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Niban Gene Is Commonly Expressed in the Renal Tumors: a New Candidate Marker for Renal Carcinogenesis

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Niban Gene Is Commonly Expressed in the Renal Tumors: a New Candidate Marker for Renal Carcinogenesis Oncogene (2004) 23, 3495–3500 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc Niban gene is commonly expressed in the renal tumors: a new candidate marker for renal carcinogenesis Hiroyuki Adachi1,2, Shuichi Majima1, Shigeyuki Kon1,3, Toshiyuki Kobayashi1, Kazunori Kajino1, Hiroaki Mitani1, Youko Hirayama1, Hiroaki Shiina2, Mikio Igawa2 and Okio Hino*,1 1Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan; 2Department of Urology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo-shi, Shimane 693-8501, Japan; 3Immuno-Biological Laboratories Co., Ltd., 1091-1 Naka, Fujioka-shi, Gunma 375-0005, Japan Functional inactivation of tuberous sclerosis 2 gene (Tsc2) one of the Tsc2 allele is inactivated genetically by the leads to renal carcinogenesis in the hereditary renal insertion of a transposon-like sequence (Hino et al., carcinoma Eker rat models. Recent studies revealed a role 1994; Yeung et al., 1994; Kobayashi et al., 1995). At the of tuberin,a TSC2 product,in suppressing the p70 S6 histological level, multiple stages in the development of kinase (p70S6K) activity via inhibition of mammalian renal carcinomas have been observed, beginning with target of rapamycin (mTOR). Phosphorylated S6 protein, isolated, phenotypically altered renal tubules (Hino a substrate of p70S6K,was expressed in the early lesions et al., 1993). We have demonstrated the inactivation of in Eker rats,and this expression was suppressed by the the wild-type Tsc2 allele in phenotypically altered renal treatment of rapamycin,an inhibitor of mTOR. We tubules and provided evidence that two-hit mutation of previously isolated the novel gene Niban expressed in the Tsc2 gene is the causative step in renal carcinogen- renal carcinogenesis of Eker rats. In this study,we esis (Kubo et al., 1995). demonstrated that the expression of Niban was detected Carcinogenesis consists of multiple steps and carci- from early preneoplastic lesions in Eker rats. Interest- noma development is associated with multiple genetic ingly,in contrast to the phosphorylated S6 protein,the alterations even in hereditary cancers. Although the expression of Niban was unchanged and early lesions still inactivation of Tsc2 results in the initiation of renal remained even after treatment with rapamycin. These carcinogenesis, it is not sufficient for tumor progression. results might suggest the existence of another pathway Progression to carcinomas may require additional independent of mTOR-S6K pathway in Tsc2 mutant renal genetic and epigenetic modification (Hino et al., 2003). carcinogenesis. In addition,Niban was also expressed in To identify the genes associated with multistep renal other renal carcinoma models,including Tsc1 and Tsc2 carcinogenesis, we previously performed the differential knockout mice,and various types of human renal cell display analysis for two cell lines established from the carcinomas. Thus,Niban was commonly expressed in Eker rat renal carcinoma, and isolated the novel gene renal carcinomas and might be a new marker for renal Niban (Majima et al., 2000). The Niban gene consists of carcinogenesis. 14 exons and is located on rat chromosome 13, or mouse Oncogene (2004) 23, 3495–3500. doi:10.1038/sj.onc.1207468 and human chromosome 1. Published online 1 March 2004 Recent biochemical analyses revealed that tuberin, the TSC2 gene product, is a substrate of Akt and can Keywords: Niban; Tsc2 mutant (Eker) rats; multistep inhibit the phosphatidylinositol 3-kinase (PI3K)-depen- renal carcinogenesis; tumor marker; human renal cell dent activation of p70 S6 kinase (p70S6K) via the carcinoma inhibition of mammalian target of rapamycin (mTOR) (Dan et al., 2002; Gao et al., 2002; Inoki et al., 2002; Manning et al., 2002). The phosphorylated form of S6 ribosomal protein, a substrate of p70S6K, was expressed ONCOGENOMICS Introduction in early preneoplastic lesions in Eker rats, and the expression of this phosphorylated protein was sup- Hereditary renal carcinoma in the rat, originally pressed by treatment with rapamycin, an inhibitor of reported by R Eker in 1954, is an example of a specific mTOR (Kenerson et al., 2002; Kobayashi et al., 2003). cancer in an experimental animal (Eker and Mossige, In this study, we demonstrated that the expression of 1961). We and others have demonstrated that the gene Niban was also detected in early preneoplastic lesions in responsible for renal carcinoma in the Eker rat is the rat Eker rats. Interestingly, the expression of Niban was homologue of the human TSC2 gene. In the Eker rat, unchanged and Niban-positive early preneoplastic lesions still remained after treatment with rapamycin. *Correspondence: O Hino; E-mail: [email protected] Furthermore, Niban was commonly expressed in other Received 17 October 2003; revised 14 December 2003; accepted 6 renal carcinogenesis models and sporadic human renal January 2004; Published online 1 March 2004 carcinomas. Niban