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Title: SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma
Authors: Kawai, Takayuki
Yasuchika, Kentaro
Ishii, Takamichi  kyouindb  KAKEN_id  orcid (unconfirmed)
Miyauchi, Yuya
Kojima, Hidenobu
Yamaoka, Ryoya
Katayama, Hokahiro
Yoshitoshi, Elena Yukie
Ogiso, Satoshi  kyouindb  KAKEN_id
Kita, Sadahiko
Yasuda, Katsutaro
Fukumitsu, Ken
Komori, Junji
Hatano, Etsuro
Kawaguchi, Yoshiya  kyouindb  KAKEN_id
Uemoto, Shinji  kyouindb  KAKEN_id
Author's alias: 安近, 健太郎
波多野, 悦朗
川口, 義弥
上本, 伸二
Issue Date: 26-Jul-2016
Publisher: Nature Publishing Group
Journal title: Scientific Reports
Volume: 6
Thesis number: 30489
Abstract: The current lack of cancer stem cell (CSC) markers that are easily evaluated by blood samples prevents the establishment of new therapeutic strategies in hepatocellular carcinoma (HCC). Herein, we examined whether sex determining region Y-box 9 (SOX9) represents a new CSC marker, and whether osteopontin (OPN) can be used as a surrogate marker of SOX9 in HCC. In HCC cell lines transfected with a SOX9 promoter-driven enhanced green fluorescence protein gene, FACS-isolated SOX9+ cells were capable of self-renewal and differentiation into SOX9-cells, and displayed high proliferation capacity in vitro. Xenotransplantation experiments revealed that SOX9+ cells reproduced, differentiated into SOX9-cells, and generated tumors at a high frequency in vivo. Moreover, SOX9+ cells were found to be involved in epithelial-mesenchymal transition (EMT) and activation of TGFb/Smad signaling. Gain/loss of function experiments showed that SOX9 regulates Wnt/beta-catenin signaling, including cyclin D1 and OPN. Immunohistochemistry of 166 HCC surgical specimens and serum OPN measurements showed that compared to SOX9-patients, SOX9+ patients had significantly poorer recurrence-free survival, stronger venous invasion, and higher serum OPN levels. In conclusion, SOX9 is a novel HCCCSC marker regulating the Wnt/beta-catenin pathway and its downstream target, OPN. OPN is a useful surrogate marker of SOX9 in HCC.
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
DOI(Published Version): 10.1038/srep30489
PubMed ID: 27457505
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