FOXA1 Promotes Tumor Progression in Prostate Cancer via the Insulin-Like Growth Factor Binding Protein 3 Pathway

被引：50

作者：

Imamura, Yusuke ^{[1
]}

Sakamoto, Shinichi ^{[1
]}

Endo, Takumi ^{[2
]}

Utsumi, Takanobu ^{[1
]}

Fuse, Miki ^{[1
]}

Suyama, Takahito ^{[1
]}

Kawamura, Koji ^{[1
]}

Imamoto, Takashi ^{[1
]}

Yano, Kojiro ^{[3
]}

Uzawa, Katsuhiro ^{[4
]}

Nihei, Naoki ^{[1
]}

Suzuki, Hiroyoshi ^{[2
]}

Mizokami, Atsushi ^{[5
]}

Ueda, Takeshi ^{[6
,7
]}

Seki, Naohiko ^{[8
]}

Tanzawa, Hideki ^{[4
]}

Ichikawa, Tomohiko ^{[1
]}

机构：

[1] Chiba Univ, Grad Sch Med, Dept Urol, Chiba, Japan

[2] Toho Univ, Med Ctr, Sakura Hosp, Dept Urol, Chiba 2748510, Japan

[3] Osaka Inst Technol, Fac Informat Sci & Technol, Osaka 535, Japan

[4] Chiba Univ, Grad Sch Med, Dept Clin Mol Biol, Chiba, Japan

[5] Kanazawa Univ, Dept Urol, Grad Sch Med Sci, Kanazawa, Ishikawa 9201192, Japan

[6] Chiba Canc Ctr, Div Urol, Chiba 2608717, Japan

[7] Chiba Canc Ctr, Prostate Ctr, Chiba 2608717, Japan

[8] Chiba Univ, Grad Sch Med, Dept Funct Genom, Chiba, Japan

来源：

PLOS ONE | 2012年 / 7卷 / 08期

关键词：

FORKHEAD BOX A1; LARGE GENE LISTS; ANDROGEN RECEPTOR; TRANSCRIPTION FACTORS; LUMINAL SUBTYPE; BREAST-CANCER; STROMAL CELLS; HIGH-LEVEL; EXPRESSION; LNCAP;

D O I：

10.1371/journal.pone.0042456

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Fork-head box protein A1 (FOXA1) is a "pioneer factor" that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

引用

页数：14

共 46 条

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