Disruption of crosstalk between LX-2 and liver cancer stem-like cells from MHCC97H cells by DFOG via inhibiting FOXM1.

Autor:	Chen A; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China.; Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China.; Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China., Xu C; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China.; Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China.; Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China., Luo Y; Pathology department, Medical College, University of South China, Hengyang 421001, China., Liu L; Department of Pharmacology, Shenzhen People's Hospital 2nd Clinical Medical College of Jinan University, Shenzhen 518020, China., Song K; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China., Deng G; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China., Yang M; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China., Cao J; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China.; Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China.; Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China., Yuan L; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China., Li X; Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha 410013, China.; Department of Pharmaceutical Science, Me dical College, Hunan Normal University, Changsha 410013, China.; Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha 410013, China.
Jazyk:	angličtina
Zdroj:	Acta biochimica et biophysica Sinica [Acta Biochim Biophys Sin (Shanghai)] 2019 Dec 13; Vol. 51 (12), pp. 1267-1275.
DOI:	10.1093/abbs/gmz129
Abstrakt:	Hepatic stellate cell (HSC) line LX-2 is activated by liver cancer stem-like cells (LCSLCs) and produces various cytokines that make up most of the hepatocellular carcinoma (HCC) microenvironment. The new genistein derivative, 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), shows anticancer effects in multiple malignancies by controlling forkhead box M1 (FOXM1). In this study, we aimed to assess whether DFOG disrupts the crosstalk between human HSC LX-2 cells and LCSLCs. Distinct generations of MHCC97H-derived spheres were obtained with the second generation considered as LCSLCs which displayed enhanced self-renewal ability and elevated expression levels of CD133, CD44, and EpCAM proteins, as well as tumorigenicity, as revealed by colony formation assay in vitro and tumorigenicity assay in vivo. LX-2 and MHCC97H cells were co-cultured with/without DFOG (1, 5, and 10 μM, respectively) using the transwell system. FOXM1 overexpression and/or knockdown were employed for mechanistic investigations. Our results suggested that Co-CM promoted LX-2 cell transformation into liver cancer-associated HSCs. Meanwhile, FOXM1 was up-regulated and the level of hepatocyte growth factor (HGF) was increased in LX-2 cells and in the supernatant after Co-CM stimulation. Sphere and colony formation abilities in MHCC97H cells, and protein levels of CD133, CD44, and EpCAM, were also markedly elevated. DFOG dose-dependently inhibited the above effects, similar to FOXM1 knockdown in LX-2 cells. FOXM1 overexpression reversed the inhibitory effects of DFOG or FOXM1 knockdown or both on LX-2 cell activation and LCSLC feature induction in MHCC97H cells by LCSLC/LX-2 co-culture. This study demonstrated that DFOG disrupts the crosstalk between HSCs and LCSLCs to suppress LCSLC features via down-regulating FOXM1 expression and reducing HGF secretion in HSCs. (© The Author(s) 2019. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu