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Acquisition of stem cell properties in tumor-derived hepatocyte-like cells leads to metabolic reprogramming and chemoresistance

ABSTRACT: Gene expression profile analysis allowed to identify a panel of genes and pathways characteristic of HepaRG Sphere-forming cells and HepaRG Side population

ORGANISM(S): Homo sapiens

PROVIDER: GSE75752 | GEO | 2019/06/01

SECONDARY ACCESSION(S): PRJNA305271

REPOSITORIES: GEO

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Acquisition of a side population fraction through downregulation of MSL3, ZNF691, VPS45, ITGB3BP, TLE2, and ZNF498 augments malignant phenotype in ovarian cancer.

Project description:Side population (SP) cells harbor malignant phenotypes, such as sphere forming capacity, single cell clonogenicity and in vivo tumorigenicity. These malignant phenotypes are related to a poor prognosis for women with ovarian cancer. The aim of this study was to identify key factor(s) that increase the proportion of ovarian cancer SP cells through a functional genomics screen. A library of 81 000 shRNAs targeting 15 000 genes was transfected into CH1 and SKOV3 cells, followed by SP analysis. We found that suppression of MSL3, ZNF691, VPS45, ITGB3BP, TLE2, and ZNF498 markedly increased the proportion of SP cells. Newly generated SP cells exhibit significantly greater capacity for sphere formation, single cell clonogenicity, and in vivo tumorigenicity. On the contrary, overexpression of MSL3, VPS45, ITGB3BP, TLE2, and ZNF498 significantly decreased the proportion of SP cells, sphere formation capacity and single cell clonogenicity. In ovarian cancer cases, low expression of MSL3, ZNF691 and VPS45 was related to poor prognosis. Suppression of these six genes tended to increase some stem cell-related pathways, and significantly enhanced activity of the hedgehog pathway. Cyclopamine, a hedgehog pathway inhibitor, significantly decreased the number of newly generated SP cells and their sphere forming ability. Our results provide new information regarding molecular mechanisms favoring SP cells and suggest that Hedgehog signaling may provide a viable target for improving ovarian cancer survival.

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