The major products of the trichothecene mycotoxin biosynthetic pathway produced in a species-and sometimes isolatespecific manner by cereal-pathogenic Fusarium fungi include T-2 toxin, diacetoxyscirpenol, deoxynivalenol and nivalenol. This paper briefly reviews the major effects of such trichothecenes on the gross morphology, cytology and molecular signalling within eukaryotic cells. The gross toxic effects of select trichothecenes on animals include growth retardation, reduced ovarian function and reproductive disorders, immuno-compromization, feed refusal and vomiting. The phytotoxic effects of deoxynivalenol on plants can be summarized as growth retardation, inhibition of seedling and green plant regeneration. Trichothecenes are now recognized as having multiple inhibitory effects on eukaryote cells, including inhibition of protein, DNA and RNA synthesis, inhibition of mitochondrial function, effects on cell division and membrane effects. In animal cells, they induce apoptosis, a programmed cell death response. Current knowledge about the eukaryotic signal transduction cascades and downstream gene products activated by trichothecenes is limited, especially in plants. In mammalian cells, certain trichothecenes trigger a ribotoxic stress response and activate mitogen-activated protein kinases. DON mediates the inflammatory response by modulating the binding activities of specific transcription factors and subsequently inducing cytokine gene expression. Several genes are up-regulated in wheat in response to trichothecene mycotoxins; the significance, if any, of these genes in the host response to trichothecenes has yet to be elucidated.

HOTAIR is a long noncoding RNA (lncRNA) that is transcribed from the antisense strand of HOXC gene locus in chromosome 12. HOTAIR coordinates with chromatin modifying enzymes and regulates gene silencing. It is overexpressed in various carcinomas including breast cancer. Herein, we demonstrated that HOTAIR is crucial for cell growth and viability and its knockdown induced apoptosis in breast cancer cells. We also demonstrated that HOTAIR is transcriptionally induced by estradiol (E2). Its promoter contains multiple functional estrogen-response-elements (EREs). Estrogen receptors (ERs) along with various ER-coregulators such as histone methylases MLL1 and MLL3 and CBP/p300 bind to the promoter of HOTAIR in an E2-dependent manner. Level of histone H3K4-trimethylation, histone acetylation and RNA polymerase II recruitment is enriched at the HOTAIR promoter in presence of E2. Knockdown of ERs and MLLs down regulated the E2-induced HOTAIR expression. Thus, similar to protein coding gene transcription, E2-induced transcription of antisense transcript HOTAIR is coordinated via ERs and ER-coregulators and this mechanism of HOTAIR over expression potentially contributes towards breast cancer progression.

Long-non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia inducible lncRNA, up-regulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal and hypoxia-dependent molecular reprogramming. Amongst the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Down-regulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome/targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context.

Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in cancer, including by conveying tumor-promoting microRNAs between cells, but their regulation is poorly understood. In this study, we report the findings of a comparative microRNA profiling and functional analysis in human glioblastoma (GBM) that identifies miR-1 as an orchestrator of EV function and GBM growth and invasion. Ectopic expression of miR-1 in GBM cells blocked in vivo growth, neovascularization and invasiveness. These effects were associated with a role for miR-1 in intercellular communication in the microenvironment mediated by EVs released by cancer stem-like GBM cells. An EV-dependent phenotype defined by GBM invasion, neurosphere growth and endothelial tube formation was mitigated by loading miR-1 into GBM-derived EVs. Protein cargo in EVs was characterized to learn how miR-1 directed EV function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in GBM-derived EVs, was found to be a direct target of miR-1 control. In addition, EV-derived miR-1 along with other ANXA2 EV networking partners targeted multiple pro-oncogenic signals in cells within the GBM microenvironment. Together, our results showed how EV signalling promotes the malignant character of GBM and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for GBM management.