RESUMO
Cancer stem cells in liver cancer are thought to be responsible for tumor recurrence and metastasis. However, the factors that mediate this mechanism have yet to be completely elucidated. In this study, we isolated CD13+CD44+ sphere cells (SCs) derived from liver cancer tissues and SK-Hep-1 cells, which possessed cancer stem cell-like properties. Through cytokine array analysis, growth differentiation factor 15 (GDF15) was significantly increased in SCs. Clinical data showed GDF15 was overexpressed in liver cancer tissues and was positively related to pathological grading. GDF15 knockdown significantly inhibited the growth and metastasis of SCs through AKT/GSK-3ß/ß-catenin pathway suppression. Moreover, a PI3K inhibitor LY294002 inhibited AKT/GSK-3ß/ß-catenin pathway activated by GDF15 and attenuated GDF15-induced proliferation, colony formation and invasion of SCs. CONCLUSION: Our studies suggest that CD13+CD44+ SCs may represent a subset of LCSCs. GDF15 promotes the growth and metastasis of SCs by activating AKT/GSK-3ß/ß-catenin signaling pathway. Promisingly, GDF15 could be considered as a potential therapeutic target in liver cancer.
Assuntos
Carcinoma Hepatocelular/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Animais , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Morfolinas/farmacologia , Metástase Neoplásica , Células-Tronco Neoplásicas/patologia , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Transplante HeterólogoRESUMO
Highly upregulated in liver cancer (HULC), a lncRNA that is considered a key molecule in human liver cancer, has recently been revealed to be involved in hepatocellular carcinoma (HCC) development and progression [1, 2]. It has been reported that HULC can promote tumor invasion and metastasis of HCC, but its function and mechanism of action in HCC have not been elucidated. In this study, we found that HULC was aberrantly up-regulated in HCC tissues and associated with TNM stage, intrahepatic metastases, HCC recurrence, and postoperative survival. HULC depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo. Moreover, HULC contributes to ZEB1-induced epithelial-mesenchymal transition (EMT), a requirement for tumor invasion and metastasis that plays a key role in cancer progression. This effect of ZEB1 was inhibited by HULC siRNA. We conclude that the HULC functioned as a competing endogenous RNA (ceRNA) to mediate EMT via up-regulating ZEB1. In this way, it sequesters the miR-200a-3p signaling pathway to facilitate HCC metastasis. HULC comes into play as an oncogene in HCC, acting mechanistically by inducing HCC cells to activate EMT. Such an effect promotes tumor progression and metastasis through the miR-200a-3p/ZEB1 signaling pathway. The identification of this novel pathway that links high expression levels of HULC with EMT in HCC cells may serve as the foundation for the development of novel anti-tumor therapeutics.