UNASSIGNED: Colon adenocarcinoma (COAD) is one of the leading causes of cancer death worldwide. Alternative polyadenylation (APA) is relevant to the variability of the 3\'-UTR of mRNA. However, the posttranscriptional dysregulation of APA in COAD is poorly understood.
UNASSIGNED: We collected APA data from The Cancer Genome Atlas (TCGA) COAD (n =7692). APA events were evaluated using PDUI values, and the prognostically significant APA events were screened by LASSO Cox regression to construct a prognostic model. Then, prognostic model functions and possible regulatory genes of characteristic APA events were analyzed. Finally, the immune regulatory network based on APA regulatory genes was analyzed and established.
UNASSIGNED: A total of 95 APA events were found to influence the COAD outcomes. Among them, 39 genes were screened as characteristic prognostic APA events by LASSO Cox regression to construct a COAD prognostic signature. The analysis results suggested that a high signature score was associated with poor prognosis and was significantly correlated with a variety of immune cells, including NK and Th1, 2 and 17 cells. Further analysis showed that APA regulators mainly served roles in the prognosis of COAD. Based on the above results, we constructed an immunoregulatory network for APA regulatory genes-APA genes-immune cells.
UNASSIGNED: Our study revealed that APA events in COAD may regulate tumor progression by influencing immune cells, which provides a new direction for exploring the influencing mechanism of the tumor immune microenvironment and is expected to provide a potential new target for COAD immunotherapy.

Transcriptome analysis of head and neck squamous cell carcinoma (HNSCC) has been pivotal to comprehending the convoluted biology of HNSCC tumors. MAPKAPK2 or MK2 is a critical modulator of the mRNA turnover of crucial genes involved in HNSCC progression. However, MK2-centric transcriptome profiles of tumors are not well known. This study delves into HNSCC progression with MK2 at the nexus to delineate the biological relevance and intricate crosstalk of MK2 in the tumor milieu. We performed next-generation sequencing-based transcriptome profiling of HNSCC cells and xenograft tumors to ascertain mRNA expression profiles in MK2-wild type and MK2-knockdown conditions. The findings were validated using gene expression assays, immunohistochemistry, and transcript turnover studies. Here, we identified a pool of crucial MK2-regulated candidate genes by annotation and differential gene expression analyses. Regulatory network and pathway enrichment revealed their significance and involvement in the HNSCC pathogenesis. Additionally, 3\'-UTR-based filtering recognized important MK2-regulated downstream target genes and validated them by nCounter gene expression assays. Finally, immunohistochemistry and transcript stability studies revealed the putative role of MK2 in regulating the transcript turnover of IGFBP2, MUC4, and PRKAR2B in HNSCC. Conclusively, MK2-regulated candidate genes were identified in this study, and their plausible involvement in HNSCC pathogenesis was elucidated. These genes possess investigative values as targets for diagnosis and therapeutic interventions for HNSCC.

In the messenger RNA (mRNA) maturation process, the 3\'-end of pre-mRNA is cleaved and a poly(A) sequence is added, this is an important determinant of mRNA stability and its cellular functions. More than 60%-70% of human genes have three or more polyadenylation (APA) sites and can be cleaved at different sites, generating mRNA transcripts of varying lengths. This phenomenon is termed as alternative cleavage and polyadenylation (APA) and it plays role in key biological processes like gene regulation, cell proliferation, senescence, and also in various human diseases. Loss of regulatory microRNA binding sites and interactions with RNA-binding proteins leading to APA are largely investigated in human diseases. However, the functions of the core APA machinery and related factors during disease conditions remain largely unknown. In this review, we discuss the roles of polyadenylation machinery in relation to brain disease, cardiac failure, pulmonary fibrosis, cancer, infectious conditions, and other human diseases. Collectively, we believe this review will be a useful avenue for understanding the emerging role of APA in the pathobiology of various human diseases.