expressed in renal carcinogenesis H Adachi et al 3496 Results Demonstration of the specificity of anti-rat and human Niban polyclonal antibodies For the detection of Niban proteins, we generated rabbit polyclonal antibodies against rat or human Niban proteins. First, we assessed the specificity of these polyclonal antibodies by Western blotting and immu- nohistochemical analysis (Figure 1). The predicted size of Niban proteins was about 130 kDa. This predicted size was clearly detected in extracts from HeLa cells and NIH3T3 cells transiently transfected with plasmids expressing the rat or human Niban proteins, respec- tively. This band could not be detected in extracts from cells transiently transfected with empty vector (Figures 1a and b; lanes R and E). The expression of rat Niban was not detected in normal kidneys from non- Eker rats (Figure 1a; lane C). Interestingly, the smaller band (about 70 kDa) was detected in renal tumors from Eker rats, and this band disappeared with the addition of the antigen peptide by Western blotting analysis (Figure 1a; lanes 1–3). Next, we examined the specificity of antibody against human Niban using cell lines established from human renal cell carcinomas. Two bands (about 70 and 130 kDa) were detected, and both of these bands disappeared with the addition of the antigen peptide (Figure 1b; lanes 1–3). The same results were obtained from immunohistochemical ana- lyses (Figures 1c–f). Thus, we consider that these antibodies specifically react with a peptide correspond- ing to the internal sequences of rat or human Niban proteins. Expression of Niban is detected from the early stage of renal carcinogenesis in Eker rats Next, we examined the expression of Niban in renal tumors developed in Eker rats using anti-rat Niban antibody. In the proximal tubules of normal kidneys from non-Eker rats, we could not detect the expression of Niban (Figure 2a). Strong staining was observed in phenotypically altered renal tubules, hyperplasias and adenomas (Figures 2b–d). A brush border was identified in phenotypically altered renal tubules (Figure 2b, arrow), so we considered that these renal tumors were derived from the proximal tubules. In advanced adenocarcinoma, we identified two groups, which Figure 1 Confirmation of the specificity of the rabbit polyclonal revealed positive or negative expressions of Niban antibodies against the rat (a) or human (b) Niban proteins by (Figure 2e). Western blotting and immunohistochemical analysis (c–f). (a) Recombinant rat Niban protein: lane R; empty vector (pcDNA 3.1): lane E; normal rat kidney tissues: lane C; renal tumor tissues Expression of Niban is commonly induced in renal from Eker rats: lanes 1–3. (b) Recombinant human Niban protein: carcinomas lane R; empty vector (pcDNA 3.1): lane E; renal tumor cell lines: lanes 1–3. (c–f) Positive staining was identified in Eker rat renal After we checked the crossreactivity of anti-rat Niban tumors (c) and human renal cell carcinomas (e), and most antibody between rat and mouse Niban proteins, we immunoreactivity disappeared when the anti-peptide antibodies analysed the expression of Niban in other renal were pretreated with the immunologic peptides, respectively (d and f). Eker rat renal tumors: (c) and (d); human renal cell carcinomas: carcinogenesis models, including Tsc1 (Figure 3a) and (e) and (f). Original magnification  100 Tsc2 knockout mouse (Figure 3b). The expression of Niban was also detected in renal tumors developed in these models. Furthermore, we can detect the expression of Niban in the sporadic human renal cell carcinomas Oncogene Niban expressed in renal carcinogenesis H Adachi et al 3497 Figure 2 Immunohistochemistry of Niban in normal kidneys from non-Eker rats and renal tumors developed in Eker rats. In the proximal tubules of normal kidneys, we could not detect the expression of Niban (a). However, positive staining was detected from phenotypically altered renal tubules (b–e). A brush border Figure 3 Immunohistochemistry of Niban in the hereditary renal was identified in phenotypically altered renal tubules (b, arrow). In carcinoma models and human renal cell carcinomas. Niban was advanced adenocarcinoma, we identified two groups, which also detected in renal carcinoma models, including Tsc1 (a) and revealed positive or negative expressions of Niban (e). Normal Tsc2 knockout mice (b). In addition, positive staining was observed rat kidney tissues from non-Eker rats: (a); Phenotypically altered in human renal cell carcinomas, including clear cell carcinomas (c renal tubules: (b); hyperplasias: (c); adenomas: (d); adenocarcino- and d), granular cell carcinoma (e) and spindle cell carcinoma (f). The expression of Niban was mainly observed in the cytoplasm (d– mas: (e). Original magnification  200 f). Nuclear staining of Niban was also observed in part of clear cell carcinoma (c). Renal tumor tissues from Tsc1 knockout mice: (a); renal tumor tissues from Tsc2 knockout mice: (b); clear cell using anti-human Niban antibody (Figures 3c–f). These carcinomas: (c) and (d); granular cell carcinomas: (e); spindle cell sporadic carcinomas consisted of various types, includ- carcinomas: (f).
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