Targeting c-Myc transactivation by LMNA inhibits tRNA processing essential for malate-aspartate shuttle and tumour progression.

BACKGROUND: A series of studies have demonstrated the emerging involvement of transfer RNA (tRNA) processing during the progression of tumours. Nevertheless, the roles and regulating mechanisms of tRNA processing genes in neuroblastoma (NB), the prevalent malignant tumour outside the brain in children, are yet unknown. METHODS: Analysis of multi-omics results was conducted to identify crucial regulators of downstream tRNA processing genes. Co-immunoprecipitation and mass spectrometry methods were utilised to measure interaction between proteins. The impact of transcriptional regulators on expression of downstream genes was measured by dual-luciferase reporter, chromatin immunoprecipitation, western blotting and real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) methods. Studies have been conducted to reveal impact and mechanisms of transcriptional regulators on biological processes of NB. Survival differences were analysed using the log-rank test. RESULTS: c-Myc was identified as a transcription factor driving tRNA processing gene expression and subsequent malate-aspartate shuttle (MAS) in NB cells. Mechanistically, c-Myc directly promoted the expression of glutamyl-prolyl-tRNA synthetase (EPRS) and leucyl-tRNA synthetase (LARS), resulting in translational up-regulation of glutamic-oxaloacetic transaminase 1 (GOT1) as well as malate dehydrogenase 1 (MDH1) via inhibiting general control nonrepressed 2 or activating mechanistic target of rapamycin signalling. Meanwhile, lamin A (LMNA) inhibited c-Myc transactivation via physical interaction, leading to suppression of MAS, aerobic glycolysis, tumourigenesis and aggressiveness. Pre-clinically, lobeline was discovered as a LMNA-binding compound to facilitate its interaction with c-Myc, which inhibited aminoacyl-tRNA synthetase expression, MAS and tumour progression of NB, as well as growth of organoid derived from c-Myc knock-in mice. Low levels of LMNA or elevated expression of c-Myc, EPRS, LARS, GOT1 or MDH1 were linked to a worse outcome and a shorter survival time of clinical NB patients. CONCLUSIONS: These results suggest that targeting c-Myc transactivation by LMNA inhibits tRNA processing essential for MAS and tumour progression.

Non-small cell lung cancer and immune checkpoint inhibitor therapy: does non-alcoholic fatty liver disease have an effect?

BACKGROUND: Immunotherapy based on the application of immune checkpoint inhibitors (ICIs) is one of the standard treatments for advanced non-small cell lung cancer (NSCLC). Non-alcoholic fatty liver Disease (NAFLD) has demonstrated predictive value for response to immunotherapy in non-lung cancer types. Our study investigated the effect of NAFLD on the efficacy of real-life use of ICIs for patients with stage III / IV NSCLC. METHODS: The clinical and imaging data of patients with stage III / IV NSCLC who were first admitted to Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from March 2020 to July 2022 were retrospectively collected to ensure that they underwent at least one CT scan before treatment. A total of 479 patients were divided into the NAFLD group (Liver/Spleen density ratio ≤ 1) and the non-NAFLD group (Liver/Spleen density ratio > 1) by measuring the baseline liver and spleen CT value. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) of the patients were obtained. RESULTS: A total of 118 patients with NAFLD and 361 patients without NAFLD were included in the study. Patients with NAFLD tended to have higher BMI and higher total bilirubin compared to patients without NAFLD. The median duration of follow-up in the study was 22 m (IQR, 17-29 m). Both of 2 groups had a higher DCR (94% vs. 92%, p = 0.199) and ORR (38.1% vs. 44.9%, p = 0.452) respectively. There was no difference in efficacy between the two groups. In univariate analysis, NAFLD had no significant effect on PFS (p = 0.785) and OS (p = 0.851). Surprisingly, the presence of hypertension was observed to be associated with a higher OS (HR 1.471 95%CI 1.018-2.127, p = 0.040). Besides, based on multivariate analysis, lactic dehydrogenase was associated with PFS (HR 1.001 95%CI 1.000,1.002, p = 0.037) and OS (HR 1.002, 95%CI 1.001-1.003, p < 0.001). CONCLUSIONS: Among patients with NSCLC, NAFLD did not result in changes in survival or disease progression after immune checkpoint inhibitor therapy.

The impact of pulmonary artery to ascending aorta diameter ratio progression on the prognosis of NSCLC patients treated with immune checkpoint inhibitors.