PCSK9 has emerged as a promising new therapeutic target for hyperlipidemia. The efficacy of PCSK9 siRNA in clinic trials clues the feasibility of exploring more PCSK9 inhibitors based on genetic inhibition in the treatment of hyperlipidemia. MicroRNAs (miRNAs) as a class of endogenous non-coding small RNAs can regulate genes at transcriptional and/or translational level. Here, we screened miRNAs from the prediction of TargetScan database with possible inhibitory activities in PCSK9 protein level via AlphaLISA and Western blotting, in which miR-552-3p was selected out for its strongest inhibitory effect. MiR-552-3p could bind to the 3\' untranslated region (3\'-UTR) of PCSK9 to inhibit translation and interact with the promoter of PCSK9 to suppress transcription. Further in vitro and in vivo experiments proved the effects of miR-552-3p on PCSK9 and downstream effectors: it could increase LDLR protein level, promote LDL-C uptake in HepG2 cells and lower serum LDL-C in high fat diet (HFD)-fed mice. In conclusion, our findings firstly identified miR-552-3p as a new PCSK9 inhibitor with the dual-inhibition mechanism, which suggested the possible application of miR-552-3p in the treatment of hyperlipidemia.

Background: Human leukocyte antigen G belongs to the family of non-classical HLA class I genes, its expression considered an important immune escape mechanism of cancer cells. The polymorphisms in the 3\'-untranslated region (UTR) region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. We hypothesised links between any of eight (UTR) single nucleotide polymorphisms (SNPs) and their haplotype of the HLA-G gene with breast cancer. Materials and Methods: Peripheral blood DNA from 100 patients affected by breast cancer and 100 controls was PCR sequenced for genotyping of 25 HLA-G 3\'-UTR regions, including rs371194629 (+2960), rs1707 (+3003), rs1710 (+3010), rs17179101 (+3027), rs1063320 (+3142), rs9380142 (+3187), rs1610696 (+3196), and rs1233331 (+3227). Results: The 14-bp deletion (p = 0.01), and the +3010 (p = 0.021), +3142 (p = 0.006) and +3187 (p = 0.046) variants were significantly more prevalent in patients than in controls. In combining these data, two haplotypes of all eight SNPs and deletion/insertion (UTR-1 and UTR-4) are associated with breast cancer. Conclusion: Certain variants in the 3-UTR, and their combination as a haplotype, of the HLA-G gene are linked to breast cancer.

To investigate the role of Tobacco vein banding mosaic virus (TVBMV) 3\'-UTR in virus systemic infection, three types of deletions were introduced into TVBMV infectious clone pCaTVBMV-GFP. Mutants with deletions at the nucleotide position 8-42, 43-141, or 163-174 in the 3\'-UTR failed to cause systemic infection in N. benthamiana plants. Other deletion mutants caused delayed systemic infection and milder vein clearing and mosaic symptoms. Most progeny mutant virus had acquired nucleotides, similar to or different from the deleted nucleotide sequences, after a single passage in the host plant. Nucleotides at the position 8-42 near the 5\'-terminus of TVBMV 3\'-UTR could form a stem-loop (SL) like structure which was crucial for TVBMV systemic movement in tobacco. We proposed that this SL like structure, and thus 3\'-UTR, has an essential role in TVBMV systemic infection.

Mitochondrial antiviral signaling (MAVS) gene plays a key role in antiviral regulation in mammals potentially by activating IRF3/7 and NF-κB and leading to the induction of type I interferon (IFN)-mediated antiviral and inflammatory responses. In this study, we screened genetic polymorphisms of the MAVS gene in various Chinese domestic chicken breeds/populations and evaluated its potential effect on gene expression. Among the sequenced fragment (4678bp), a total of 75 single nucleotide polymorphisms (SNPs) were identified in 46 chickens from 10 breeds/populations, including 30 coding SNPs and 45 non-coding SNPs. Extremely high haplotype diversity (37 nucleotide haplotypes, 18 amino acid haplotypes) was observed in the coding region (CDS), and a similar pattern of high polymorphisms was also observed for the 3\'-untranslated region (3\'-UTR). Luciferase assays of two representative 3\'-UTR haplotypes were performed in both HEK293 cells and DF-1 chicken fibroblast cells, and we found that they were differentially associated with different abilities on regulating mRNA expression level (P<0.05). Collectively, we observed a considerably high genetic variability of the MAVS gene, and the 3\'-UTR variants had an ability to regulate mRNA expression. These results would cast some clues on understanding the potential role of MAVS on viral resistance in chicken.