A LATS2 and ALKBH5 positive feedback loop supports their oncogenic roles.

N(6)-methyladenosine (m6A) critically regulates RNA dynamics in various biological processes. The m6A demethylase ALKBH5 promotes tumorigenesis of glioblastoma, while the intricate web that orchestrates its regulation remains enigmatic. Here, we discover that cell density affects ALKBH5 subcellular localization and m6A dynamics. Mechanistically, ALKBH5 is phosphorylated by the large tumor suppressor kinase 2 (LATS2), preventing its nuclear export and enhancing protein stability. Furthermore, phosphorylated ALKBH5 reciprocally erases m6A from LATS2 mRNA, thereby stabilizing this transcript. Unexpectedly, LATS2 depletion suppresses glioblastoma stem cell self-renewal independent of yes-associated protein activation. Additionally, deficiency in either LATS2 or ALKBH5 phosphorylation impedes tumor progression in mouse xenograft models. Moreover, high levels of LATS2 expression and ALKBH5 phosphorylation are associated with tumor malignancy in patients with gliomas. Collectively, our study unveils an oncogenic positive feedback loop between LATS2 and ALKBH5, revealing a non-canonical branch of the Hippo pathway for RNA processing and suggesting potential anti-cancer interventions.

The global research of artificial intelligence in lung cancer: a 20-year bibliometric analysis.

Background: Lung cancer (LC) is the second-highest incidence and the first-highest mortality cancer worldwide. Early screening and precise treatment of LC have been the research hotspots in this field. Artificial intelligence (AI) technology has advantages in many aspects of LC and widely used such as LC early diagnosis, LC differential classification, treatment and prognosis prediction. Objective: This study aims to analyze and visualize the research history, current status, current hotspots, and development trends of artificial intelligence in the field of lung cancer using bibliometric methods, and predict future research directions and cutting-edge hotspots. Results: A total of 2931 articles published between 2003 and 2023 were included, contributed by 15,848 authors from 92 countries/regions. Among them, China (40%) with 1173 papers,USA (24.80%) with 727 papers and the India(10.2%) with 299 papers have made outstanding contributions in this field, accounting for 75% of the total publications. The primary research institutions were Shanghai Jiaotong University(n=66),Chinese Academy of Sciences (n=63) and Harvard Medical School (n=52).Professor Qian Wei(n=20) from Northeastern University in China were ranked first in the top 10 authors while Armato SG(n=458 citations) was the most co-cited authors. Frontiers in Oncology(121 publications; IF 2022,4.7; Q2) was the most published journal. while Radiology (3003 citations; IF 2022, 19.7; Q1) was the most co-cited journal. different countries and institutions should further strengthen cooperation between each other. The most common keywords were lung cancer, classification, cancer, machine learning and deep learning. Meanwhile, The most cited papers was Nicolas Coudray et al.2018.NAT MED(1196 Total Citations). Conclusions: Research related to AI in lung cancer has significant application prospects, and the number of scholars dedicated to AI-related research on lung cancer is continually growing. It is foreseeable that non-invasive diagnosis and precise minimally invasive treatment through deep learning and machine learning will remain a central focus in the future. Simultaneously, there is a need to enhance collaboration not only among various countries and institutions but also between high-quality medical and industrial entities.

PRRSV degrades MDA5 via dual autophagy receptors P62 and CCT2 to evade antiviral innate immunity.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically devastating pathogen that has evolved various strategies to evade innate immunity. Downregulation of antiviral interferon largely promotes PRRSV immunoevasion by utilizing cytoplasmic melanoma differentiation-associated gene 5 (MDA5), a receptor that senses viral RNA. In this study, the downregulated transcription and expression levels of porcine MDA5 in PRRSV infection were observed, and the detailed mechanisms were explored. We found that the interaction between P62 and MDA5 is enhanced due to two factors: the phosphorylation modification of the autophagic receptor P62 by the upregulated kinase CK2α and the K63 ubiquitination of porcine MDA5 catalyzed by the E3 ubiquitinase TRIM21 in PRRSV-infected cells. As a result of these modifications, the classic P62-mediated autophagy is triggered. Additionally, porcine MDA5 interacts with the chaperonin containing TCP1 subunit 2 (CCT2), which is enhanced by PRRSV nsp3. This interaction promotes the aggregate formation and autophagic clearance of MDA5-CCT2-nsp3 independently of ubiquitination. In summary, enhanced MDA5 degradation occurs in PRRSV infection via two autophagic pathways: the binding of MDA5 with the autophagy receptor P62 and the aggrephagy receptor CCT2, leading to intense innate immune suppression. The research reveals a novel mechanism of immune evasion in PRRSV infection and provides fundamental insights for the development of new vaccines or therapeutic strategies.

