MAGE-A9, a well-characterized cancer testis antigen (CTA), belongs to a member of melanoma antigen gene (MAGE) family. In human malignancies, aberrant expression of MAGE genes correlated with poor clinical prognosis, increased tumor growth, metastases, and enrichment in stem cell populations of certain cancers. Cancer stem cells (CSCs) have been proposed to contribute to the major malignant phenotypes of liver cancer, including recurrence, metastasis and chemoresistance. However, expression and potential role of MAGE-A9 in liver cancer stem cells (LCSCs) still remain unclear. In the present study, we first analyzed the expression profiling of MAGE family genes in EpCAM+ and EpCAM- human hepatocellular carcinoma (HCC), based on public Gene Expression Omnibus (GEO) database. Among these examined MAGE members, MAGE-A9 is the only one with significantly higher expression in EpCAM+ HCC specimens as compared with EpCAM- HCC. Quantitative PCR analysis further confirmed that MAGE-A9 expression significantly elevated in a subtype of HCC patients that had features of hepatic stem/progenitor cells with high-level expression of EpCAM and α-fetoprotein (AFP). Moreover, MAGE-A9 displayed remarkably enriched expression in EpCAM+ HCC cells that were sorted by fluorescence-activated cell sorting and cultured HCC cell spheroids with characteristics of stem/progenitor cells. Functional experiments further revealed that MAGE-A9 overexpression promoted cell proliferation, colony formation, migration, chemoresistance, and tumorigenicity in the context of EpCAM+ HCC cells, whereas MAGE-A9 knockdown significantly inhibited anchorage-dependent and spheroid colony formation and in vivo tumorigenicity. Collectively, these data demonstrate that MAGE-A9 functions as an important regulator of LCSCs, and MAGE-A9 may serve as a potential therapeutic target against HCC stem/progenitor cells.
The present study aimed to investigate the effect of resveratrol on inflammatory pain. Mice were injected intraperitoneally with lipopolysaccharide (LPS) for 5 consecutive days to induce subacute systemic inflammation. Acetic acid‑induced writhing tests and tail‑flick tests were performed following the final LPS injection. Glial fibrillary acidic protein (GFAP; an astrocyte‑specific activation marker), ionized calcium binding adapter molecule 1 (Iba‑1; a microglia‑specific activation marker) and sirtuin 1 (SIRT1) protein expression levels were detected using immunohistochemistry analysis or western blotting. Following administration of LPS for 5 days, the number of writhes increased and the tail‑flick latency decreased. Resveratrol (10 or 20 mg/kg) partly inhibited LPS‑induced hyperalgesia and prevented the increase in tumor necrosis factor‑α and interleukin 6 levels induced by LPS. LPS injection reduced the SIRT1 protein expression and increased the number of GFAP‑positive and Iba‑1‑positive cells in the spinal cord. Resveratrol increased the SIRT1 protein expression levels and decreased the number of GFAP‑positive and Iba‑1‑positive cells in LPS‑treated mice. The protective effect of resveratrol was partly blocked by a selective SIRT1 inhibitor, EX‑257. Results from the present study suggest that subacute treatment with LPS induced the activation of glial cells and hyperalgesia. Resveratrol was demonstrated to inhibit the activation of glial cells and attenuate inflammatory hyperalgesia in a SIRT1‑dependent manner.
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