Abstract P5-07-10: MiR-146a functions as suppressive non-coding gene via indirect upregulation of Let-7 to promote asymmetric division and inhibit the self-renewal ability of breast cancer stem-like cells
Authors: X Sun, N Du, G Li, J Zhang, J Zhang, G Xiao, J Wang, S-C Tang, H Ren
Journal: Cancer Research (2017)

Abstract MiR-146a plays as diverse roles in systemic malignancies, stimulating the tumor growth or blocking the tumor proliferation. However, its roles in breast cancer stem-like cells are barely known. We first identified the suppressive role of miR-146a in stem cells' renewal, promoting the asymmetric division of stem-like cells, and the expression of miR-146a was positively related with Let-7b level in vitro and in clinical specimens. Previous studies of Let-7 revealed its suppressive functions in stem-like cells expansion, and miR-146 was predicated to target and bind to the 3'UTR of LIN28, a negative regulator of Let-7 maturation. By using luc-assay and western, results showed that miR-146a increased the Let-7b level through degrading Lin28, and Lin28 is required for miR-146a induction of stem cells arresting and more asymmetric stem cells division. Moreover, Let-7 controlled Wnt signaling pathway activity is governed and strengthened by miR-146a, contributing to decrease the ratio of stem-like cells, forcing stem cells dividing asymmetrically. MiR-146a in turn formed negative feedback loop with Let-7 via the repression of NF-kB and Snai1 caused by Let-7b. Our results suggested the possible miR-146a/LIN28/Let-7/Snai1 signaling pathway in restraining the symmetric cells division, which was referred to the self-renewal capacity of breast cancer-stem like cells, and this axis helps to prohibit long–term tumor resistance and recurrence.MiR-146a plays as diverse roles in systemic malignancies, stimulating the tumor growth or blocking the tumor proliferation. However, its roles in breast cancer stem-like cells are barely known. We first identified the suppressive role of miR-146a in stem cells' renewal, promoting the asymmetric division of stem-like cells, and the expression of miR-146a was positively related with Let-7b level in vitro and in clinical specimens. Previous studies of Let-7 revealed its suppressive functions in stem-like cells expansion, and miR-146 was predicated to target and bind to the 3'UTR of LIN28, a negative regulator of Let-7 maturation. By using luc-assay and western, results showed that miR-146a increased the Let-7b level through degrading Lin28, and Lin28 is required for miR-146a induction of stem cells arresting and more asymmetric stem cells division. Moreover, Let-7 controlled Wnt signaling pathway activity is governed and strengthened by miR-146a, contributing to decrease the ratio of stem-like cells, forcing stem cells dividing asymmetrically. MiR-146a in turn formed negative feedback loop with Let-7 via the repression of NF-kB and Snai1 caused by Let-7b. Our results suggested the possible miR-146a/LIN28/Let-7/Snai1 signaling pathway in restraining the symmetric cells division, which was referred to the self-renewal capacity of breast cancer-stem like cells, and this axis helps to prohibit long–term tumor resistance and recurrence. Citation Format: Sun X, Du N, Li G, Zhang J, Zhang J, Xiao G, Wang J, Tang S-C, Ren H. MiR-146a functions as suppressive non-coding gene via indirect upregulation of Let-7 to promote asymmetric division and inhibit the self-renewal ability of breast cancer stem-like cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-07-10.