Unknown,Transcriptomics,Genomics,Proteomics

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Next-generation sequencing facilitates quantitative analysis of AcKLF5 and unAcKLF5 transcriptomes in xenografts of DU-145 cell line

ABSTRACT: KLF5 possesses both tumor-suppressing and tumor-promoting activities, though the mechanism controlling these opposing functions is unknown. In cultured non-cancerous epithelial cells, KLF5 converts from pro-proliferative to anti-proliferative activity upon TGFÎ²-induced acetylation, which sequentially alters the KLF5 transcriptional complex and the expression of genes such as p15 and MYC. In nude mice, KLF5 also suppressed tumor growth in an acetylation-dependent manner. Furthermore, deacetylation switched KLF5 to tumor-promoting activity, and blocking TGFÎ² signaling attenuated the tumor suppressor activity of KLF5. The results from RNA-Seq indicated the different downstream genes of AcKLF5 and unAcKLF5 and the mechanisms that determine the opposing functions of AcKLF5 and unAcKLF5. These results provide novel insights into the mechanism by which KLF5 switches from anti-tumorigenic to pro-tumorigenic function, and also suggest the roles of AcKLF5 and unAcKLF5, respectively, in the tumor-suppressing and tumor-promoting functions of TGFÎ². Xenografts of DU-145 cell lines expressing KLF5, KLF5 mutant K369R or the empty vector PLHCX were surgically isolated from mice at day 38 after injection. RNA-Seq was performed using these three groups of xenografts.

ORGANISM(S): Homo sapiens

SUBMITTER: jintang dong

PROVIDER: E-GEOD-56343 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The cellular heterogeneity of one patient derived orthotopic breast cancer xenograft model (PDBCX) was investigated using flow cytometry , combined with assessment of in vivo tumorigenicity and whole genome expression profiling. Epithelial cell adhesion molecule (EpCAM) was revealed as a highly specific cell surface marker of the human tumor cell population in both xenografts. Based on expression patterns observed in primary tumor tissue, SSEA-4 and CD24 were chosen as markers to further subdivide the luminal tumor cells into four subpopulations. FACS sorting was used to isolate four cell subpopulations. Results: In vivo tumorigenicity assay showed that SSEA-4+/CD24+ cells were non-tumorigenic, while the three other subpopulations were tumorigenic. Tumors resulting from the SSEA-4+/CD24- subpopulation of luminal cancer cells, did not express CD24, while tumors arising from the SSEA-4-/CD24-, and SSEA-4-/CD24+ populations both recapitulated the original tumor containing all four subpopulations. Whole genome expression analysis revealed distinct transcriptional profiles, and 44 genes were significantly differentially expressed when comparing the tumorigenic vs non-tumorigenic populations. Several interesting genes putatively suppressing the cancer cells ability to initiate tumors in vivo were upregulated in the non-tumorigenic population. We here show that tumor initiating cells within one primary tumor evidently included more than one phenotype. Furthermore, with respect to cell surface marker expression, one of the subpopulations produced tumors unlike both the originating cells, and the original tumor. Discussion: Our results imply that subpopulations from one primary tumor can give rise to dissimilar daughter tumors. These tumors may not necessarily respond to the same targeted treatment, and thereby represent a therapy escape mechanism. This study highlights that to remove the risk of breast cancer recurrence, inhibition of the molecules critical for driving the tumor progression in several tumor cell subpopulations might be essential Gene expression was measured in four cell subpopulations isolated from Patient derived human luminal-like breast cancer xenograft. Four replicates from three subpopulations and three replicates from one subpopulation.

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Next-generation sequencing facilitates quantitative analysis of AcKLF5 and unAcKLF5 transcriptomes in xenografts of DU-145 cell line

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