Estrogen Receptor–Binding Fragment–Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma

Ogushi, Tetsuo; Takahashi, Satoru; Takeuchi, Takumi; Urano, Tomohiko; Horie‐Inoue, Kuniko; Kumagai, Jun; Kitamura, Tadaichi; Ouchi, Yasuyoshi; Muramatsu, Masami; Inoue, Satoshi

doi:10.1158/0008-5472.can-04-3497

Cited by 27 publications

(44 citation statements)

References 27 publications

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“…Expression of EBAG9, which is homologous to RCAS1, reportedly was correlated with in vivo tumor growth. 18 However, no apparent association between EBAG9 expression and in vitro cell growth was observed. Because the number of infiltrating CD8-positive T lymphocytes decreased in tumors composed of EBAG9-overexpressing cells in vivo, it is possible that immunosurveillance status may be suppressed by EBAG9 expression.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the murine renal cell carcinoma cell line RenCa, which harbors EBAG9 in BALB/c nude mice, had tumor growth potential similar to that of RenCa cells, which expresses vector alone. 18 The discrepancy between these 2 studies is unclear. However, other cell lines, including the endometrial cancer Hec-1 cells and Ishikawa cells, also formed larger tumors in nude mice after the RCAS1-encoding gene was introduced (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…16 EBAG9 also has been associated with the prognosis of patients with prostatic and renal cancer. 17,18 In vivo tumor growth was affected by EBAG9 expression: Tumor size was suppressed by the administration of small interfering ribonucleic acid (siRNA) that was specific to EBAG9, whereas tumor growth was enhanced by introduction of the gene encoding EBAG9. 18 These findings indicated that the reduced number of infiltrating CD8-positive lymphocytes in tumors contributed to enhanced in vivo growth.…”

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confidence: 99%

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Biologic significance of receptor‐binding cancer antigen expressed on SiSo cells (RCAS1) as a pivotal regulator of tumor growth through angiogenesis in human uterine cancer

Sonoda

Miyamoto

Yamazaki

et al. 2007

Cancer

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BACKGROUND.The expression of receptor‐binding cancer antigen expressed on SiSo cells (RCAS1) is related significantly to the overall survival of patients with various cancers. RCAS1 reportedly induces apoptotic cell death in peripheral lymphocytes, which may contribute to the escape of tumor cells from immune surveillance. RCAS1 expression also has been related to tumor invasiveness and size in uterine cervical cancer. To clarify whether RCAS1 exacerbates tumor progression, the authors investigated the association between RCAS1 expression and tumor growth potential.METHODS.The authors constructed small interfering ribonucleic acid (RNA) (siRNA) to target RCAS1. After transfection of siRNA and the RCAS1‐encoding gene, growth of tumor cells was assessed in vitro and in vivo. The correlation between RCAS1 expression and angiogenesis was investigated in the transfected cells and in inoculated tumors from nude mice. In addition, the same association was investigated immunohistochemically with tissue samples from patients with uterine cervical cancer.RESULTS.Knockdown of RCAS1 expression by siRNA significantly suppressed the in vivo growth of SiSo and HOUA tumor cells (P < .005); however, in vitro cell growth was not affected significantly. Enhanced RCAS1 expression significantly promoted in vivo growth, but not in vitro growth, of tumors derived from COS‐7 cells (P = .0039). Introduction of the RCAS1‐encoding gene increased expression of vascular endothelial growth factor (VEGF). In uterine cervical cancer, RCAS1 expression was associated significantly with VEGF expression (P = .0407) and with microvessel density (P = .0108).CONCLUSIONS.RCAS1 may be a pivotal regulator of tumor growth through angiogenesis. Continued exploration of the biologic function of RCAS1 may allow the development of novel therapeutic strategies for uterine cancer. Cancer 2007. © 2007 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Biologic significance of receptor‐binding cancer antigen expressed on SiSo cells (RCAS1) as a pivotal regulator of tumor growth through angiogenesis in human uterine cancer

Sonoda

Miyamoto

Yamazaki

et al. 2007

Cancer

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“…Although several researchers have suggested a potential link between advanced malignancy and high-level expression of EBAG9 in tumor tissue (3,(23)(24)(25)(26)(27)(28), evidence that this molecule itself exerts an in vivo tumor-promoting function has been lacking. Recently, Ogushi et al reported for the first time that the enhanced expression of EBAG9 in Renca mouse renal cancer cells leads to accelerated in vivo cell growth, using two representative clones generated by transfection of a human EBAG9 cDNA (12). Importantly, they also demonstrated in the same Renca-BALB/c model that the repression of endogenous EBAG9 expression, using RNA interference technology, slows tumor growth (12).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Ogushi et al demonstrated that the overexpression of EBAG9 in a murine renal carcinoma cell line enhanced in vivo tumorigenesis, providing the first evidence of a tumorpromoting function for EBAG9 (12 involvement of an immune-evasion mechanism in the observed effect mediated by EBAG9, but did not describe whether this overexpressed EBAG9 protein was localized on the cell surface or at the Golgi membrane to exert tumor promotion (12).…”

Section: Introductionmentioning

confidence: 99%

Intracellular estrogen receptor-binding fragment-associated antigen 9 exerts in vivo tumor-promoting effects via its coiled-coil region

