H19 Regulation of Oestrogen Induction of Symmetric Division is Achieved by Antagonizing Let-7c in Breast Cancer Stem-like Cells

Objectives: Breast cancer stem-like cells (BrCSCs) are the major reason for tumour generation, resistance and recurrence. The turbulence of their self-renewal ability could help to constrain the stem cell expansion. The way BrCSCs divided was related to their self-renewal capacity, and the symmetric division contributed to a higher ability. Non-coding long RNA of H19 was involved in multiple malignant procedures; the role and mechanistic proof of non-coding long RNA of H19 in controlling the divisions of BrCSCs were barely known.

Materials And Methods: Indicative functions of H19 in preclinical study were analysed by using the TCGA data base. Division manners were defined by using fluorescence staining.

Results: We identified the stimulation of H19 on symmetric division of BrCSCs, which subsequently resulted in self-renewing increasing. H19 inhibited the Let-7c availability by acting as its specific molecular sponge, and with Let-7c inhibition, oestrogen receptor activated Wnt signalling was unconstrained. Similarly, restoring Let-7c constrained oestrogen receptor activated Wnt factors, which sequentially inhibited the H19 decreasing of Let-7 bioavailability. Let-7c is reactivated in vitro where H19 was knockdown, and later inhibited the symmetric division of BrCSCs. Reciprocally, Wnt pathway activation leads to H19 increasing, which in turn decreased Let-7c bioavailability.

Conclusions: Our results revealed a previously undescribed double negative feedback loop between sponge H19 and targeted Let-7c through oestrogen activated Wnt signalling that dominated in stem cells' division.