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							| Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007



	

				
						
 
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																Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007
										

				


				
				
					
					
						
																					
				
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					Vol. 12 No. 5 (2022): May 2022
				
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									Research Articles
							
		



	
		  	 

		
	
		Combination of vitamins A, D2 and D3 reduce tumor load and alter the expression of miRNAs that regulate genes involved with apoptosis, tumor suppression, and the epithelial-mesenchymal transition in HCT-116 colon cancer cells
	


	
	
		

							
					Authors

						
							
								Karen D. Garay Buenrostro
							
															
									School of Medicine and Health Sciences, Tecnológico University de Monterrey Monterrey, N.L., México and Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA 60612
																	
																																		
	
							
								Keila C. Ostos Mendoza
							
																																		
	
							
								Pinal N. Kanabar
							
																																		
	
							
								Nina S. Los
							
																																		
	
							
								Temitope O. Lawal
							
																																		
	
							
								Shitalben M. Patel
							
																																		
	
							
								Alice M. López
							
																																		
	
							
								Paulina Cabada-Aguirre
							
																																		
	
							
								Gail B. Mahady
							
																																		
	
							
								Mark Maienschein-Cline
							
																																		
	
							
								Zarema Arbieva
							
																																		
	
							
								Nishikant A. Raut
							
																																		


				
			
																	
					
												DOI:
					

					
						
							https://doi.org/10.31989/ffhd.v12i5.925
						
					
				
			

						
										
					Abstract

					Introduction: In previous work, we have shown the synergistic effects of combinations of vitamins A, D2, and D3 in reducing the proliferation of HCT-116 colon cancer cells. This combination also induced apoptosis and altered gene expression patterns as determined by transcriptomic profiling. 
Aims: The aims of this study were to investigate the effects of vitamins A and D in HCT-116 Crl:NU(NCr)-Foxn1nu mouse xenographs. Also, to determine potential mechanisms of action using miRNA-seq and correlated these data with results from RNA-seq.
Methods: HCT-116 colon cancer cells were cultured and used for the xenograph study. Crl:NU(NCr)-Male Foxn1nu mice were injected subcutaneously with HCT-116-cells (1 X 106 in 100 µl 50% Matrigel and Sterile PBS), and after 7 days, were treated with vitamin A and D in feed for 21 days. The mice were imaged on day 28, sacrificed and the tumors were excised and measured. RNA was isolated from the HCT-116 cells and tumors, and RNA-seq and miRNA-seq were performed.
Results: There was a concentration-dependent reduction in the HCT-116 colon cancer cell viability after treatment with vitamin A and D combinations. In Crl:NU(NCr)-Foxn1nu mice injected with HCT-116 colon tumor cells, treatment with vitamin A (25,000 IU) and vitamin D (4,000 IU) or vitamin A (35,000 IU) and vitamin D (5,000 IU) for 21 days significantly reduced tumor growth by ~38% and ~58%, respectively (p < 0.001). In the HCT-116 cells and excised tumors, treatment upregulated the expression of Bim, Bax, p53, and PTEN, and downregulated AXIN2, ID2 and DDX20 mRNAs, all well-known pro-apoptotic proteins, tumor suppressors, and molecules involved in the epithelial-mesenchymal transition. Ingenuity Pathway Analysis of miRNA-seq paired with RNA-seq showed correlations between miRNAs expression and expression of these genes. For example, miRNA-mRNA correlation pairing showed that treatment downregulated miR-30c-3p and miR-125b-3p which was associated with upregulated TP53. Upregulation of the tumor suppressor PTEN was associated with the downregulation of eleven miRNAs, including oncogenic miR17 and miR21.
Conclusion: The results suggest that the combinations of vitamins A and D reduced the HCT-116 tumor burden in mice and altered the expression of miRNAs directly associated with genes in the apoptosis, tumor suppression, and epithelial-mesenchymal transition pathways. The data supports the hypothesis that vitamin A and D combinations impact multiple cancer signaling pathways and thus may be more effective in the treatment and prevention of cancer, as well as reducing cancer metastasis.   
Keywords: apoptosis, cholcalciferol, colon cancer, DDX20, epithelial-mesenchymal transition, ergocalciferol, p53, RNA-seq, miRNA-seq, PTEN, synergism, transcriptome

				
			
			

						
																																																																																																
						
		


		

						
										
					
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																			2022-05-17
																	

				
							

			
						
										

											
							
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									Vol. 12 No. 5 (2022): May 2022
								
							

						
					
											
							
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								Research Articles
							

						
					
									

			
						
										
					
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