EBAG9 inducing hyporesponsiveness of T cells promotes tumor growth and metastasis in 4T1 murine mammary carcinoma.
The estrogen receptor-binding fragment-associated gene 9 (EBAG9) has been identified as an estrogen-responsive gene and was recently identified as a tumor-promoting and prognostic factor for renal cell carcinoma. We investigated whether EBAG9 expression was correlated with primary tumor growth and distant tumor metastasis in a murine breast carcinoma model. Knockdown expression of EBAG9 by small interfering RNA significantly suppressed tumor growth and metastasis in vivo in a highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model. 4T1 cells stably overexpressing EBAG9 developed larger and faster tumor growth and lung metastasis compared with parental 4T1 or 4T1 expressing vector alone. Strong specific cytotoxic T lymphocyte activity and enhanced gamma-interferon and interleukin-2 productions were induced in mice that received EBAG9 small interfering RNA therapy. Gene silencing of EBAG9 prolonged the survival of tumor-bearing mice and induced more intensive infiltration of CD8+ T cells in tumor mass. EBAG9 induced apoptosis of T cells, enhanced glycogen synthase kinase 3beta phosphorylation and inhibited gamma-interferon production of T cells when T lymphocytes were cocultured with 4T1 cells overexpressing EBAG9. Furthermore, overexpression of EBAG9 in 4T1 cells was accompanied with enhanced expression of chemokine (C-X-C motif) receptor 4, which might be involved in tumor metastasis. Taken together, our results suggested that EBAG9 promoted primary 4T1 mammary carcinoma growth and distant metastasis, and EBAG9 small interfering RNA exerted overt regression of tumor growth and metastasis. These findings might provide insights into the mechanism through which tumors evade immunosurveillance and provide a strategy for therapeutic intervention of cancer metastases.
Hong
Xuejun
X
Institute of Immunology, Zhejiang University, Hangzhou 310058, China.
Liu
Yang
Y
Hu
Guili
G
Zhao
Dekuang
D
Shen
Jiangen
J
Shen
Fenping
F
Cao
Xuetao
X
Wang
Qingqing
Q
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D010768:Phosphoserine / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D000951:Antigens, Neoplasm; C534295:EBAG9 protein, mouse; D034741:RNA, Small Interfering; D010768:Phosphoserine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3