RÉSUMÉ
Hypoxia is arguably the first recognized cancer microenvironment hallmark and affects virtually all cellular populations present in tumors. During the past decades the complex adaptive cellular responses to oxygen deprivation have been largely elucidated, raising hope for new anti cancer agents. Despite undeniable preclinical progress, therapeutic targeting of tumor hypoxia is yet to transition from bench to bedside. This review focuses on new pharmacological agents that exploit tumor hypoxia or interfere with hypoxia signaling and discusses strategies to maximize their therapeutic impact.
Sujet(s)
Facteurs de transcription à motif basique hélice-boucle-hélice , Tumeurs , Humains , Facteurs de transcription à motif basique hélice-boucle-hélice/métabolisme , Hypoxie , Transduction du signal , Microenvironnement tumoral , Tumeurs/traitement médicamenteux , Tumeurs/étiologie , Hypoxie cellulaireRÉSUMÉ
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RÉSUMÉ
We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.
Sujet(s)
Homéostasie , Oxygène/métabolisme , ARN long non codant/physiologie , Stérols/biosynthèse , Facteurs de transcription à motif basique hélice-boucle-hélice/métabolisme , Hypoxie cellulaire , Lignée cellulaire tumorale , Noyau de la cellule/métabolisme , Cholestérol/métabolisme , Oestrogènes/métabolisme , Régulation de l'expression des gènes , Étude d'association pangénomique , Ribonucléoprotéine nucléaire hétérogène du groupe C/génétique , Ribonucléoprotéine nucléaire hétérogène du groupe C/métabolisme , Humains , Cellules MCF-7 , Phénotype , Polymorphisme de nucléotide simple , ARN long non codant/génétique , ARN long non codant/métabolismeRÉSUMÉ
SIGNIFICANCE: The emerging connections between an increasing number of long noncoding RNAs (lncRNAs) and oncogenic hallmarks provide a new twist to tumor complexity. Recent Advances: In the present review, we highlight specific lncRNAs that have been studied in relation to tumorigenesis, either as participants in the neoplastic process or as markers of pathway activity or drug response. These transcripts are typically deregulated by oncogenic or tumor-suppressing signals or respond to microenvironmental conditions such as hypoxia. CRITICAL ISSUES: Among these transcripts are lncRNAs sufficiently divergent between mouse and human genomes that may contribute to biological differences between species. FUTURE DIRECTIONS: From a translational standpoint, knowledge about primate-specific lncRNAs may help explain the reason behind the failure to reproduce the results from mouse cancer models in human cell-based systems. Antioxid. Redox Signal. 29, 922-935.