Regulation of MicroRNA-155 and Its Related Genes Expression by Inositol Hexaphosphate in Colon Cancer Cells

Abstract

Inositol hexaphosphate (IP6), a natural dietary component, has been found as an antitumor agent by stimulating apoptosis and inhibiting cancer cell proliferation, their migration, and metastasis in diverse cancers including colon cancer. However, molecular mechanisms of its action have not been well understood. In recent years, microRNAs (miRNAs) have been reported to play important roles in a broad range of biologic processes, such as cell growth, proliferation, apoptosis, or autophagy. These small noncoding molecules regulate post-transcriptional expression of targets genes via degradation of transcript or inhibition of protein synthesis. Aberrant expression and/or dysregulation of miRNAs have been characterized during tumor development and progression, thus, they are potential molecular targets for cancer prevention. The aim of this study was to investigate the effect of IP6 on the miRNAs expression profile in Caco-2 colon cancer cells. 84 miRNAs were analyzed in Caco-2 cells treated with 2.5 mM and 5 mM IP6 by the use of PCR (Polymerase Chain Reaction) array. The effect of 5 mM IP6 on selected potential miR-155 targets was determined by real-time (RT)-qPCR and ELISA (quantitative Polymerase Chain Reaction and Enzyme-Linked Immunosorbent Assay )method. The results indicated alteration in the specific 10 miRNA expression in human colon cancer cells following their treatment with 5 mM IP6. It down-regulated 8 miRNAs (miR-155, miR-210, miR-144, miR-194, miR-26b, miR-126, miR-302c, and miR-29a) and up-regulated 2 miRNAs (miR-223 and miR-196b). In silico analysis revealed that FOXO3a, HIF-1α, and ELK3 mRNAs are those of predicted targets of miR-155. IP6 at the concentration of 5 mM markedly induced FOXO3a and HIF-1a genes’ expression at both mRNA and protein level and decreased the amount of ELK3 mRNA as well as protein concentration in comparison to the control. In conclusion, the present study indicates that one of the mechanisms of antitumor potential of IP6 is down-regulation of the miR-155 expression in human colon cancer cells. Moreover, the expression of genes that are targeted by miRNA are also modulated by IP6.

Phytic Acid Decreases Oxidative Stress and Intestinal Lesions Induced by Fumonisin B1 and Deoxynivalenol in Intestinal Explants of Pigs

“…The reduction in mycotoxin-induced apoptosis by IP6 demonstrates its potent antioxidant effect, since ROS generation is directly linked to apoptosis activation. Similar modulation of cell viability has been observed in inflammatory bowel studies [19,38,39]. IP6 induced a significant reduction in cox-2 expression compared to the explants exposed to all mycotoxin treatments.…”

“…The reduction in cox-2 expression observed in the present study can be associated with the ability of IP6 to inhibit ROS production, lipid peroxidation, and inflammatory stimuli [40] induced by DON and FB 1 . Moreover, studies have demonstrated that IP6 reduces the expression of cox-2 by inhibition of p38 MAPK, as well as the conversion of arachidonic acid into prostaglandins and suppression of β-catenin activity [19,40,41].…”

“…Several studies have demonstrated the preventive and therapeutic effects of IP6 in diseases associated with mineral and endocrine disturbances, chronic inflammation, and cancer development [14,15,16]. Specifically in models of intestinal inflammation and cancer, IP6 has shown protective effects by decreasing aberrant crypt formation, increasing cell viability, and downregulating pro-inflammatory cytokine, chemokine and cox-2 expression [17,18,19].…”

Phytic acid improves intestinal mucosal barrier damage and reduces serum levels of proinflammatory cytokines in a 1,2-dimethylhydrazine-induced rat colorectal cancer model

“…This can induce and promote the inflammation process. In vivo and in vitro studies have demonstrated that PA has a chemopreventive action in CRC due to its antiinflammatory property (51)(52)(53) . Our results showed that the serum expressions of TNF-α, IL-1β and IL-6 in the MG were significantly higher than those in the CG, which indicated that inflammation played a critical role in CRC.…”

Hypotheses on the Potential of Rice Bran Intake to Prevent Gastrointestinal Cancer through the Modulation of Oxidative Stress

“…In addition to the above effects, phytic acid treatment of cells was also found to increase the expression of I-κB [ 102 ], an inhibitor of NF-κB, which was indicated above to be a mediator of both inflammation and cell proliferation. More recently, a study also showed that phytic acid treatment of Caco-2 cells was able to reverse the pro-inflammatory effects of the treatment with inflammatory mediators through the down-regulation of the expression of inducible nitric oxide synthase (iNOS) [ 103 ], an enzyme whose over-expression was observed in patients with IBD [ 104 ]. Furthermore, in vitro γ-tocotrienol treatment was shown to inhibit the activity of NF-κB, leading to a decrease in the expression of pro-inflammatory and pro-proliferative genes, including cyclo-oxygenase 2, cyclin D1 and c-myc [ 105 , 106 ].…”