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Title: Amino-terminal enhancer of split gene AES encodes a tumor and metastasis suppressor of prostate cancer
Authors: Okada, Yoshiyuki
Sonoshita, Masahiro
Kakizaki, Fumihiko
Aoyama, Naoki
Itatani, Yoshiro
Uegaki, Masayuki
Sakamoto, Hiromasa
Kobayashi, Takashi
Inoue, Takahiro
Kamba, Tomomi
Suzuki, Akira
Ogawa, Osamu
Taketo, M. Mark
Author's alias: 岡田, 能幸
園下, 将大
柿崎, 文彦
青山, 尚規
坂元, 宏匡
小林, 恭
井上, 貴博
神波, 大己
小川, 修
武藤, 誠
Keywords: Androgen receptors
neoplasm invasiveness
neoplasm metastasis
prostatic neoplasms
transcription factors
Issue Date: Apr-2017
Publisher: John Wiley & Sons Australia, Ltd.
Journal title: Cancer Science
Volume: 108
Issue: 4
Start page: 744
End page: 752
Abstract: A major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples. We then performed overexpression and knockdown of AES in human PCa cell lines LNCaP, DU145 and PC3, and determined the effects on proliferation, invasion and metastasis in culture and in a xenograft model. We also compared the PCa phenotypes of Aes/Pten compound knockout mice with those of Pten simple knockout mice. Expression levels of AES were inversely correlated with clinical stages of human PCa. Exogenous expression of AES suppressed the growth of LNCaP cells, whereas the AES knockdown promoted it. We also found that AES suppressed transcriptional activities of androgen receptor and Notch signaling. Notably, AES overexpression in AR-defective DU145 and PC3 cells reduced invasion and metastasis to lymph nodes and bones without affecting proliferation in culture. Consistently, prostate epithelium-specific inactivation of Aes in Ptenflox/flox mice increased expression of Snail and MMP9, and accelerated growth, invasion and lymph node metastasis of the mouse prostate tumor. These results suggest that AES plays an important role in controlling tumor growth and metastasis of PCa by regulating both AR and Notch signaling pathways.
Rights: © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
URI: http://hdl.handle.net/2433/225273
DOI(Published Version): 10.1111/cas.13187
Appears in Collections:Journal Articles

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