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mRNA 3' end processing is an essential step in gene expression. It is well established that canonical eukaryotic pre-mRNA 3' processing is carried out within a macromolecular machinery consisting of dozens of trans-acting proteins. However, it is unknown whether RNAs play any role in this process. Unexpectedly, we found that a subset of small nucleolar RNAs (snoRNAs) are associated with the mammalian mRNA 3' processing complex. These snoRNAs primarily interact with Fip1, a component of cleavage and polyadenylation specificity factor (CPSF). We have functionally characterized one of these snoRNAs and our results demonstrated that the U/A-rich SNORD50A inhibits mRNA 3' processing by blocking the Fip1-poly(A) site (PAS) interaction. Consistently, SNORD50A depletion altered the Fip1-RNA interaction landscape and changed the alternative polyadenylation (APA) profiles and/or transcript levels of a subset of genes. Taken together, our data revealed a novel function for snoRNAs and provided the first evidence that non-coding RNAs may play an important role in regulating mRNA 3' processing.

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone‐metastasis remain largely unknown. In the current study, HCC‐secreted lectin galactoside‐binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone‐metastasis‐free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal‐related events by forming a bone pre‐metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219‐meidated α‐catenin degradation prompts YAP1/β‐catenin complex‐dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC‐secreted LGALS3 in pre‐metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone‐metastasis. [ABSTRACT FROM AUTHOR]

Abdominal exploration revealed ruptured spleen and gastric herniation caused by left hemidiaphragm rupture. Combined with the above symptoms and imaging examinations, we performed exploratory laparotomy and found dense adhesion between the stomach, diaphragm, and abdominal wall. [Extracted from the article]

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α -catenin degradation prompts YAP1/ β -catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley‐VCH GmbH.)

The N 6 -methyladenosine (m 6 A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m 6 A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m 6 A modification peaks were enriched at metabolic pathway-related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m 6 A modification levels of serine- and arginine-rich splicing factors ( SRSF ), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m 6 A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression. SIGNIFICANCE: These findings establish the oncogenic role of m 6 A writer METTL3 in glioblastoma stem cells., (©2019 American Association for Cancer Research.)