Suchergebnisse

Li-Hua Yang,1,2,* Ye Wang,1,3,* Shi Qiao,1,* Min-Jun Wang,1 Fei Chen,1 Xiao-Yuan Zi,1 Jian-Xiu Li,1 Hai-Bin Zhang,4 Bing Yu,1,4 Yi-Ping Hu1 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, People's Republic of China; 2Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, People's Republic of China; 3Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China; 4Department of Hepatic Surgery V, Eastern Hepatobiliary Surgery Hospital, Shanghai, People's Republic of China *These authors contributed equally to this work Purpose: Liver cancer stem cells (CSCs) are known to be associated with the development, survival, proliferation, metastasis, and recurrence of liver tumors. The aim of this study was to investigate the association of liver-enriched activator protein 1 (LAP1) with hepatocellular carcinoma (HCC) and liver CSCs (LCSCs) and explore the impact of LAP1 on LCSCs. Materials and methods: Differences in LAP1 expression in liver cancer tissues versus matched para-tumoral liver tissues and LCSCs versus non-CSCs were analyzed by Western blotting, real-time polymerase chain reaction, immunohistochemistry, and flow cytometry. The effect of LAP1 on liver cancer cells was evaluated by the expression of CSC markers, oncosphere formation, proliferation, migration, and invasion in vitro. Cell cycle distribution and the number of apoptotic cells were analyzed to assess cell cycle and cell apoptosis. Furthermore, a mouse subcutaneous tumor implant model was established to explore the role of LAP1 in the development of HCC in vivo. Finally, the expression of CSC markers in paraffin-embedded sections was evaluated by immunofluorescence. Results: LAP1 was weakly expressed in HCC tumors and cell lines and even weaker in LCSCs. LAP1 inhibited the expression of stem cell–associated genes and reduced the abilities of oncosphere formation, proliferation, migration, and invasion in vitro. Cell cycle assay revealed that LAP1 induced G1/G0 arrest. Furthermore, LAP1 decreased subcutaneous tumor-formation ability and the expression of CSC markers and Ki67 in vivo. Conclusion: LAP1 suppressed the stem cell features of HCC, indicating that it possessed an antitumor effect in liver cancer, both in vitro and in vivo; therefore, LAP1 may prove to be a potential target in liver CSC-targeted therapy. Keywords: LAP1, liver-enriched activator protein 1, hepatocellular carcinoma, HCC, liver cancer stem cell

Min-Jun Wang,1,* Jia-Jia Chen,1,* Shao-Hua Song,2,* Jing Su,1,* Ling-Hao Zhao,3 Qing-Gui Liu,1 Tao Yang,1 Zhiwen Chen,4 Chang Liu,4 Zhi-Ren Fu,2 Yi-Ping Hu,1 Fei Chen1 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University (Navy Medical University), Shanghai, People's Republic of China; 2Department of General Surgery, Liver Transplantation Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China; 3National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People's Republic of China; 4State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People's Republic of China*These authors contributed equally to this workCorrespondence: Fei Chen Yi-Ping HuDepartment of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, ChinaTel +86-21-81870943Email feelchen@smmu.edu.cn; yphu9@yeah.netPurpose: Cancer stem cells (CSCs) have been considered involving in tumorigenesis, local recurrence, and therapeutic drug resistance of hepatocellular carcinoma (HCC). To investigate novel and effective methods for targeting hepatic CSCs is crucial for a permanent cure of liver cancer.Methods: The expression level of SIRT1 was detected in CSCs of HCC tissues and cancer cell lines. Expression of CSC markers, the self-renewal and tumorigenic ability of liver CSCs were analyzed with SIRT1 inhibition. Cellular senescence-related markers were used to detect CSCs senescence after inhibition of SIRT1.Results: SIRT1 was highly expressed in CSCs of HCC cell lines and human HCC tissues. In vitro study revealed that decreasing of SIRT1 level significantly downregulated the stemness-associated genes of liver CSCs and reduced the CSC stemness properties. Also, downregulated SIRT1 suppressed liver CSCs proliferation by decreasing their self-renewal abilities. Furthermore, CSCs with decreased SIRT1 expression showed limited tumorigenicity and formed smaller HCC tumor in vivo. And SIRT1 decreased CSCs became more susceptible to chemotherapeutic drugs. Mechanistically, SIRT1 decreased CSCs became senescence through the activation of p53-p21 and p16 pathway. The data further indicated that the tumor formed from SIRT1-knockdown CSCs exhibited higher senescence-associated β-galactosidase (SA-β-Gal) activity but lower proliferative capacity.Conclusion: Taken together, these findings pointed that induction of senescence in liver CSCs is an effective tumor suppression method for HCC, and SIRT1 may be served as a promising target for HCC treatment.Keywords: SIRT1, hepatocellular carcinoma, liver cancer stem cells, cellular senescence, stemness, self-renewal