Integrinß-1 in disorders and cancers: molecular mechanisms and therapeutic targets.

Integrinß-1 (ITGB1) is a crucial member of the transmembrane glycoprotein signaling receptor family and is also central to the integrin family. It forms heterodimers with other ligands, participates in intracellular signaling and controls a variety of cellular processes, such as angiogenesis and the growth of neurons; because of its role in bidirectional signaling regulation both inside and outside the membrane, ITGB1 must interact with a multitude of substances, so a variety of interfering factors can affect ITGB1 and lead to changes in its function. Over the past 20 years, many studies have confirmed a clear causal relationship between ITGB1 dysregulation and cancer development and progression in a wide range of benign diseases and solid tumor types, which may imply that ITGB1 is a prognostic biomarker and a therapeutic target for cancer treatment that warrants further investigation. This review summarizes the biological roles of ITGB1 in benign diseases and cancers, and compiles the current status of ITGB1 function and therapy in various aspects of tumorigenesis and progression. Finally, future research directions and application prospects of ITGB1 are suggested. Video Abstract.

SP1-activated USP27X-AS1 promotes hepatocellular carcinoma progression via USP7-mediated AKT stabilisation.

BACKGROUND: Hepatocellular carcinoma (HCC) continues to pose a significant threat to patient survival. Emerging evidence underscores the pivotal involvement of long non-coding RNAs (lncRNAs) in the cancer process. Nevertheless, our understanding of the roles and processes of lncRNAs in HCC remains limited. METHODS: The expression level of USP27X-AS1 was assessed in an HCC patient cohort through a combination of bioinformatics analysis and qRT-PCR. Subsequent biological experiments were conducted to delve into the functional aspects of USP27X-AS1. Additional molecular biology techniques, including RNA pulldown and RNA immunoprecipitation (RIP), were employed to elucidate the potential mechanisms involving USP27X-AS1 in HCC. Finally, CUT-RUN assay and other investigations were carried out to determine the factors contributing to the heightened expression of USP27X-AS1 in HCC. RESULTS: High expression of the novel oncogene USP27X-AS1 predicted poor prognosis in HCC patients. Further investigation confirmed that USP27X-AS1 promoted the proliferation and metastasis of HCC by enabling USP7 to interact with AKT, which reduced level of AKT poly-ubiquitylation and enhanced AKT protein stability, which improves protein stabilisation of AKT and promotes the progression of HCC. Moreover, we also revealed that SP1 binds to USP27X-AS1 promoter to activate its transcription. CONCLUSIONS: Novel oncogenic lncRNA USP27X-AS1 promoted HCC progression via recruiting USP7 to deubiquitinate AKT. SP1 transcriptionally activated USP27X-AS1 expression. These findings shed light on HCC and pointed to USP27X-AS1 as a potential predictive biomarker and treatment target for the malignancy.

The Role of Nuclear Receptors in the Pathogenesis and Treatment of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.

DEAD-Box Helicase 17 exacerbates non-alcoholic steatohepatitis via transcriptional repression of cyp2c29, inducing hepatic lipid metabolism disorder and eliciting the activation of M1 macrophages.

OBJECTIVE: Our study was to elucidate the role of RNA helicase DEAD-Box Helicase 17 (DDX17) in NAFLD and to explore its underlying mechanisms. METHODS: We created hepatocyte-specific Ddx17-deficient mice aim to investigate the impact of Ddx17 on NAFLD induced by a high-fat diet (HFD) as well as methionine and choline-deficient l-amino acid diet (MCD) in adult male mice. RNA-seq and lipidomic analyses were conducted to depict the metabolic landscape, and CUT&Tag combined with chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted. RESULTS: In this work, we observed a notable increase in DDX17 expression in the livers of patients with NASH and in murine models of NASH induced by HFD or MCD. After introducing lentiviruses into hepatocyte L02 for DDX17 knockdown or overexpression, we found that lipid accumulation induced by palmitic acid/oleic acid (PAOA) in L02 cells was noticeably weakened by DDX17 knockdown but augmented by DDX17 overexpression. Furthermore, hepatocyte-specific DDX17 knockout significantly alleviated hepatic steatosis, inflammatory response and fibrosis in mice after the administration of MCD and HFD. Mechanistically, our analysis of RNA-seq and CUT&Tag results combined with ChIP and luciferase reporter assays indicated that DDX17 transcriptionally represses Cyp2c29 gene expression by cooperating with CCCTC binding factor (CTCF) and DEAD-Box Helicase 5 (DDX5). Using absolute quantitative lipidomics analysis, we identified a hepatocyte-specific DDX17 deficiency that decreased lipid accumulation and altered lipid composition in the livers of mice after MCD administration. Based on the RNA-seq analysis, our findings suggest that DDX17 could potentially have an impact on the modulation of lipid metabolism and the activation of M1 macrophages in murine NASH models. CONCLUSION: These results imply that DDX17 is involved in NASH development by promoting lipid accumulation in hepatocytes, inducing the activation of M1 macrophages, subsequent inflammatory responses and fibrosis through the transcriptional repression of Cyp2c29 in mice. Therefore, DDX17 holds promise as a potential drug target for the treatment of NASH.

Disrupting CCDC137-mediated LZTS2 and ß-TrCP interaction in the nucleus inhibits hepatocellular carcinoma development via ß-catenin and AKT.

Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor, with its biological characteristics intricately linked to the activation of oncogenes. This research specifically explored CCDC137, a molecule within the CCDC family exhibiting the closest association with HCC. Our investigation aimed to unravel the role, underlying mechanisms, and potential therapeutic implications of CCDC137 in the context of HCC. We observed a close correlation between elevated CCDC137 expression and poor prognosis in HCC patients, along with a promotive effect on HCC progression in vitro and in vivo. Mechanistically, we identified LZTS2, a negative regulator of ß-catenin, as the binding protein of CCDC137. CCDC137 facilitated K48-linked poly-ubiquitination of LZTS2 at lysine 467 via recruiting E3 ubiquitin ligase ß-TrCP in the nucleus, triggering AKT phosphorylation and activation of ß-catenin pathway. Moreover, the 1-75 domain of CCDC137 was responsible for the formation of the CCDC137-LZTS2-ß-TrCP complex. Subsequently, designed peptides targeting the 1-75 domain of CCDC137 to disrupt CCDC137-LZTS2 interaction demonstrated efficacy in inhibiting HCC progression. This promising outcome was further supported by HCC organoids and patient-derived xenograft (PDX) models, underscoring the potential clinical utility of the peptides. This study elucidated the mechanism of the CCDC137-LZTS2-ß-TrCP protein complex in HCC and offered clinically significant therapeutic strategies targeting this complex.