1 is a member of the FOX family; however, its function in human Human renal cell carcinoma (RCC) is the most common type renal cell carcinoma (RCC) has remained to be elucidated. of malignant kidney tumor in adults worldwide, and ~85% of Therefore, the present study evaluated the expression of RCCs are clear cell RCC (CCRCC) (1). RCC is regarded as a FOXJ1 in human clear cell RCC and the effect of FOXJ1 on the localized disease in the early stages, however, 30% of patients proliferative ability of RCC cells. The RCC specimens analyzed with RCC that present with localized disease at the time of in the present study were obtained from 286 patients with RCC diagnosis develop metastatic disease within three years (2). who underwent nephrectomy. FOXJ1 mRNA expression levels Furthermore, the prognosis for metastatic RCC is poor (3) as were determined using reverse transcription-quantitative RCC is resistant to traditional chemotherapy (4,5) and alter- polymerase chain reaction, and FOXJ1 protein expression native therapeutic strategies for advanced RCC are limited. levels were determined using immunohistochemistry and At present, novel strategies for the treatment of advanced western blot analysis. To determine the effect of FOXJ1 on the RCC include molecular targeted therapy (6), monoclonal proliferative ability of RCC cells, the expression of FOXJ1 was antibodies (7), immunotherapy (8) and the suppression of decreased using small interfering (si)RNA, and a FOXJ1 vector signaling pathways (9). Although specific markers predicting was stably transfected into RCC cell lines. The proliferative the prognosis of advanced RCC and its potential therapeutic ability of RCC cells was then examined using a WST-1 assay response to treatment have been investigated, the molecular and xenograft experiments with BALB/c nude mice, where the mechanisms underlying the progression and development of association between FOXJ1 expression and patient survival RCC have remained elusive. was determined using Kaplan-Meier analysis. FOXJ1 expres- The forkhead box (FOX) family comprises numerous sion was significantly higher in RCC tissues compared with proteins with a wide spectrum of biological processes, that of healthy renal tissues. Furthermore, FOXJ1 expression including differentiation, metabolism, apoptosis, prolif- was associated with tumor stage, histologic grade and size. In eration, migration and invasion. FOX proteins contain addition, FOXJ1 significantly enhanced the proliferation of conserved transcriptional factors defined by a common RCC cells in vitro and in vivo. The present study identified that DNA-binding domain (10). Furthermore, the FOX family is FOXJ1 expression was upregulated in RCC and enhanced the divided into 19 subclasses and consists of 50 genes in the proliferative ability of RCC cells. Therefore, FOXJ1 may serve human genome (11). Previous studies have determined that as an independent prognostic marker and a therapeutic target FOX proteins are associated with carcinogenesis and the for the treatment of patients with RCC. progression of malignancies. For example, the expression of FOXM1 was increased in a variety of types of tumor, including basal cell and hepatocellular carcinoma, as well as lung, breast, prostate and colorectal cancer (12-17). FOXM1 may be associated with carcinogenesis due to its role as a key regu- lator in the G1/S and G2/M phases of the cell cycle (18-21). In addition, FOXO has been reported to be dysregulated in Correspondence to: Dr Yongrui Piao, Department of Urology, Affiliated Hospital of Yanbian University, 1327 Juzi Street, Yanji, various types of tumor, including prostate and breast cancer, Jilin 133000, P.R. China leukemia, glioblastoma and endometrial carcinoma (22-28); E-mail: [email protected] FOXA1 was overexpressed in thyroid, lung and esophageal cancer (29,30); and FOXC2 appears to be a key gene involved Key words: forkhead box J1, renal cell carcinoma, proliferation, in tumor progression and angiogenesis (31). prognosis, therapeutic target FOXJ1 is a transcription factor that is significant in the central nervous and reproductive systems (32-34). Previous studies have demonstrated that abnormal expression of 1488 ZHU et al: EXPRESSION OF FOXJI IN RENAL CELL CARCINOMA FOXJ1 is associated with autoimmune diseases and certain to staining intensity (-, negative; +, weak; ++, moderate; and inflammatory diseases (35,36). This association appears to be +++, strong). due to the ability of