Identifying prognostic genes related PANoptosis in lung adenocarcinoma and developing prediction model based on bioinformatics analysis.

Cell death-related genes indicate prognosis in cancer patients. PANoptosis is a newly observed form of cell death that researchers have linked to cancer cell death and antitumor immunity. Even so, its significance in lung adenocarcinomas (LUADs) has yet to be elucidated. We extracted and analyzed data on mRNA gene expression and clinical information from public databases in a systematic manner. These data were utilized to construct a reliable risk prediction model for six regulators of PANoptosis. The Gene Expression Omnibus (GEO) database validated six genes with risk characteristics. The prognosis of LUAD patients could be accurately estimated by the six-gene-based model: NLR family CARD domain-containing protein 4 (NLRC4), FAS-associated death domain protein (FADD), Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), Receptor-interacting serine/threonine-protein kinase 1 (RIPK1), Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), and Mixed lineage kinase domain-like protein (MLKL). Group of higher risk and Cluster 2 indicated a poor prognosis as well as the reduced expression of immune infiltrate molecules and human leukocyte antigen. Distinct expression of PANoptosis-related genes (PRGs) in lung cancer cells was verified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, we evaluated the relationship between PRGs and somatic mutations, tumor immune dysfunction exclusion, tumor stemness indices, and immune infiltration. Using the risk signature, we conducted analyses including nomogram construction, stratification, prediction of small-molecule drug response, somatic mutations, and chemotherapeutic response.

ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis-mediated neoplastic fibrocyte generation in myeloproliferative neoplasms.

Apart from the central role of the activated JAK/STAT signaling pathway, ASXL1 mutations are the most recurrent additional mutations in myeloproliferative neoplasms and occur much more commonly in myelofibrosis than in essential thrombocythemia and polycythemia vera. However, the mechanism of the association with ASXL1 mutations and bone marrow fibrosis remains unknown. Here, integrating our own data from patients with myeloproliferative neoplasms and a hematopoietic-specific Asxl1 deletion/Jak2V617F mouse model, we show that ASXL1 mutations are associated with advanced myeloproliferative neoplasm phenotypes and onset of myelofibrosis. ASXL1 mutations induce skewed monocyte/macrophage and neoplastic monocyte-derived fibrocyte differentiation, consequently they enhance inflammation and bone marrow fibrosis. Consistently, the loss of ASXL1 and JAK2V617F mutations in hematopoietic stem and progenitor cells leads to enhanced activation of polycomb group target genes, such as EGR1. The upregulation of EGR1, in turn, accounts for increased hematopoietic stem and progenitor cell commitment to the monocyte/macrophage lineage. Moreover, EGR1 induces the activation of TNFA and thereby further drives the differentiation of monocytes to fibrocytes. Accordingly, combined treatment with a TNFR antagonist and ruxolitinib significantly reduces fibrocyte production in vitro. Altogether, these findings demonstrate that ASXL1 mutations accelerate fibrocyte production and inflammation in myeloproliferative neoplasms via the EGR1-TNFA axis, explaining the cellular and molecular basis for bone marrow fibrosis and the proof-ofconcept for anti-fibrosis treatment.

Construction and validation of prognostic signature for hepatocellular carcinoma basing on hepatitis B virus related specific genes.

BACKGROUND: Hepatocellular carcinoma (HCC) is a frequent primary liver cancer, and it is one of the leading cause of cancer-related deaths. Hepatitis B virus (HBV) infection is a crucial risk factor for HCC. Thus, this study aimed to explore the prognostic role of HBV-positive HCC related specific genes in HCC. METHODS: The HCC related data were downloaded from three databases, including The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO). Univariate Cox regression analysis and LASSO Cox regression analysis were conducted to build the Risk score. Multivariate Cox regression analysis and survival analysis determined the independent prognostic indicators. RESULTS: After cross analysis of differentially expressed genes (DEGs), we have identified 106 overlapped DEGs, which were probably HBV-positive HCC related specific genes. These 106 DEGs were significantly enriched in 213 GO terms and 8 KEGG pathways. Among that, 11 optimal genes were selected to build a Risk score, and Risk score was an independent prognostic factor for HCC. High risk HCC patients had worse OS. Moreover, five kinds of immune cells were differentially infiltrated between high and low risk HCC patients. CONCLUSION: The prognostic signature, based on HMMR, MCM6, TPX2, KIF20A, CCL20, RGS2, NUSAP1, FABP5, FZD6, PBK, and STK39, is conducive to distinguish different prognosis of HCC patients.

