BACKGROUND Mounting evidence has suggested the essential role of long non-coding RNAs (lncRNAs) in a plethora of malignant tumors, including hepatocellular carcinoma. However, the underlyling mechanisms of lncRNAs remain unidentified in HCC. The present work was aimed to explore the regulatory functions and mechanisms of LncRNA LNCAROD in HCC progression and chemotherapeutic response. METHODS The expression of LNCAROD in HCC tissues and cell lines were detected by quantitative reverse transcription PCR (qPCR). Cancer cell proliferation, migration, invasion, and chemoresistance were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and chemosensitivity assays. Methylated RNA immunoprecipitation qRCR (MeRIP-qPCR) was used to determine N6-methyladenosine (m6A) modification level. RNA immunoprecipitation (RIP) and RNA pull down were applied to identify the molecular sponge role of LNCAROD for modulation of miR-145-5p via the competing endogenous RNA (ceRNA) mechanism, as well as the interaction between LNCAROD and serine-and arginine-rich splicing factor 3 (SRSF3). The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and LNCAROD was also identified by RIP assay. Gain- or-loss-of-function assays were used to identify the function and underlying mechanisms of LNCAROD in HCC. RESULTS We found that LNCAROD was significantly upregulated and predicted a poorer prognosis in HCC patients. LNCAROD upregulation was maintained by increased m6A methylation-mediated RNA stability. LNCAROD significantly promoted HCC cell proliferation, migration, invasion, and chemoresistance both in vitro and in vivo. Furthermore, mechanistic studies revealed that pyruvate kinase isoform M2 (PKM2)-mediated glycolysis enhancement is critical for the role of LNACROD in HCC. According to bioinformatics prediction and our experimental data, LNCAROD directly binds to SRSF3 to induce PKM switching towards PKM2 and maintains PKM2 levels in HCC by acting as a ceRNA against miR-145-5p. The oncogenic effects of LNCAROD in HCC were more prominent under hypoxia than normoxia due to the upregulation of hypoxia-triggered hypoxia-inducible factor 1α. CONCLUSIONS In summary, our present study suggests that LNCAROD induces PKM2 upregulation via simultaneously enhancing SRSF3-mediated PKM switching to PKM2 and sponging miR-145-5p to increase PKM2 level, eventually increasing cancer cell aerobic glycolysis to participate in tumor malignancy and chemoresistance, especially under hypoxic microenvironment. This study provides a promising diagnostic marker and therapeutic target for HCC patients.

/pdf/lncarod-enhances-hepatocellular-carcinoma-malignancy-by-4gqvja2f9k.pdf

LNCAROD enhances hepatocellular carcinoma malignancy by activating glycolysis through induction of pyruvate kinase isoform PKM2.

Transfer RNAs (tRNAs) harbor the most diverse posttranscriptional modifications. Among such modifications, those in the anticodon loop, either on nucleosides or base groups, compose over half of the identified posttranscriptional modifications. The derivatives of modified nucleotides and the crosstalk of different chemical modifications further add to the structural and functional complexity of tRNAs. These modifications play critical roles in maintaining anticodon loop conformation, wobble base pairing, efficient aminoacylation, and translation speed and fidelity as well as mediating various responses to different stress conditions. Posttranscriptional modifications of tRNA are catalyzed mainly by enzymes and/or cofactors encoded by nuclear genes, whose mutations are firmly connected with diverse human diseases involving genetic nervous system disorders and/or the onset of multisystem failure. In this review, we summarize recent studies about the mechanisms of tRNA modifications occurring at tRNA anticodon loops. In addition, the pathogenesis of related disease-causing mutations at these genes is briefly described.

Modifications of the human tRNA anticodon loop and their associations with genetic diseases

Proline-rich Akt substrate of 40 kD (PRAS40) is not only the substrate of protein kinase B (PKB/Akt), but also the binding protein of 14-3-3 protein. PRAS40 is expressed in a variety of tissues in ...

