Concomitant Targeting of Multiple Key Transcription Factors Effectively Disrupts Cancer Stem Cells Enriched in Side Population of Human Pancreatic Cancer CellsReport as inadecuate




Concomitant Targeting of Multiple Key Transcription Factors Effectively Disrupts Cancer Stem Cells Enriched in Side Population of Human Pancreatic Cancer Cells - Download this document for free, or read online. Document in PDF available to download.

Background

A major challenge in the treatment of pancreatic ductal adenocarcinoma is the failure of chemotherapy, which is likely due to the presence of the cancer stem cells CSCs.

Objective

To identify side population SP cells and characterize s-like properties in human pancreatic cancer cell lines h-PCCLs and to exploit the efficacy of concomitant targeting of multiple key transcription factors governing the stemness of pancreatic CSCs in suppressing CSC-like phenotypes.

Methods

Flow cytometry and Hoechst 33342 DNA-binding dye efflux assay were used to sort SP and non-SP NSP cells from three h-PCCLs: PANC-1, SW1990, and BxPc-3. The self-renewal ability, invasiveness, migration and drug resistance of SP cells were evaluated. Expression of CSC marker genes was analyzed. Tumorigenicity was assessed using a xenograft model in nude mice. Effects of a complex decoy oligonucleotide cdODN-SCO designed to simultaneously targeting Sox2, Oct4 and c-Myc were assessed.

Results

CSCs were enriched in the side proportion SP cells contained in the h-PCCLs and they possessed aggressive growth, invasion, migration and drug-resistance properties, compared with NSP cells. SP cells overexpressed stem cell markers CD133 and ALDH1, pluripotency maintaining factors Nanog, Sox2 and Oct4, oncogenic transcription factor c-Myc, signaling molecule Notch1, and drug resistant gene ABCG2. Moreover, SP cells consistently demonstrated significantly greater tumorigenicity than NSP cells in xenograft model of nude mice. CdODN–SOC efficiently suppressed all CSC properties and phenotypes, and minimized the tumorigenic capability of the SP cells and the resistance to chemotherapy. By comparison, the negative control failed to do so.

Conclusion

The findings indicate that targeting the key genes conferring the stemness of CSCs can efficiently eliminate CSC-like phenotypes, and thus may be considered a new approach for cancer therapy. Specifically, the present study establishes the combination of Sox2-Oct4-c-Myc targeting as a potential anti-pancreatic cancer agent worthy of further studies in preclinical settings.



Author: Xiyan Wang , Quentin Liu , Benxin Hou, Wei Zhang, Min Yan, Huimin Jia, Haijun Li, Dong Yan, Feimeng Zheng, Wei Ding, Chao Yi, Hai

Source: http://plos.srce.hr/



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