Graphical AbstractHighlights d Constructed comprehensive structural maps of ZIKV RNA genomes in infected cells d Discovered functional RNA structural elements in ZIKV genomes d Identified an Asian lineage-specific RNA-RNA interaction that affects ZIKV infectivity SUMMARY Zika virus (ZIKV) strains can be classified into the ancestral African and contemporary Asian lineages, with the latter responsible for recent epidemics associated with neurological conditions. To understand how Asian strains lead to exacerbated disease, a crucial step is identifying genomic variations that affect infectivity and pathogenicity. Here we use two high-throughput sequencing approaches to assess RNA secondary structures and intramolecular RNA-RNA interactions in vivo for the RNA genomes of Asian and African ZIKV lineages. Our analysis identified functional RNA structural elements and a functional long-range intramolecular interaction specific for the Asian epidemic strains. Mutants that disrupt this extended RNA interaction between the 5 0 UTR and the E protein coding region reduce virus infectivity, which is partially rescued with compensatory mutants, restoring this RNA-RNA interaction. These findings illuminate the structural basis of ZIKV regulation and provide a resource for the discovery of RNA structural elements important for ZIKV infection.

Emerging evidence has identified the vital role of long noncoding RNAs (lncRNAs) in the development of colorectal cancer. In this study, we aimed to investigate the role of lncRNA gastric carcinoma highly expressed transcript 1 (GHET1) in colorectal cancer. We analyzed the expression of GHET1 in colorectal cancer (CRC) tissues by using ISH. We found that GHET1 expression was significantly increased in the CRC samples compared with adjacent tissues. Furthermore, the cancer tissues had higher GHET1 mRNA levels than their matched adjacent tissues. GHET1 expression was also significantly increased in the CRC cell lines compared with human normal colon epithelial cells. Downregulation of GHET1 mediated by shRNA suppressed the proliferation, cell cycle arrest, migration, and invasion of colorectal cancer cells in vitro. In addition, inhibition of GHET1 reversed the epithelial-mesenchymal transition in colorectal cancer cell lines. Taken together, our results suggest the potential use of GHET1 as a therapeutic target of colorectal cancer.

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.

BackgroundInterleukin-24(IL-24), also referred to as melanoma differentiation-associated gene-7(mda-7), is a unique member of the IL-10 gene family, which displays nearly ubiquitous cancer-specific toxicity. The most notable feature of IL-24 is selectively induced growth suppression and apoptosis in various cancer cells, with no harmful effects toward normal cells. Autophagy is a self-protective mechanism in many kinds of tumor cells that respond to anticancer treatment. It is reported that autophagy inhibition could enhance the effects of many kinds of anticancer treatments, including gene therapy. However, whether IL-24 is effective to treat oral squamous cell carcinomas (OSCC) and if autophagy inhibition could improve the anticancer effect of IL-24 towards OSCC is has not been detected.MethodsMTT assays were carried out to determine the cell proliferation; Transfection was used to gene transfer; Western Blot was performed to detect the protein level of LC3II, P62, Beclin 1, Cleaved caspase-3, β-Tubulin and β-actin; Apoptosis rates and cell cycle alteration were analyzed using flow cytometry; Autophagy induction was confirmed by MDC staining, GFP-LC3 staining and transmission electron microscopy. Amount of IL-24 in the culture medium was quantified by ELISA. Apoptosis in vivo was analyzed by TUNEL assay. HE staining was used to observe the morphology of the samples.ResultsIn the present study, we proved that IL-24 have a novel anticancer effect towards KB cells and that autophagy inhibition could improve the anticancer effect of IL-24. IL-24 treated cells showed autophagy characteristics and autophagy inhibition by 3-methyladenine (3-MA) significantly enhanced IL-24-induced apoptosis. Similar results were obtained in the KB cells xenograft tumor model.ConclusionsThese results suggest that the combination of autophagy inhibitors and IL-24 based on the AdLTR2EF1α-mediated gene transfer could be a promising way to cure OSCC.

The transcription factor p63 is a member of the p53 gene family that plays a complex role in cancer due to its involvement in epithelial differentiation, cell cycle arrest and apoptosis. MicroRNAs are a class of small, non-coding RNAs with an important regulatory role in various cellular processes, as well as in the development and progression of cancer. A number of microRNAs have been shown to function as transcriptional targets of p63. Conversely, microRNAs also can modulate the expression and activity of p63. However, the p63–microRNA regulatory circuit has not been addressed in depth so far. Here, computational genomic analysis was performed using miRtarBase, Targetscan, microRNA.ORG, DIANA-MICROT, RNA22-HSA and miRDB to analyze miRNA binding to the 3′UTR of p63. JASPAR (profile score threshold 80%) and TFSEARCH datasets were used to search transcriptional start sites for p53/p63 response elements. Remarkably, these data revealed 63 microRNAs that targeted p63. Furthermore, there were 39 microRNAs targeting p63 that were predicted to be regulated by p63. These analyses suggest a crosstalk between p63 and microRNAs. Here, we discuss the crosstalk between p63 and the microRNA network, and the role of their interactions in cancer.