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Understanding the molecular basis that underlies the expansion of the neocortex during primate, and notably human, evolution requires the identification of genes that are particularly active in the neural stem and progenitor cells of the developing neocortex. Here, we have used existing transcriptome datasets to carry out a comprehensive screen for protein-coding genes preferentially expressed in progenitors of fetal human neocortex. We show that 15 human-specific genes exhibit such expression, and many of them evolved distinct neural progenitor cell-type expression profiles and levels compared to their ancestral paralogs. Functional studies on one such gene, NOTCH2NL, demonstrate its ability to promote basal progenitor proliferation in mice. An additional 35 human genes with progenitor-enriched expression are shown to have orthologs only in primates. Our study provides a resource of genes that are promising candidates to exert specific, and novel, roles in neocortical development during primate, and notably human, evolution.

Insulin-like growth factors (IGFs) induce proliferation of various cell types and play important roles in somatic growth and cancer development. Phosphorylation of insulin receptor substrate (IRS)-1/2 by IGF-I receptor tyrosine kinase is essential for IGF action. Here we identify Nedd4 as an IRS-2 ubiquitin ligase. Nedd4 monoubiquitinates IRS-2, which promotes its association with Epsin1, a ubiquitin-binding protein. Nedd4 recruits IRS-2 to the membrane, probably through promoting Epsin1 binding, and enhances IGF-I receptor-induced IRS-2 tyrosine phosphorylation. In thyroid FRTL-5 cells, activation of the cyclic AMP pathway increases the association of Nedd4 with IRS-2, thereby enhancing IRS-2-mediated signalling and cell proliferation induced by IGF-I. The Nedd4 and IRS-2 association is also required for maximal activation of IGF-I signalling and cell proliferation in prostate cancer PC-3 cells. Nedd4 overexpression accelerates zebrafish embryonic growth through IRS-2 in vivo . We conclude that Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity. Phosphorylation of insulin receptor substrate (IRS)-1/2 by insulin-like growth factor (IGF)-I receptor tyrosine kinase is essential for IGF signalling. Here, the authors show that monoubiquitination of IRS-2 by the ubiquitin ligase Nedd4 recruits IRS-2 to the cell membrane and increases IRS-2 phosphorylation and IGF signalling.

Background Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance. Methods Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI ( n  = 198) or no presurgical treatment (control n  = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67. Results High baseline ESR1 expression associated with better AI response in HER2+ tumours but not HER2− tumours. In HER2− tumours, baseline expression of 48 genes associated with poor antiproliferative response ( p  < 0.005) including PERP and YWHAQ , the two most significant, and the transcription co-regulators ( SAP130 , HDAC4 , and NCOA7 ) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling ( ERBB2-GS , RET/ GDNF-GS , and IGF-1-GS ), and immune activity ( STAT1-GS ) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2− and HER2+ patients. Conclusions There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors. Trial registration ISRCTN, ISRCTN63882543 , registered on 18 December 2007.

Cancer cells adapt their metabolism to support aberrant cell proliferation. However, the functional link between metabolic reprogramming and cell cycle progression remains largely unexplored. Mitochondria rely on the transfer of multiple lipids from the endoplasmic reticulum (ER) to their membranes to be functional. Several mitochondrial‐derived metabolites influence cancer cell proliferation by modulating the epigenome. Here, the loss of STARD7, a lipid transfer protein whose expression is enhanced in breast cancer, is shown to lead a metabolic reprogramming characterized by the accumulation of carnitine derivatives and S‐Adenosyl‐L‐methionine (SAM). Elevated SAM levels cause the increase of H3K27 trimethylation on many gene promoters coding for candidates involved in cell cycle progression. Likewise, STARD7 deficiency triggers cell cycle arrest and impairs ERα‐dependent cell proliferation. Moreover, EGFR signaling is also impaired in triple negative breast cancer cells lacking STARD7, at least due to deregulated EGFR trafficking to lysosomes. Therefore, mitochondria rely on STARD7 to support cell cycle progression in breast cancer. Breast cancer cells undergo metabolic and transcriptomic reprogramming to support aberrant cell proliferation. Their mitochondria rely on the transfer of phosphatidylcholine from the endoplasmic reticulum to their membranes by STARD7, a candidate upregulated in breast cancer, to be functional. The loss of STARD7 leads to enhanced S‐Adenosyl‐L‐methionine (SAM) levels, which ultimately impairs ERα‐ and EGFR‐dependent signaling pathways through epigenetic mechanisms.