The Otubain YOD1 Suppresses Aggregation and Activation of the Signaling Adaptor MAVS through Lys63-Linked Deubiquitination.

MAVS is a critical adaptor required for activating an innate antiviral immune response against viral infection. The activation of MAVS requires modification of the Lys63-linked ubiquitination and formation of prion-like aggregates. However, the molecular mechanisms regulating MAVS activity remain largely obscured. In this study, we identified a deubiquitinase YOD1, also known as a member of the ovarian tumor family, as a negative regulator of MAVS activation in both human and murine cells. YOD1 was recruited to mitochondria to interact with MAVS through its UBX and Znf domains after viral infection. Subsequently, YOD1 cleaved the K63-linked ubiquitination and abrogated the formation of prion-like aggregates of MAVS, which led to attenuation of IRF3, P65 activation, and IFN-ß production. Knockdown of YOD1 potentiated IRF3 and P65 activation, IFN-ß production, and antiviral innate immune response to RNA virus. Our findings thus provided, to our knowledge, novel insights into the regulatory cascade of the cellular antiviral response through YOD1-mediated K63-linked deubiquitination and aggregation of MAVS.

SNF5 deficiency induces apoptosis resistance by repressing SATB1 expression in Sézary syndrome.

SNF5, is a core member of the SWI/SNF chromatin remodeling complex. It's deficiency leads to multiple types of aggressive cancer. Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma, is characterized by its resistance to apoptosis. Although the cause of apoptosis resistance is still poorly understood, recent evidence has revealed the importance of SATB1 in the apoptosis resistance of Sézary syndrome. In this study, we show that SNF5 is an upstream regulator of SATB1 in several conditions and that both are deficient in Sézary cells. Additionally, SNF5 not only controls the expression of SATB1, but also utilizes SATB1 to recruit itself to specific sites. Overexpression of SNF5 induces SATB1 expression and partially reverse apoptosis resistance phenotype in Sézary cells. These results suggest that both SNF5 and SATB1 may regulate apoptosis-related genes in Sézary syndrome. Thus, targeting SWI/SNF complex may represent a promising approach for Sézary syndrome therapy.

Insulin-like growth factor 2 axis supports the serum-independent growth of malignant rhabdoid tumor and is activated by microenvironment stress.

Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers. Here, we evaluated the role of IGF2 axis in MRT cell proliferation. We showed that microenvironment stress, including starvation treatment and chemotherapy exposure, lead to elevated expression of IGF2 in the SNF5-deficient MRT cell line. The autocrine IGF2, in turn, activated insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), followed by PI3K/AKT pathway and RAS/ERK pathway to promote cancer cell proliferation and survival. We further demonstrated that impairment of IGF2 signaling by IGF2 neutralizing antibody, IGF1R inhibitor NVP-AEW541 or AKT inhibitor MK-2206 2HCl treatment prevented MRT cell growth in vitro. Taken together, our characterization of this axis defines a novel mechanism for MRT cell growth in the microenvironment of stress. Our results also demonstrated the necessity to test the treatment effect targeting this axis in future research.

Syndecan-4 negatively regulates antiviral signalling by mediating RIG-I deubiquitination via CYLD.

Retinoic acid-inducible gene I (RIG-I) plays important roles in pathogen recognition and antiviral signalling transduction. Here we show that syndecan-4 (SDC4) is a RIG-I-interacting partner identified in a yeast two-hybrid screen. We find that SDC4 negatively regulates the RIG-I-mediated antiviral signalling in a feedback-loop control manner. The genetic evidence obtained by using knockout mice further emphasizes this biological role of SDC4 in antiviral signalling. Mechanistically, we show that SDC4 interacts with both RIG-I and deubiquitinase CYLD via its carboxyl-terminal intracellular region. SDC4 likely promotes redistribution of RIG-I and CYLD in a perinuclear pattern post viral infection, and thus enhances the RIG-I-CYLD interaction and potentiates the K63-linked deubiquitination of RIG-I. Collectively, our findings uncover a mechanism by which SDC4 antagonizes the activation of RIG-I in a CYLD-mediated deubiquitination-dependent process, thereby balancing antiviral signalling to avoid deleterious effects on host cells.