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Open AccessArticle

FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells

1
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
2
Hollings Cancer Center, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas St, Charleston, SC 29425, USA
3
Department of Biomedical Engineering/ND20, Cleveland Clinic, Cleveland, OH 44195, USA
4
Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 753; https://doi.org/10.3390/ijms22020753
Received: 16 December 2020 / Revised: 4 January 2021 / Accepted: 9 January 2021 / Published: 13 January 2021
Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1, BCL2, FZD1, GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs. View Full-Text
Keywords: CD44v6; YB-1; MDR1; CIC; stemness genes; CD44v6 CRISPR/Cas9 knockout; YB-1 CRISPR/Cas9 knockout; CD44v6-therapy; colorectal cancer (CRC) CD44v6; YB-1; MDR1; CIC; stemness genes; CD44v6 CRISPR/Cas9 knockout; YB-1 CRISPR/Cas9 knockout; CD44v6-therapy; colorectal cancer (CRC)
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MDPI and ACS Style

Ghatak, S.; Hascall, V.C.; Markwald, R.R.; Misra, S. FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells. Int. J. Mol. Sci. 2021, 22, 753. https://doi.org/10.3390/ijms22020753

AMA Style

Ghatak S, Hascall VC, Markwald RR, Misra S. FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells. International Journal of Molecular Sciences. 2021; 22(2):753. https://doi.org/10.3390/ijms22020753

Chicago/Turabian Style

Ghatak, Shibnath; Hascall, Vincent C.; Markwald, Roger R.; Misra, Suniti. 2021. "FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells" Int. J. Mol. Sci. 22, no. 2: 753. https://doi.org/10.3390/ijms22020753

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