Background Chronic obstructive pulmonary disease (COPD), characterized by persistent airflow limitation, was a disease mediated by a combination of inflammatory factors, immune cells, and immune mediators. COPD was an inflammatory and autoimmune disease involving T‐lymphocytes triggered by cigarette smoke and other factors that progressively affected the bronchi, lung parenchyma, and pulmonary blood vessels. LncRNAs were reported to be implicated in COPD pathogenesis and development. Methods Non‐smokers, smokers (non‐COPD), and COPD patients were randomly selected in an established COPD surveillance cohort. Demographic and clinical information of all subjects were collected. Pulmonary function was measured by post‐bronchodilator testing. qRT‐PCR and ELISA assays were performed to detect the expression levels of lncRNA LUCAT1, miR‐181a‐5p, and inflammatory cytokines. An in vitro exposure model was constructed using cigarette smoke extract (CSE)‐induced human bronchial epithelial (16HBE) cells. The dual‐luciferase reporter and RNA pull‐down assays were used to detect the binding relationship between lncRNA LUCAT1 and miR‐181a‐5p; meanwhile, Spearman's correlation assay was used to verify the correlation between lncRNA LUCAT1 and miR‐181a‐5p. Afterward, the lncRNA LUCAT1 silencing plasmid was constructed and co‐transfected with a miR‐181a‐5p inhibitor to evaluate the effects on CSE‐induced 16HBE cell proliferation and apoptosis. Finally, a Western blot assay was utilized to determine the mechanism of lncRNA LUCAT1/miR‐181a‐5p/Wnt/β‐catenin axis in COPD. Results LncRNA LUCAT1 was upregulated in the serums of COPD patients. Correlation analysis further confirmed the strong correlation between LUCAT1 expression and inflammatory cytokines IL‐1β, IL‐6, and TNF‐α. Receiver operating characteristic (ROC) analysis verified the potential of LUCAT1 in COPD diagnosis. After treatment with CSE, LUCAT1 was significantly increased while its target miR‐181a‐5p was decreased in 16HBE cells. Cell proliferation and apoptosis assays showed that LUCAT1 silencing alleviated CSE’s effects on 16HBE cell proliferation and apoptosis. Mechanically, rescue assays demonstrated that miR‐181a‐5p inhibition could partially counteract the impact of LUCAT1 on COPD progression through the Wnt/β‐catenin pathway. Conclusions LncRNA LUCAT1 may be a valuable indicator for differentiating COPD. Moreover, LncRNA LUCAT1/miR‐181‐5p/Wnt/β‐catenin axis behaved as a critical role in COPD development, shedding new sights for clinical treatment. Chronic obstructive pulmonary disease (COPD) was a chronic, non‐homogeneous lung disease characterized by persistent excessive inflammation that led to tissue remodeling, alveolar damage, airflow limitation, and accelerated lung function decline. The clinical manifestations of COPD include chronic cough, coughing sputum, dyspnea, and acute exacerbation in the presence of infections and other triggering factors. Pulmonary function tests were the primary means of confirming the diagnosis of COPD (Respiratory Care, 57, 2012 and 165). Appropriate drug therapy can effectively relieve symptoms, reduce the number and frequency of acute exacerbations, improve exercise tolerance, and improve quality of life. Cigarette smoking was a significant risk factor for COPD. Inhaled cigarette smoke first encountered respiratory epithelial cells, causing the release of pro‐inflammatory mediators such as interleukin (IL)‐1, IL‐6, and tumor necrosis factor (TNF)‐α. Although inflammation‐based airway injury was recognized as a core feature of COPD, the underlying mechanism was unclear. From the results, we found that lncRNA LUCAT1 was upregulated in the serums of COPD patients. Correlation analysis further confirmed the strong correlation between LUCAT1 expression and inflammatory cytokines IL‐1β, IL‐6, and TNF‐α. Receiver operating characteristic (ROC) analysis verified the potential of LUCAT1 in COPD diagnosis. After treatment with CSE, LUCAT1 was significantly increased, while its target miR‐181a‐5p was decreased in 16HBE cells. Cell proliferation and apoptosis assays showed that LUCAT1 silencing alleviated CSE’s effects on 16HBE cell proliferation and apoptosis. Mechanically, rescue assays demonstrated that miR‐181a‐5p inhibition could partially counteract the impact of LUCAT1 on COPD progression through the Wnt/β‐catenin pathway. In sum, lncRNA LUCAT1 may be a valuable indicator for differentiating COPD. Moreover, lncRNA LUCAT1/miR‐181‐5p/Wnt/β‐catenin axis behaved as a critical role in COPD development, shedding new sights for clinical treatment.

Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.

Abstract Objectives Hypocellular acute myeloid leukemia (AML) is uncommon. Despite the prognostic and therapeutic importance of mutational analysis, the mutational landscape of hypocellular AML is not well understood. Methods We identified 25 patients with hypocellular AML, and 141 patients with nonhypocellular AML were identified as a control group. We applied next-generation sequencing for the first time to profile this entity. Results The hypocellular AML patients were older than those with nonhypocellular AML (P = .037). At diagnosis, hypocellular AML had lower leukocyte counts (P = .012), higher hemoglobin (P = .003), and lower blast counts in the peripheral blood (P < .001) and bone marrow (P = .003). Hypocellular AML was less likely to have mutations involving cell proliferation (P = .027) and NPM1 (P = .022) compared with nonhypocellular AML. Hypocellular AML showed a high incidence of spliceosomal mutations and myelodysplastic syndrome-defining chromosome abnormalities (65%), but the incidence was not significantly different from that in nonhypocellular AML. There was no significant survival difference between hypocellular and nonhypocellular AML. Conclusions To our knowledge, this study is the first to demonstrate hypocellular AML showed fewer genetic alterations involving cell proliferation and NPM1 when compared directly with nonhypocellular AML; this finding likely contributes to the low marrow cellularity in at least a portion of the patients with hypocellular AML.

Yes-associated protein 1 (YAP1) exerts significant effects in various malignancies. However, the oncogenic role of YAP1 remains controversial, and the mechanism by which YAP1 regulates non-coding RNAs is still largely unknown. The present study aimed to assess the effect of YAP1 on the malignant behaviors of colorectal carcinoma (CRC) and explore the underlying regulatory mechanism of the YAP1-MALAT1-miR-126-5p axis. YAP1 was highly expressed in CRC tissues as assessed by GSE20916 and its expression was negatively correlated with overall survival in 83 CRC cases. Meanwhile, YAP1 promoted proliferation, invasion, and migration in colon cancer cells, in vitro and in vivo. MALAT1 was obviously expressed, with differential expression of 11 lncRNAs in HCT116 cells after transfection with siYAP1 or si-Ctl. Based on bioinformatics prediction, immunoprecipitation (IP), and chromatin immunoprecipitation (ChIP), the interaction of YAP1 with TCF4/β-catenin was regulated by MALAT1. Bioinformatics prediction, dual luciferase assay, RNA-IP, and RNA pull-down assay demonstrated that YAP1-induced MALAT1 promoted the expression of metastasis-associated molecules such as VEGFA, SLUG, and TWIST, by sponging miR-126-5p in CRC. These findings indicated that the YAP1-MALAT1-miR-126-5p axis could control angiogenesis and epithelial-mesenchymal transition in CRC, providing potential biomarkers and therapeutic targets for CRC.

The deposition of chemical modifications into RNA is a crucial regulator of temporal and spatial gene expression programs during development. Accordingly, altered RNA modification patterns are widely linked to developmental diseases. Recently, the dysregulation of RNA modification pathways also emerged as a contributor to cancer. By modulating cell survival, differentiation, migration and drug resistance, RNA modifications add another regulatory layer of complexity to most aspects of tumourigenesis. Sylvain et al. review cellular functions of various RNA modifications and their roles in regulating cell fate in normal and cancer tissues.

Hepatocellular carcinoma (HCC), the major form of liver cancer, has shown increasing incidence and poor prognosis. Adipose tissue is known to function in energy storage and metabolism regulation by the secretion of adipokines. Circular RNAs (circRNAs), a novel type of noncoding RNA, have recently been recognized as key factors in tumor development, but the role of exosome circRNAs derived from adipose tissues has not been defined yet. Here, adipose-secreted circRNAs were found to regulate deubiquitination in HCC, thus facilitating cell growth. It was observed that exosome circ-deubiquitination (circ-DB) is upregulated in HCC patients with higher body fat ratios. Moreover, in vitro and in vivo studies showed that exo-circ-DB promotes HCC growth and reduces DNA damage via the suppression of miR-34a and the activation of deubiquitination-related USP7. Finally, the results showed that the effects of adipose exosomes on HCC cells can be reversed by knockdown of circ-DB. These results indicate that exosome circRNAs secreted from adipocytes promote tumor growth and reduce DNA damage by suppressing miR-34a and activating the USP7/Cyclin A2 signaling pathway.