Dysregulation of the miR-30c/DLL4 axis by circHIPK3 is essential for KSHV lytic replication.

Non-coding RNA (ncRNA) regulatory networks are emerging as critical regulators of gene expression. These intricate networks of ncRNA:ncRNA interactions modulate multiple cellular pathways and impact the development and progression of multiple diseases. Herpesviruses, including Kaposi's sarcoma-associated herpesvirus, are adept at utilising ncRNAs, encoding their own as well as dysregulating host ncRNAs to modulate virus gene expression and the host response to infection. Research has mainly focused on unidirectional ncRNA-mediated regulation of target protein-coding transcripts; however, we identify a novel host ncRNA regulatory network essential for KSHV lytic replication in B cells. KSHV-mediated upregulation of the host cell circRNA, circHIPK3, is a key component of this network, functioning as a competing endogenous RNA of miR-30c, leading to increased levels of the miR-30c target, DLL4. Dysregulation of this network highlights a novel mechanism of cell cycle control during KSHV lytic replication in B cells. Importantly, disruption at any point within this novel ncRNA regulatory network has a detrimental effect on KSHV lytic replication, highlighting the essential nature of this network and potential for therapeutic intervention.

Platelet-derived microvesicles isolated from type-2 diabetes mellitus patients harbour an altered miRNA signature and drive MDA-MB-231 triple-negative breast cancer cell invasion.

The underlying causes of breast cancer are diverse, however, there is a striking association between type 2 diabetes and poor patient outcomes. Platelet activation is a common feature of both type 2 diabetes and breast cancer and has been implicated in tumourigenesis through a multitude of pathways. Here transcriptomic analysis of type 2 diabetes patient-derived platelet microvesicles revealed an altered miRNA signature compared with normoglycaemic control patients. Interestingly, interrogation of these data identifies a shift towards an oncogenic signature in type 2 diabetes-derived platelet microvesicles, with increased levels of miRNAs implicated in breast cancer progression and poor prognosis. Functional studies demonstrate that platelet microvesicles isolated from type 2 diabetes patient blood are internalised by triple-negative breast cancer cells in vitro, and that co-incubation with type 2 diabetes patient-derived platelet microvesicles led to significantly increased expression of epithelial to mesenchymal transition markers and triple-negative breast cancer cell invasion compared with platelet microvesicles from healthy volunteers. Together, these data suggest that circulating PMVs in type 2 diabetes patients may contribute to the progression of triple-negative breast cancer.

The Hippo pathway transcription factors YAP and TAZ play HPV-type dependent roles in cervical cancer.

Human papillomaviruses (HPVs) cause most cervical cancers and an increasing number of anogenital and oral carcinomas, with most cases caused by HPV16 or HPV18. HPV hijacks host signalling pathways to promote carcinogenesis. Understanding these interactions could permit identification of much-needed therapeutics for HPV-driven malignancies. The Hippo signalling pathway is important in HPV+ cancers, with the downstream effector YAP playing a pro-oncogenic role. In contrast, the significance of its paralogue TAZ remains largely uncharacterised in these cancers. We demonstrate that TAZ is dysregulated in a HPV-type dependent manner by a distinct mechanism to that of YAP and controls proliferation via alternative cellular targets. Analysis of cervical cancer cell lines and patient biopsies revealed that TAZ expression was only significantly increased in HPV18+ and HPV18-like cells and TAZ knockdown reduced proliferation, migration and invasion only in HPV18+ cells. RNA-sequencing of HPV18+ cervical cells revealed that YAP and TAZ have distinct targets, suggesting they promote carcinogenesis by different mechanisms. Thus, in HPV18+ cancers, YAP and TAZ play non-redundant roles. This analysis identified TOGARAM2 as a previously uncharacterised TAZ target and demonstrates its role as a key effector of TAZ-mediated proliferation, migration and invasion in HPV18+ cancers.

Decosus: An R Framework for Universal Integration of Cell Proportion Estimation Methods.

The assessment of the cellular heterogeneity and abundance in bulk tissue samples is essential for characterising cellular and organismal states. Computational approaches to estimate cellular abundance from bulk RNA-Seq datasets have variable performances, often requiring benchmarking matrices to select the best performing methods for individual studies. However, such benchmarking investigations are difficult to perform and assess in typical applications because of the absence of gold standard/ground-truth cellular measurements. Here we describe Decosus, an R package that integrates seven methods and signatures for deconvoluting cell types from gene expression profiles (GEP). Benchmark analysis on a range of datasets with ground-truth measurements revealed that our integrated estimates consistently exhibited stable performances across datasets than individual methods and signatures. We further applied Decosus to characterise the immune compartment of skin samples in different settings, confirming the well-established Th1 and Th2 polarisation in psoriasis and atopic dermatitis, respectively. Secondly, we revealed immune system-related UV-induced changes in sun-exposed skin. Furthermore, a significant motivation in the design of Decosus is flexibility and the ability for the user to include new gene signatures, algorithms, and integration methods at run time.