Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance.

• Keywords
• adaptive immune system, chemoresistance., hepatocellular carcinoma, histone macroH2A1,
• MeSH
• Hyaluronan Receptors metabolism   MeSH
• Drug Resistance, Neoplasm * MeSH
• Forkhead Transcription Factors metabolism   MeSH
• Gene Knockdown Techniques MeSH
• Glycolysis MeSH
• Carcinoma, Hepatocellular drug therapy   immunology   metabolism   pathology   MeSH
• Histones metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Metabolomics methods   MeSH
• Cell Line, Tumor MeSH
• Neoplastic Stem Cells drug effects   immunology   pathology   MeSH
• Tumor Microenvironment immunology   MeSH
• Liver Neoplasms drug therapy   immunology   metabolism   pathology   MeSH
• Paracrine Communication * MeSH
• Interleukin-2 Receptor alpha Subunit metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hyaluronan Receptors MeSH
• CD44 protein, human MeSH Browser
• Forkhead Transcription Factors MeSH
• FOXP3 protein, human MeSH Browser
• Histones MeSH
• macroH2A histone MeSH Browser
• Interleukin-2 Receptor alpha Subunit MeSH

PURPOSE: The purpose of the study was to determine whether the GDF-15 is present in follicular fluid; to evaluate if there is a relation between follicular and serum levels of GDF-15 and fertility status of study subjects; and to test whether granulosa cells, oocytes, or both produce GDF-15. METHODS: This study used follicular fluid (FF, serum, and oocytes obtained under informed consent from women undergoing oocyte retrieval for in vitro fertilization. It also used ovaries from deceased preterm newborns. Collection of FF and blood at the time of oocyte retrieval, ELISA and western blot were performed to determine levels and forms of GDF-15. Concentrations of GDF-15 in FF and serum, its expression in ovarian tissue, and secretion from granulosa cells were analyzed. RESULTS: GDF-15 concentration in FF ranged from 35 to 572 ng/ml, as determined by ELISA. Western blot analysis revealed the GDF-15 pro-dimer only in FF. Both normal healthy and cancerous granulosa cells secreted GDF-15 into culture media. Primary oocytes displayed cytoplasmic GDF-15 positivity in immunostained newborn ovaries, and its expression was also observed in fully grown human oocytes. CONCLUSIONS: To the best of our knowledge, this is the first documentation of cytokine GDF-15 presence in follicular fluid. Its concentration was not associated with donor/patient fertility status. Our data also show that GDF-15 is expressed and inducible in both normal healthy and cancerous granulosa cells, as well as in oocytes.

• Keywords
• Follicular fluid, Follicular granulosa cells, Growth/differentiation factor-15, IVF,
• MeSH
• Cell Differentiation genetics   MeSH
• Adult MeSH
• Fertilization in Vitro MeSH
• Granulosa Cells metabolism   MeSH
• Follicular Fluid metabolism   MeSH
• Humans MeSH
• Oocyte Retrieval MeSH
• Oocytes metabolism   MeSH
• Growth Differentiation Factor 15 genetics   isolation & purification   MeSH
• Gene Expression Regulation, Developmental MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• GDF15 protein, human MeSH Browser
• Growth Differentiation Factor 15 MeSH