SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma

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 HCC-CSC marker regulating the Wnt/beta-catenin pathway and its downstream target, OPN. OPN is a useful surrogate marker of SOX9 in HCC.

Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

“…E2F8, which belongs to the E2F transcriptional factor family, promotes cell proliferation via regulating cyclin D1 expression in HCC . Sox9, a Notch1 classical downstream target, can promote cancer cell proliferation by promoting the expression of cyclin D1 . Cyclin D1 can form a complex with CDK4 or CDK6, which promotes cell cycle progression from G1‐phase to S‐phase , a phenomenon that was consistent with our results (see supplementary material, Figure S5B).…”

Expression profile of the STAND protein Nwd1 in the developing and mature mouse central nervous system

“…NWD1 might also be involved in cell division; a previous study showed that NWD1 expression levels positively correlate with the malignancy and tumor progression of human prostate cancer, and that the expression of NWD1 mRNA is upregulated by the transcription factor SOX9 in human prostate cancer cell lines, as mentioned above (Correa et al, ). Sox9, a member of the SRY (sex‐determining region Y) family of transcription factors, has been implicated in the maintenance of the stem cell pool in various organs (Kawai et al, ; Kiefer, ; Pritchett, Athwal, Roberts, Hanley, & Hanley, ). Sox9 is expressed in neural stem cells of different CNS regions, and is indispensable for their establishment and maintenance (Scott et al, ).…”

Clinical Trial Watch: Reports from the EASL International Liver Congress (ILC), Vienna, April 2015

“…The study presented by Kawai et al provided experimental evidence on the role of SOX9 as a novel CSC marker [47]. Authors performed a number of experiments on isolated SOX9(+) cells and found that they are able to self-renew and differentiate into SOX9(-) cells.…”