Targeting PRAS40: a novel therapeutic strategy for human diseases.

Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4-17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF. 

/pdf/identification-of-a-braf-pa28g-mek1-signaling-axis-and-its-23zcvmbd.pdf

Identification of a BRAF/PA28γ/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis

/pdf/intestinal-cellular-heterogeneity-and-disease-development-302wf2fg.pdf

Intestinal cellular heterogeneity and disease development revealed by single-cell technology

Leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), a marker of intestinal stem cells (ISCs), is considered to play key roles in tissue homoeostasis and regeneration after acute radiation injury. However, the activation of Lgr5 by integrated signaling pathways upon radiation remains poorly understood. Here, we show that irradiation of mice with whole-body depletion or conditional ablation of REGγ in Lgr5+ stem cell impairs proliferation of intestinal crypts, delaying regeneration of intestine epithelial cells. Mechanistically, REGγ enhances transcriptional activation of Lgr5 via the potentiation of both Wnt and Hippo signal pathways. TEAD4 alone or cooperates with TCF4, a transcription factor mediating Wnt signaling, to enhance the expression of Lgr5. Silencing TEAD4 drastically attenuated β-catenin/TCF4 dependent expression of Lgr5. Together, our study reveals how REGγ controls Lgr5 expression and expansion of Lgr5+ stem cells in the regeneration of intestinal epithelial cells. Thus, REGγ proteasome appears to be a potential therapeutic target for radiation-induced gastrointestinal disorders.

REGγ drives Lgr5+ stem cells to potentiate radiation induced intestinal regeneration.

Liver damage is a dynamic process, and evaluation of liver injury degree is the key step in disease diagnosis. However, few common markers among different types of liver injury have been reported. Herein, we generated three liver injury mouse models, including Con A-induced, CCl4-injected, and subjected bile duct ligation mouse models, to simulate different types of liver damage in humans and then performed a label-free mass spectrometry to identify differentially expressed proteins in liver tissues. Interestingly, two proteins, G3BP and ABCC6, were conserved regulated in different liver injury models and are proposed to be biomarkers in liver injury, with G3BP upregulated and ABCC6 downregulated. Overall, our study identified two novel biomarkers of liver injury, and they might be used as potential drug targets of liver damage research studies.

Mapping Novel Biomarkers of Liver Injury by Tissue Proteomic Analysis.

Despite significant progression in the study of hepatocellular carcinoma (HCC), the role of the proteasome in regulating cross talk between mTOR signaling and glycolysis in liver cancer progression is not fully understood. Here, we demonstrate that deficiency of REGγ, a proteasome activator, in mice significantly attenuates DEN-induced liver tumor formation. Ablation of REGγ increases the stability of PP2Ac (protein phosphatase 2 catalytic subunit) in vitro and in vivo, which dephosphorylates PRAS40 (AKT1 substrate 1) and stabilizes the interaction between PRAS40 and Raptor to inactive mTORC1-mediated hyper-glycolytic metabolism. In the DEN-induced animal model and clinical hepato-carcinoma samples, high levels of REGγ in HCC tumor regions contribute to reduced expression of PP2Ac, leading to accumulation of phosphorylated PRAS40 and mTORC1-mediated activation of HIF1α. Interestingly, mTORC1 enhances REGγ activity in HCC, forming a positive feedback regulatory loop. In conclusion, our study identifies REGγ-PP2Ac-PRAS40 axis as a new layer in regulating mTORC1 activity and downstream glycolytic alterations during HCC development, highlighting the REGγ-proteasome as a potential target for personalized HCC therapy.

Reciprocal REGγ-mTORC1 regulation promotes glycolytic metabolism in hepatocellular carcinoma

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REGγ drives Lgr5+ stem cells to potentiate radiation induced intestinal regeneration.

Mapping Novel Biomarkers of Liver Injury by Tissue Proteomic Analysis.

Reciprocal REGγ-mTORC1 regulation promotes glycolytic metabolism in hepatocellular carcinoma