TY - JOUR
T1 - Embigin promotes prostate cancer progression by S100A4-dependent and-independent mechanisms
AU - Ruma, I. Made Winarsa
AU - Kinoshita, Rie
AU - Tomonobu, Nahoko
AU - Inoue, Yusuke
AU - Kondo, Eisaku
AU - Yamauchi, Akira
AU - Sato, Hiroki
AU - Sumardika, I. Wayan
AU - Chen, Youyi
AU - Yamamoto, Ken Ichi
AU - Murata, Hitoshi
AU - Toyooka, Shinichi
AU - Nishibori, Masahiro
AU - Sakaguchi, Masakiyo
N1 - Funding Information:
Author Contributions: Conceptualization, I Made Winarsa Ruma, Shinichi Toyooka, Masahiro Nishibori and Masakiyo Sakaguchi; Data curation, I Made Winarsa Ruma, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka and Masahiro Nishibori; Formal analysis, I Made Winarsa Ruma, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka and Masahiro Nishibori; Funding acquisition, Masakiyo Sakaguchi; Investigation, I Made Winarsa Ruma, Rie Kinoshita, Nahoko Tomonobu, Yusuke Inoue, Eisaku Kondo, Akira Yamauchi and Hiroki Sato; Methodology, I Made Winarsa Ruma and Rie Kinoshita; Supervision, Masakiyo Sakaguchi; Validation, I Wayan Sumardika, Youyi Chen and Hitoshi Murata; Visualization, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto and Hitoshi Murata; Writing—original draft, I Made Winarsa Ruma and Masakiyo Sakaguchi. IMW, ST, MN, and MS were involved in conceptual guidance and data interpretation. IMW and MS wrote the manuscript. IMW performed in vitro experiments and WB. RK performed bioinformatics analysis of RNAseq data and protein purification. IMW, NT, and HS performed animal study. YI performed RT-PCR and RNA seq analysis. EK, and AY provided clinical samples and performed IHC. IWS, YC, KIY, and HM were involved in data processing, analysis and graphical presentation. MS responsible for funding acquisition and supervised the study. All authors read and approved the manuscript.
Funding Information:
Funding: This study was partly supported by grants from the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from the Japan Agency for Medical Research and Development to M.S. and JSPS KAKENHI Grant Number 17H03577 to M.S.
Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2018/7/23
Y1 - 2018/7/23
N2 - Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin’s roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid-and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.
AB - Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin’s roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid-and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.
KW - AMPK
KW - Embigin
KW - Extracellular S100A4
KW - Prostate cancer progression
KW - mTORC1
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UR - http://www.scopus.com/inward/citedby.url?scp=85050687682&partnerID=8YFLogxK
U2 - 10.3390/cancers10070239
DO - 10.3390/cancers10070239
M3 - Article
AN - SCOPUS:85050687682
SN - 2072-6694
VL - 10
JO - Cancers
JF - Cancers
IS - 7
M1 - 239
ER -
