Abstract
Retinoic acid (RA) is an important biological signal that directly differentiates cells during embryonic development and tumorigenesis. However, the molecular mechanism of RA-mediated differentiation in hepatic cancer stem cells (hCSCs) is not well understood. In this study, we found that mRNA expressions of RA-biosynthesis-related dehydrogenases were highly expressed in hepatocellular carcinoma. All-trans retinoic acid (ATRA) differentiated hCSCs through inhibiting the function of β-catenin in vitro. ATRA also inhibited the function of PI3K-AKT and enhanced GSK-3β-dependent degradation of phosphorylated β-catenin. Furthermore, ATRA and β-catenin silencing both increased hCSC sensitivity to docetaxel treatment. Our results suggest that targeting β-catenin will provide extra benefits for ATRA-mediated treatment of hepatic cancer patients.
Highlights
Cancer stem cells (CSCs) represent a small but unique population of cancer cells that can sustain their self-renewal and multipotentiality
To address Retinoic acid (RA) metabolism in hepatocellular carcinoma (HCC), we investigated three kinds of RA synthesis-related enzymes in HCC, including three alcohol dehydrogenases (ADH1, ADH2, ADH 3), two retinol dehydrogenases (RDH1, RDH10) and three retinaldehyde dehydrogenases (RALDH1, RALDH 2, RALDH 3) (Fig 1A)
Results from a total of 1,911 individual cancer patients demonstrated that the mRNA expressions of RALDH1, ADH1 and RDH10 were highest in HCC patients (Fig 1B–1D, dark blue histogram bars)
Summary
Cancer stem cells (CSCs) represent a small but unique population of cancer cells that can sustain their self-renewal and multipotentiality. These cells are considered cancer-initiating cells (CICs) because their tumorigenic potency allows CSCs/CICs to form de novo tumors [1,2]. Clinical studies suggest that CSCs/CICs are resistant to traditional chemo- or radio-therapies due to their specialized microenvironments [3,4]. Liver cancer is one of the most common and lethal cancers worldwide [5,6]. Clinical therapies for liver cancer are still not available due to the heterogeneous nature of the cellular components within the tumors [5]. In hepatocellular carcinoma (HCC), cell membrane proteins such as CD133, CD13, CD90, EpCAM and CD44 have been widely applied to isolate
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