Background/aims: Schlafen12 (SLFN12) promotes human intestinal and prostatic epithelial differentiation. We sought to determine whether SLFN12 reduces triple-negative breast cancer (TNBC) aggressiveness.
Methods: We validated bioinformatics analyses of publicly available databases by staining human TNBC. After virally overexpressing or siRNA-reducing SLFN12 in TNBC cell lines, we measured proliferation by CCK-8 assay, invasion into basement-membrane-coated pores, mRNA by q-RT-PCR and protein by Western blotting. Flow cytometry assessed proliferation and stem cell marker expression, and sorted CD44+/CD24- cells. Stemness was also assessed by mammosphere formation, and translation by click-it-AHA chemistry.
Results: SLFN12 expression was lower in TNBC tumors and correlated with survival. SLFN12 overexpression reduced TNBC MDA-MB-231, BT549, and Hs578T proliferation. In MDA-MB-231 cells, AdSLFN12 reduced invasion, promoted cell cycle arrest, increased E-cadherin promoter activity, mRNA, and protein, and reduced vimentin expression and protein. SLFN12 knockdown increased vimentin. AdSLFN12 reduced the proportion of MDA-MB-231 CD44CD24 cells, with parallel differentiation changes. SLFN12 overexpression reduced MDA-MB-231 mammosphere formation. SLFN12 overexpression decreased ZEB1 and Slug protein despite increased ZEB1 and Slug mRNA in all three lines. SLFN12 overexpression accelerated MDA-MB-231 ZEB1 proteasomal degradation and slowed ZEB1 translation. SLFN12 knockdown increased ZEB1 protein. Coexpressing ZEB1 attenuated the SLFN12 effect on E-cadherin mRNA and proliferation in all three lines.
Conclusion: SLFN12 may reduce TNBC aggressiveness and improve survival in part by a post-transcriptional decrease in ZEB1 that promotes TNBC cancer stem cell differentiation.
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http://dx.doi.org/10.33594/000000191 | DOI Listing |
Cancers (Basel)
November 2024
Department of Surgery, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
Background/objectives: Schlafen12 (SLFN12) is an intermediate human Schlafen protein shown to correlate with survivability in triple-negative breast cancer (TNBC). SLFN12 causes differential expressions of significant cancer genes, but how they change in response to chemotherapy remains unknown. Our aim is to identify the effect of chemotherapy on genes that improve TNBC outcomes and other SLFN family members following SLFN12 knockout or overexpression.
View Article and Find Full Text PDFClin Cancer Res
December 2024
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancers (Basel)
January 2023
Department of Pathology, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
The Schlafen 12 (SLFN12) protein regulates triple-negative breast cancer (TNBC) growth, differentiation, and proliferation. SLFN12 mRNA expression strongly correlates with TNBC patient survival. We sought to explore SLFN12 overexpression effects on in vivo human TNBC tumor xenograft growth and performed RNA-seq on xenografts to investigate related SLFN12 pathways.
View Article and Find Full Text PDFCells
October 2022
Department of Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
Background: The intestinal lining renews itself in a programmed fashion that can be affected by adaptation to surgical procedures such as gastric bypass.
Methods: To assess adaptive mechanisms in the human intestine after Roux-en-Y gastric bypass (RYGB), we biopsied proximal jejunum at the anastomotic site during surgery to establish a baseline and endoscopically re-biopsied the same area 6-9 months after bypass for comparison. Laser microdissection was performed on pre- and post-RYGB biopsies to isolate enterocytes for RNA sequencing.
Cancer Genomics Proteomics
April 2022
Department of Surgery, School of Medicine and the Health Sciences, University of North Dakota, Grand Forks, ND, U.S.A.;
Background/aim: Schlafen 12 (SLFN12) expression correlates with survival in triple negative breast cancer (TNBC). SLFN12 slows TNBC proliferation and induces TNBC differentiation, but whether SLFN12 affects the tumoral response to chemotherapy or radiation is unknown.
Materials And Methods: We over-expressed SLFN12 in MDA-MB-231 cells using two different lentiviral vectors.
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