Milk Exosomal miR-27b Worsen Endoplasmic Reticulum Stress Mediated Colorectal Cancer Cell Death

Abstract

The relationship between dietary constituents and the onset and prevention of colorectal cancer (CRC) is constantly growing. Recently, the antineoplastic profiles of milk and whey from Mediterranean buffalo (Bubalus bubalis) have been brought to attention. However, to date, compared to cow milk, the potential health benefits of buffalo milk exosome-miRNA are still little explored. In the present study, we profiled the exosomal miRNA from buffalo milk and investigated the possible anticancer effects in CRC cells, HCT116, and HT-29. Results indicated that buffalo milk exosomes contained higher levels of miR-27b, miR-15b, and miR-148a compared to cow milk. Mimic miR-27b transfection in CRC cells induced higher cytotoxic effects (p < 0.01) compared to miR-15b and miR-148a. Moreover, miR-27b overexpression in HCT116 and HT-29 cells (miR-27b+) induced apoptosis, mitochondrial reactive oxygen species (ROS), and lysosome accumulation. Exposure of miR-27b+ cells to the bioactive 3kDa milk extract aggravated the apoptosis rate (p < 0.01), mitochondrial stress (p < 0.01), and advanced endoplasmic reticulum (ER) stress (p < 0.01), via PERK/IRE1/XBP1 and CHOP protein modulation (p < 0.01). Moreover, GSK2606414, the ER-inhibitor (ER-i), decreased the apoptosis phenomenon and XBP1 and CHOP modulation in miR-27b+ cells treated with milk (p < 0.01 vs. miR-27b++Milk), suggesting the ER stress as a cell-death-aggravating mechanism. These results support the in vitro anticancer activity of 3kDa milk extract and unveil the contribution of miR-27b in the promising beneficial effect of buffalo milk in CRC prevention.

Advances in the protection of intestinal mucosal barrier function by milk-derived miRNAs

“…118 Gao et al (2021) also found that yak milk exosomes increased the survival of mouse intestinal crypt epithelial cells under hypoxia and confirmed that this was associated with the targeting of the carried miR-34a to inhibit hypoxia-inducible factor HIF-α expression, which in turn promoted intestinal epithelial cell proliferation and differentiation. 119 However, in a recent study by Martino et al (2022), it was found that miR-27b, which is abundant in buffalo milk exosomes, exhibited potent cytotoxicity and induced apoptosis in both Caco-2 cells and HT-29 cells; further studies revealed that overexpression of miR-27b suppressed the expression of PERK/ IRE1/XBP1 and CHOP proteins, further exacerbating the apoptosis rate. 120 In addition, endogenous miRNAs can also regulate intestinal tight junction protein expression at the transcriptional level.…”

“…119 However, in a recent study by Martino et al (2022), it was found that miR-27b, which is abundant in buffalo milk exosomes, exhibited potent cytotoxicity and induced apoptosis in both Caco-2 cells and HT-29 cells; further studies revealed that overexpression of miR-27b suppressed the expression of PERK/ IRE1/XBP1 and CHOP proteins, further exacerbating the apoptosis rate. 120 In addition, endogenous miRNAs can also regulate intestinal tight junction protein expression at the transcriptional level. For example, miR-29a can target and regulate CLDN1 expression and alleviate the trinitrobenzene sulfonic acidinduced pathological decrease in tight junction protein ZO-1 expression.…”

“…119 However, in a recent study by Martino et al (2022), it was found that miR-27b, which is abundant in buffalo milk exosomes, exhibited potent cytotoxicity and induced apoptosis in both Caco-2 cells and HT-29 cells; further studies revealed that overexpression of miR-27b suppressed the expression of PERK/IRE1/XBP1 and CHOP proteins, further exacerbating the apoptosis rate. 120…”

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

“…In fact, bovine MDEs exhibited anti-inflammatory effects in murine models of colitis [ 573 , 574 ]. Notably, miR-148a-3p and MDE miR-27b exert tumor suppressive functions in CRC [ 575 , 576 , 577 ].…”

Recent insights into the nutritional immunomodulation of cancer‐related microRNAs

“…N. Kumar et al, 2022;D. Li et al, 2022;Louisville, 2011;Martino et al, 2022;Munagala et al, 2016;Raimondo et al, 2015;Tajik et al, 2022;Takakura et al, 2022;H. Tao et al, 2020;Yamauchi et al, 2019;M.…”