Cancer stem cells (CSCs) are responsible for cancer initiating, recurrence, and drug resistance. Discovery of novel biomarkers for CSCs is helpful for early diagnosis and prognosis. Lung cancer stem cells (LCSCs) were closely related to the occurrence and development of lung cancer. In our study, the important role of miR-2861 in maintaining the stemness of LCSCs was investigated. The LCSC differentiation model was established through introducing serum into the medium of H460 spheres. miR-2861 expression was significantly higher in LCSCs no matter compared to the differentiation cells or normal cells. HDAC5 expression was positively correlated with miR-2861 in LCSCs, and knockdown of miR-2861 decreased the expression of HDAC5, which implied that HDAC5 may be involved in the differentiation of LCSCs mediated by miR-2861. The role of HDAC5 in the regulation of LCSC differentiation was further verified by the inhibitory effect of LMK-235 on the phosphorylation of ERK1/2, which was recognized as the regulator of CSC differentiation. Our study provided a better understanding of miR-2861 and HDAC5 axis in maintaining the stemness of LCSCs and laid a foundation for molecular targeted therapy.
Background Diabetic nephropathy (DN) is a frequent microvascular complication of diabetes. Glomerular mesangial cell (MC) hypertrophy occurs at the initial phase of DN and plays a critical role in the pathogenesis of DN. Given the role of long non coding RNA (lncRNA) in regulating MC hypertrophy and extracellular matrix (ECM) accumulation, our aim was to identify functional lncRNAs during MC hypertrophy. Methods Here, an lncRNA, C920021L13Rik (L13Rik for short), was identified to be up-regulated in DN progression. The expression of L13Rik in DN patients and diabetic mice was assessed using quantitative real-time PCR (qRT-PCR), and the function of L13Rik in regulating HG-induced MC hypertrophy and ECM accumulation was assessed through flow cytometry and western blotting analysis. Results The L13Rik levels were significantly increased while the miR-2861 levels were decreased in the peripheral blood of DN patients, the renal tissues of diabetic mice, and HG-treated MCs. Functionally, both L13Rik depletion and miR-2861 overexpression effectively reduced HG-induced cell hypertrophy and ECM accumulation. Mechanistically, L13Rik functioned as a competing endogenous RNA (ceRNA) to sponge miR-2861, resulting in the de-repression of cyclin-dependent kinase inhibitor 1B (CDKN1B), a gene known to regulate cell cycle and MC hypertrophy. Conclusions Collectively, the current results demonstrate that up-regulated L13Rik is correlated with DN and may be a hopeful therapeutic target for DN.
Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called “calcification paradox”. Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.
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