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Comparison of gene expression between parental adrenocortical carcinoma cells and a subpopulation overexpressing Ptch1

ABSTRACT: Chemotherapy resistance supposes a challenge for cancer treatment. Multidrug efflux pumps are able to extrude chemotherapeutic agents increasing their resistance to the treatment. Ptch1 is overexpressed in many metastatic cancers, where it acts as a multidrug efflux pump. Indeed, Ptch1 strongly contributes to the drug efflux in H295R, a human adrenal carcinoma cell line. This efflux is coupled to the proton motive force, restricting Ptch1 drug efflux to acidify environments like cancers. Even though Ptch1 is overexpressed in H295R cells, only 1% of these cells present Ptch1 at the cell surface (Ptch1 positive or PTC subpopulation ). We showed that these Ptch1 positive cells had an increased chemotherapy resistance, migration and clonogenicity compared to the parental cell lines. The RNA seq analysis performed on H295R Ptch1 positive cells and parental H295R cells show an increase of the expression of genes involved in the Hedgehog signaling such as Ptch1, of genes involved in EMT and drug resistance, and of genes involved in stem cell maintenance suggesting that these cells could be cancer stem cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189424 | GEO | 2022/01/19

REPOSITORIES: GEO

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Project description:Background: Cancer stem cells are presumed to have virtually unlimited proliferative and self-renewal abilities and to be highly resistant to chemotherapy, a feature that is associated with overexpression of ATP-binding cassette transporters. We investigated whether prolonged continuous selection of cells for drug resistance enriches cultures for cancer stem-like cells. Methods: Cancer stem cells were defined as CD44+/CD24– cells that could self-renew (ie, generate cells with the tumorigenic CD44+/CD24– phenotype), differentiate, invade, and form tumors in vivo. We used doxorubicin-selected MCF-7/ADR cells, weakly tumorigenic parental MCF-7 cells, and MCF-7/MDR, an MCF-7 subline with forced expression of ABCB1 protein. Cells were examined for cell surface markers and side-population fractions by microarray and flow cytometry, with in vitro invasion assays, and for ability to form mammospheres. Xenograft tumors were generated in mice to examine tumorigenicity (n = 52). The mRNA expression of multidrug resistance genes was examined in putative cancer stem cells and pathway analysis of statistically significantly differentially expressed genes was performed. All statistical tests were two-sided. Results: Pathway analysis showed that MCF-7/ADR cells express mRNAs from ABCB1 and other genes also found in breast cancer stem cells (eg, CD44, TGFB1, and SNAI1). MCF-7/ADR cells were highly invasive, formed mammospheres, and were tumorigenic in mice. In contrast to parental MCF-7 cells, more than 30% of MCF-7/ADR cells had a CD44+/CD24– phenotype, could self-renew, and differentiate (ie, produce CD44+/CD24– and CD44+/CD24+ cells), and overexpressed various multidrug resistance-linked genes (including ABCB1, CCNE1, and MMP9). MCF-7/ADR cells were statistically significantly more invasive in Matrigel than parental MCF-7 cells (MCF-7 cells = 0.82 cell per field and MCF-7/ADR = 7.51 cells per field, difference = 6.69 cells per field, 95% confidence interval = 4.82 to 8.55 cells per field, P<.001). No enrichment in the CD44+/CD24– or CD133+ population was detected in MCF-7/MDR. Conclusion: The cell population with cancer stem cell characteristics increased after prolonged continuous selection for doxorubicin resistance. PARALLEL study design with 4 samples Parental MCF-7 cell line versus Doxorubicin Resistant MCF-7 cell sublines Biological replicates: 2 parental controls, 2 drug resistant, independently grown and harvested. agent:Selection agent is multi-step doxorubicin selection: MCF7226ng, MCF7262ng biological replicate: MCF71, MCF72 biological replicate: MCF226ng, MCF7262ng

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Comparison of gene expression between parental adrenocortical carcinoma cells and a subpopulation overexpressing Ptch1

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