FOXJ1 to suppress T cell activity, resulting in spontaneous autoimmunity (37). In addition, FOXJ1 inhibits Western blot analysis. Western blot analysis was performed the humoral immune response in B cells, with FOXJ1 deficiency according to the manufacturer's instructions. Briefly, total in B cells being associated with germinal center formation protein was isolated from the CCRCC and healthy tissue samples and the development of autoantibodies (38). A previous study using lysis buffer (Sigma-Aldrich) as previously described (44), proposed that FOXJ1 expression was decreased in breast cancer, and the total protein concentration was determined using a thus, functioning as a tumor suppressor gene (39). However, Bradford dye-binding protein assay (Bio-Rad Laboratories, FOXJ1 expression was increased in hepatocellular carcinoma Inc., Hercules, CA, USA). Subsequently, 10% SDS-PAGE and was associated with poor prognosis. Furthermore, overex- (Bio-Rad Laboratories, Inc.) was performed. FOXJ1 mono- pression of FOXJ1 appears to be involved in proliferation and clonal mouse anti-rat antibody (cat. no. sc-53139; 1;1,000; Santa cell-cycle progression. In brief, little is known regarding the Cruz Biotechnology, Inc.) was applied as the experimental potential roles of FOXJ1 in carcinogenesis (40). antibody and anti-β-actin monoclonal mouse anti-human The expression of FOXJ1 and its function in human RCC antibody (cat. no. ab6276; 1:5,000; Abcam, Cambridge, UK) is unclear. Therefore, the current study aimed to determine the was applied as a loading control at 37˚C for 2 h. The immune expression of FOXJ1 in human RCC and its effect on the prolif- complexes were evaluated using an enhanced chemilumines- erative ability of human RCC cells. cence system (GE Healthcare Life Sciences, Chalfont, UK). Materials and methods Reverse transcription‑quantitative polymerase chain reac‑ tion (RT‑qPCR). Total RNA was isolated from the CCRCC and Patients and samples. The current study included 286 patients healthy kidney tissues using an illustra™ QuickPrep mRNA with RCC that had undergone radical nephrectomy in the purification kit (GE Healthcare, Life Sciences), according to Department of Urology of the Affiliated Hospital of Yanbian the manufacturer's instructions, and RT was performed using University (Yanji, China) between April 2002 and March 2003. a First-Strand complementary (c)DNA synthesis kit (GE The histological cell type of all specimen slices was determined Healthcare Life Sciences). The PCR conditions were deter- by experienced pathologists and all samples were diagnosed mined according to the manufacturer's instructions as follows: as conventional CCRCC. The clinical tumor stages and Denaturation at 95˚C for 5 min, annealing for 30 cycles characteristics were classified according to the tumor node of 95˚C for 30 sec, 60˚C for 30 sec and 72˚C for 1 min and metastasis (TNM) classification system (41), and the nuclear extension at 72˚C for 10 min. RT-qPCR was performed using grade was evaluated according to the Fuhrman grading system LightCycler® FastStart DNA Master SYBR Green I (Roche of malignant tumors (42). RCC tissue samples and corre- Diagnostics GmbH, Indianapolis, USA) and the PCR prod- sponding healthy kidney tissues located at a maximal distance ucts were detected by agarose gel electrophoresis, followed from the tumor were collected immediately following surgical by quantification of the products using LightCycler (Roche resection. The samples were formalin‑fixed (Sigma‑Aldrich, Diagnostics GmbH). The primer sequences were as follows: St. Louis, MO, USA), dehydrated and paraffin-embedded FOXJ1 forward, 5'-TCGAGATGGCGGAGAGCTGG-3' and (Sigma-Aldrich). All tissue samples were maintained in liquid reverse, 5'-GATCCCAAGAAGGCCCCCAC-3'; GAPDH nitrogen (Sigma-Aldrich) prior to protein and RNA extraction. forward, 5'-ATCAAGAAGGTGGTGAAGCAG-3' and reverse, The patients were followed up every three months for a period 5'-TGGAGGAGTGGGTGTCGC-3'. All RT-qPCR experimental of 120 months. The present study was approved by the Ethics procedures were conducted in accordance with Minimum Committee of the Affiliated Hospital of Yanbian University and Information for Publication of Quantitative Real-Time PCR written consent was obtained from all patients. Experiments guidelines (45). Immunohistochemistry. All paraffin-embedded tissue Cell culture. Four RCC cell lines (Caki-1, NC65, ACHN, sections
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