Cold-inducible lncRNA266 promotes browning and the thermogenic program in white adipose tissue.

Cold-induced nonshivering thermogenesis has contributed to the improvement of several metabolic syndromes caused by obesity. Several long noncoding RNAs (lncRNAs) have been shown to play a role in brown fat biogenesis and thermogenesis. Here we show that the lncRNA lnc266 is induced by cold exposure in inguinal white adipose tissue (iWAT). In vitro functional studies reveal that lnc266 promotes brown adipocyte differentiation and thermogenic gene expression. At room temperature, lnc266 has no effects on white fat browning and systemic energy consumption. However, in a cold environment, lnc266 promotes white fat browning and thermogenic gene expression in obese mice. Moreover, lnc266 increases core body temperature and reduces body weight gain. Mechanistically, lnc266 does not directly regulate Ucp1 expression. Instead, lnc266 sponges miR-16-1-3p and thus abolishes the repression of miR-16-1-3p on Ucp1 expression. As a result, lnc266 promotes preadipocyte differentiation toward brown-like adipocytes and stimulates thermogenic gene expression. Overall, lnc266 is a cold-inducible lncRNA in iWAT, with a key role in white fat browning and the thermogenic program.

A two-microRNA signature predicts the progression of male thyroid cancer.

In various cancers, microRNAs (miRNAs) are abnormally expressed, including thyroid cancer (TC). In recent years, the incidence of TC has increased annually around the world. Compared with female patients, male TC patients are more likely to have a postoperative recurrence and lymph node metastasis, and hence need second treatments. However, the molecular biological processes underlying this phenomenon are not understood. Therefore, we collected data on miRNA expression and clinical information of male TC patients from The Cancer Genome Atlas (TCGA) database. Differentially expressed miRNAs were identified between male TC tissues and matched normal tissues. The Kaplan-Meier method, univariate and multivariate Cox regressions, and receiver operating characteristic curve analyses were performed to assess the association between miRNAs and the disease-free survival of male TC patients. Gene Ontology (GO) and the Kyoto Encyclopaedia of Gene and Genome (KEGG) enrichment analyses were then used to explore the function of miRNA target genes. Furthermore, we evaluated the ability of the miRNA biomarker to predict survival in female TC patients. As a result, a total of 118 differentially expressed miRNAs were identified, including 25 upregulated and 93 downregulated miRNAs. Among them, miR-451a and miR-16-1-3p were confirmed to be independent prognostic factors for the disease-free survival rate. The target genes of miR-451a and miR-16-1-3p were identified, and functional analysis showed that these genes were enriched in 25 Go and KEGG accessions, including cell signal transduction, motor adhesion, phagocytosis, regulation of transcription, cell proliferation, angiogenesis, etc. Neither miR-451a and miR-16-1-3p, nor a prediction model based on both miRNAs effectively predicted survival in female TC patients. In conclusion, both miR-451a and miR-16-1-3p may play important roles in the processes of male TC. The two-miRNA signature involving miR-1258 and miR-193a may serve as a novel prognostic biomarker for male TC patients.

Corrigendum: MicroRNA-16-1-3p Represses Breast Tumor Growth and Metastasis by Inhibiting PGK1-Mediated Warburg Effect.

[This corrects the article DOI: 10.3389/fcell.2020.615154.].

MicroRNA-16-1-3p Represses Breast Tumor Growth and Metastasis by Inhibiting PGK1-Mediated Warburg Effect.

The Warburg effect (aerobic glycolysis) is a hallmark of cancer and is becoming a promising target for diagnosis and therapy. Phosphoglycerate kinase 1 (PGK1) is the first adenosine triphosphate (ATP)-generating glycolytic enzyme in the aerobic glycolysis pathway and plays an important role in cancer development and progression. However, how microRNAs (miRNAs) regulate PGK1-mediated aerobic glycolysis remains unknown. Here, we show that miR-16-1-3p inhibits PGK1 expression by directly targeting its 3'-untranslated region. Through inhibition of PGK1, miR-16-1-3p suppressed aerobic glycolysis by decreasing glucose uptake, lactate and ATP production, and extracellular acidification rate, and increasing oxygen consumption rate in breast cancer cells. Aerobic glycolysis regulated by the miR-16-1-3p/PGK1 axis is critical for modulating breast cancer cell proliferation, migration, invasion and metastasis in vitro and in vivo. In breast cancer patients, miR-16-1-3p expression is negatively correlated with PGK1 expression and breast cancer lung metastasis. Our findings provide clues regarding the role of miR-16-1-3p as a tumor suppressor in breast cancer through PGK1 suppression. Targeting PGK1 through miR-16-1-3p could be a promising strategy for breast cancer therapy.

miR-16-1-3p targets TWIST1 to inhibit cell proliferation and invasion in NSCLC.

In our study, the impact of miR-16-1-3p on cell proliferation and invasion in NSCLC was explored. miR-16-1-3p mimics were transfected to A549 cells for miR-16-1-3p overexpression. qRT- PCR and Western blot were applied to explore the relative expression of mRNA and protein in A549 cells. Furthermore, the cell proliferation capability was determined by MTT assay. Additionally, cell migration and invasion were measured using a scratch assay and transwell assay, respectively. Moreover, TargetScan and luciferase reporter assay was utilized to investigate the target of miR-16-1-3p. The results indicated that miR-16-1-3p was downregulated in NSCLC cells and upregulation of miR-16-1-3p was able to inhibit the expression of TWIST1. In addition, the reduced cell proliferation, inhibited cell migration and invasion were observed in miR-16-1-3p mimic group compared to the negative control group. The luciferase reporter gene showed that TWIST1 was a target of miR-16-1-3p. Therefore, the present study demonstrated that miR-16-1-3p may suppress A549 cell proliferation, migration and invasion by targeting TWIST1. Thus, miR-16-1-3p might play important roles in NSCLC development, which provides a novel aspect for NSCLC investigation (Fig. 6, Ref. 26).

miR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis.

MicroRNAs are a novel class of gene regulators that function as oncogenes or tumor suppressors. In our current study, we investigated the role of miR-15a-3p and miR-16-1-3p in the regulation of Twist1 expression and EMT process. Our bioinformatics analysis suggested that on the 3' UTR of Twist1, there are two conserved miRNA recognition sites for miR-15a-3p and miR-16-1-3p respectively. Interestingly, overexpression of miR-15a-3p and miR-16-1-3p significantly suppressed the activity of luciferase reporter containing Twist1-3' UTR, reduced mRNA and protein level of EMT related genes such as TWIST1, N-cadherin, α-SMA and Fibronectin, and repressed MMP9 and MMP2 activity, as well as cell migration and invasion. Conversely, inhibition of miR-15a-3p and miR-16-1-3p significantly increased TWIST1, N-cadherin, α-SMA and Fibronectin protein expression. In addition, Twist1 co-transfection significantly ameliorated the loss of cell migration and invasion. Moreover, overexpression of miR-15a-3p and miR-16-1-3p dramatically suppressed the ability of BGC823 cells to form colonies in vitro and develop tumors in vivo in nude mice. Finally, qPCR and Western blot analysis showed that miR-15a-3p and miR-16-1-3p were significantly reduced in clinical gastric cancer tissue, whereas Twist1 mRNA and protein were significantly up-regulated, suggesting that this aberrant down-regulation of miR-15a-3p and miR-16-1-3p might be associated with the abnormal regulation of Twist1 and the EMT process in gastric cancer development. Our results help to elucidate a novel and important mechanism for the regulation of Twist1 in the development of cancer.