Maeyama

Otsu²,

Kubo

et al. 2011

Int J Oncol

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Abstract. Estrogen receptor-binding fragment-associated antigen 9 (EBAG9) is a tumor-promoting factor of largely unknown function. To assess a causative role of EBAG9 in advanced malignancies, we generated the EG7-OVA and MethA murine tumor cell lines that stably express full-length or truncated EBAG9 protein, using retroviral-mediated gene transduction. Upon subcutaneous inoculation into immunocompetent mice, both cell lines showed marked acceleration of in vivo tumor growth when full-length EBAG9 was overexpressed. Interestingly, deletion of the coiled-coil region, thereby producing truncated EBAG9 protein, abolished the tumor-acceleration effect, establishing the importance of this domain in EBAG9-mediated tumor promotion. However, there was no alteration in in vitro cell proliferation or expression levels of MHC class I and co-stimulatory molecules believed to play a role in immune evasion of tumor cells in these tumor cell lines expressing full-length or truncated EBAG9 protein. Furthermore, both full-length and truncated EBAG9 proteins showed a predominantly cytoplasmic localization in the tumor cells. Collectively, these results suggest that EBAG9 overexpression can be causative in enhancing the malignant properties of tumor cells, and that tumor promotion likely requires EBAG9 intracellular association with as yet unidentified binding partners via the coiled-coil region.

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EBAG9 is a tumor‐promoting and prognostic factor for bladder cancer

Kumagai

Urano

Ogushi

et al. 2008

Intl Journal of Cancer

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Upregulation of EBAG9 expression has been observed in several malignant tumors such as advanced breast and prostate cancers, indicating that EBAG9 may contribute to tumor proliferation. In the present study, we assess the role of EBAG9 in bladder cancer. We generated human bladder cancer EJ cells stably expressing FLAG-tagged EBAG9 (EJ-EBAG9) or empty vector (EJ-vector), and investigated whether EBAG9 overexpression modulates cell growth and migration in vitro as well as the in vivo tumor formation of EJ transfectants in xenograft models of BALB/c nude mice. EBAG9 overexpression promoted EJ cell migration, while the effect of EBAG9 to cultured cell growth was rather minimal. Tumorigenic experiments in nude mice showed that the size of EJ-EBAG9-derived tumors was significantly larger than EJ-vectorderived tumors. Loss-of-function study for EBAG9 using small interfering RNA (siRNA) in xenografts with parental EJ cells showed that the intra-tumoral injection of EBAG9 siRNA markedly reduced the EJ tumor formation compared with control siRNA. Furthermore, immunohistochemical study for EBAG9 expression was performed in 60 pathological bladder cancer specimens. Intense and diffuse cytoplasmic immunostaining was observed in 45% of the bladder cancer cases. Positive EBAG9 immunoreactivity was closely correlated with poor prognosis of the patients (p 5 0.0001) and it was an independent prognostic predictor for disease-specific survival in multivariate analysis (p 5 0.003). Our results indicate that EBAG9 would be a crucial regulator of tumor progression and a potential prognostic marker for bladder cancer. ' 2008 Wiley-Liss, Inc.Key words: EBAG9; nude mouse; bladder cancer; proliferation; prognosis Bladder cancer is the fourth most common type of cancer in men and the ninth most common in women. 1 A radical cystectomy remains the most common treatment for patients with muscleinvasive bladder cancer. Despite advances in surgical techniques, the 5-year disease survival rate after radical cystectomy remains at 50-60%. 2 Moreover, current clinical and pathological variables have a limited ability to predict tumor recurrence, progression, or patient survival; thus, prognostic information regarding transitional cell carcinoma of the urinary bladder is needed. Biomarkers may be helpful for selecting patients who are best suited for adjuvant therapy.EBAG9 (Estrogen receptor-binding fragment-associated antigen 9) is a primary estrogen-responsive gene that has been originally cloned by our group from human breast cancer MCF-7 cells using the CpG-genomic binding site cloning method. 3 EBAG9 protein is predominantly expressed in estrogen-target organs as well as several other tissues, such as brain, liver, and kidney. 4 The expression of EBAG9 protein is inducible by estrogen in the uterus, as previously shown in ovariectomized mice treated with 17b-estradiol. 4 The physiologic function of EBAG9 has not been well defined; nevertheless, the molecule has been implicated in cancer pathophysiology, with several lines of evidence showing...

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Estrogen Receptor–Binding Fragment–Associated Antigen 9 Is a Tumor-Promoting and Prognostic Factor for Renal Cell Carcinoma

Cited by 27 publications

References 27 publications

Biologic significance of receptor‐binding cancer antigen expressed on SiSo cells (RCAS1) as a pivotal regulator of tumor growth through angiogenesis in human uterine cancer

Biologic significance of receptor‐binding cancer antigen expressed on SiSo cells (RCAS1) as a pivotal regulator of tumor growth through angiogenesis in human uterine cancer

Intracellular estrogen receptor-binding fragment-associated antigen 9 exerts in vivo tumor-promoting effects via its coiled-coil region

EBAG9 is a tumor‐promoting and prognostic factor for bladder cancer

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