Background: Immunotherapy, represented by immune checkpoint inhibitors (ICIs), is a major breakthrough in cancer treatment. Studies have reported that the use of ICIs is associated with an increase in the pulmonary artery to ascending aorta diameter (PAD/AoD) ratio. However, the impact of PAD/AoD ratio progression on the prognosis of patients is unclear. Methods: This retrospective cohort study included patients with stage III or IV non-small cell lung cancer (NSCLC) treated with ICIs at the Wuhan Union Hospital between March 1, 2020, and September 1, 2022. The baseline and post-treatment PAD/AoD ratios of patients were evaluated through chest CT scans. The primary outcome of this study was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Results: The PAD/AoD ratio increased after the initiation of ICIs (from 0.75 to 0.78; P < 0.001). A total of 441 patients were divided into severe group (n=221) and non-severe group (n=220) according to the median increase of PAD/AoD ratio (1.06). Compared with the non-severe group, the severe group had a lower DCR (87.8% vs. 96.0%, P = 0.005) and ORR (87.5% vs. 96.0%, P = 0.063). Over the entire duration of follow-up (median 22.0 months), 85 (38.5%) patients in the severe group and 30 (7.3%) patients in the non-severe group died. An increased PAD/AoD ratio was associated with shorter PFS (Hazard ratio (HR): 1.48 [95% CI, 1.14 to 1.93]; P = 0.003) and OS (HR: 3.50 [95% CI, 2.30 to 5.30]; P < 0.001). Similar results were obtained across subgroups. Conclusions: ICI treatment exacerbates an increase in the PAD/AoD ratio in patients with cancer, and greater increase in the PAD/AoD ratio was associated with a worse prognosis. PAD/AoD ratio could be a biomarker to stratify prognosis of NSCLC patients treated with ICIs.

Prognosis of EBV-positive gastric cancer with lymphoid stroma: systematic review and meta-analysis.

BACKGROUND: Although gastric cancer with lymphoid stroma (GCLS) presents better prognosis, uncertainty still exists regarding the association of Epstein-Barr virus (EBV) infection with prognosis of GCLS. Therefore, it is urgent to evaluate the outcome and characteristics of EBV-positive GCLS via a systematic review and meta-analysis. METHODS: Three medical databases, with a period ranging from 2000 to so far, were searched for observational studies on EBV infection, clinical characteristics and prognosis. Odds ratio (OR) was used to evaluate the mortality and clinical characteristics of EBV-positive GCLS patients. Egger's test and subgroup analysis were conducted to identify the source of heterogeneity. RESULTS: Nine retrospective studies were finally identified, which involved 618 EBV-positive and 153 EBV-negative GCLS patients. The forest plot indicated that EBV-positive GCLS patients had lower mortality (p = .009; 95% CI: 0.15-0.77; I2 = 48.6%). Both of funnel plot and Egger's tests suggested that there was no publication bias. Nonetheless, subgroup analysis indicated that T1-2 stage ratio more than 50% (p < .001; I2 = 6.7%) and male ratio more than 80% (p < .001; I2 = 0.0%) were valuable for eliminating the heterogeneity. Seven studies including valid information showed that TNM stage of EBV-positive and negative GCLS patients was not statistically different (p = .644; 95% CI: 0.50-1.53; I2 = 0.0%). CONCLUSIONS: EBV-positive GCLS tends to have lower mortality, suggesting that detection of EBV infection is necessary to predict prognosis of GCLS.

circ-hnRNPU inhibits NONO-mediated c-Myc transactivation and mRNA stabilization essential for glycosylation and cancer progression.

BACKGROUND: Recent evidence reveals the emerging functions of circular RNA (circRNA) and protein glycosylation in cancer progression. However, the roles of circRNA in regulating glycosyltransferase expression in gastric cancer remain to be determined. METHODS: Circular RNAs (circRNAs) were validated by Sanger sequencing. Co-immunoprecipitation, mass spectrometry, and RNA sequencing assays were applied to explore protein interaction and target genes. Gene expression regulation was observed by chromatin immunoprecipitation, RNA immunoprecipitation, dual-luciferase reporter, real-time quantitative RT-PCR, and western blot assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA and its partners on the glycosylation, growth, invasion, and metastasis of gastric cancer cells. RESULTS: Circ-hnRNPU, an exonic circRNA derived from heterogenous nuclear ribonuclear protein U (hnRNPU), was identified to exert tumor suppressive roles in protein glycosylation and progression of gastric cancer. Mechanistically, circ-hnRNPU physically interacted with non-POU domain containing octamer binding (NONO) protein to induce its cytoplasmic retention, resulting in down-regulation of glycosyltransferases (GALNT2, GALNT6, MGAT1) and parental gene hnRNPU via repression of nuclear NONO-mediated c-Myc transactivation or cytoplasmic NONO-facilitated mRNA stability. Rescue studies indicated that circ-hnRNPU inhibited the N- and O-glycosylation, growth, invasion, and metastasis of gastric cancer cells via interacting with NONO protein. Pre-clinically, administration of lentivirus carrying circ-hnRNPU suppressed the protein glycosylation, tumorigenesis, and aggressiveness of gastric cancer xenografts. In clinical cases, low circ-hnRNPU levels and high NONO or c-Myc expression were associated with poor survival outcome of gastric cancer patients. CONCLUSIONS: These findings indicate that circ-hnRNPU inhibits NONO-mediated c-Myc transactivation and mRNA stabilization essential for glycosylation and cancer progression.

Acetyl-CoA metabolism as a therapeutic target for cancer.

Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves as a key hub for the biosynthesis of fatty acids and isoprenoids, but also serves as a signaling substrate for acetylation reactions in post-translational modification of proteins, which is crucial for the epigenetic inheritance of cells. Acetyl-CoA links lipid metabolism with histone acetylation to create a more intricate regulatory system that affects the growth, aggressiveness, and drug resistance of malignancies such as glioblastoma, breast cancer, and hepatocellular carcinoma. These fascinating advances in the knowledge of acetyl-CoA metabolism during carcinogenesis and normal physiology have raised interest regarding its modulation in malignancies. In this review, we provide an overview of the regulation and cancer relevance of main metabolic pathways in which acetyl-CoA participates. We also summarize the role of acetyl-CoA in the metabolic reprogramming and stress regulation of cancer cells, as well as medical application of inhibitors targeting its dysregulation in therapeutic intervention of cancers.

Protection of Inonotus hispidus (Bull.) P. Karst. against Chronic Alcohol-Induced Liver Injury in Mice via Its Relieving Inflammation Response.

Alcoholic liver disease (ALD) can be induced by excessive alcohol consumption, and has a worldwide age-standardized incidence rate (ASIR) of approximately 5.243%. Inonotus hispidus (Bull.) P. Karst. (IH) is a mushroom with pharmacological effects. In ALD mice, the hepatoprotective effects of IH were investigated. IH strongly ameliorated alcohol-induced pathological changes in the liver, including liver structures and its function-related indices. Intestinal microbiota and serum metabolomics analysis showed that IH altered the associated anti-inflammatory microbiota and metabolites. According to results obtained from Western blot, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA), IH downregulated the levels of pro-inflammation factors interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α), enhanced the expressions of peroxisome proliferator-activated receptor alpha (PPARα) and 15-hydroxprostaglandin dehydrogenase (15-PGDH), and inhibited the phosphorylated activation of Janus kinase (JAK) 1 and signal transducer and activator of transcription (STAT) 3, confirming the hepatoprotection of IH against alcohol damage via anti-inflammation. This study provides the experimental evidence for the hepatoprotective effects of IH in chronic ALD.

Therapeutic targeting of FUBP3 phase separation by GATA2-AS1 inhibits malate-aspartate shuttle and neuroblastoma progression via modulating SUZ12 activity.

Malate-aspartate shuttle (MAS) is essential for maintaining glycolysis and energy metabolism in tumors, while its regulatory mechanisms in neuroblastoma (NB), the commonest extracranial malignancy during childhood, still remain to be elucidated. Herein, by analyzing multi-omics data, GATA binding protein 2 (GATA2) and its antisense RNA 1 (GATA2-AS1) were identified to suppress MAS during NB progression. Mechanistic studies revealed that GATA2 inhibited the transcription of glutamic-oxaloacetic transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2). As a long non-coding RNA destabilized by RNA binding motif protein 15-mediated N6-methyladenosine methylation, GATA2-AS1 bound with far upstream element binding protein 3 (FUBP3) to repress its liquid-liquid phase separation and interaction with suppressor of zest 12 (SUZ12), resulting in decrease of SUZ12 activity and epigenetic up-regulation of GATA2 and other tumor suppressors. Rescue experiments revealed that GATA2-AS1 inhibited MAS and NB progression via repressing interaction between FUBP3 and SUZ12. Pre-clinically, administration of lentivirus carrying GATA2-AS1 suppressed MAS, aerobic glycolysis, and aggressive behaviors of NB xenografts. Notably, low GATA2-AS1 or GATA2 expression and high FUBP3, SUZ12, GOT2 or MDH2 levels were linked with unfavorable outcome of NB patients. These findings suggest that GATA2-AS1 inhibits FUBP3 phase separation to repress MAS and NB progression via modulating SUZ12 activity.

Therapeutic targeting of CNBP phase separation inhibits ribosome biogenesis and neuroblastoma progression via modulating SWI/SNF complex activity.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial malignancy in childhood; however, the mechanisms underlying its aggressive characteristics still remain elusive. METHODS: Integrative data analysis was performed to reveal tumour-driving transcriptional regulators. Co-immunoprecipitation and mass spectrometry assays were applied for protein interaction studies. Real-time reverse transcription-polymerase chain reaction, western blotting, sequential chromatin immunoprecipitation and dual-luciferase reporter assays were carried out to explore gene expression regulation. The biological characteristics of NB cell lines were examined via gain- and loss-of-function assays. For survival analysis, the Cox regression model and log-rank tests were used. RESULTS: Cellular nucleic acid-binding protein (CNBP) was found to be an independent factor affecting NB outcome, which exerted oncogenic roles in ribosome biogenesis, tumourigenesis and aggressiveness. Mechanistically, karyopherin subunit beta 1 (KPNB1) was responsible for nuclear transport of CNBP, whereas liquid condensates of CNBP repressed the activity of switch/sucrose-nonfermentable (SWI/SNF) core subunits (SMARCC2/SMARCC1/SMARCA4) via interaction with SMARCC2, leading to alternatively increased activity of SMARCC1/SMARCA4 binary complex in facilitating gene expression essential for 18S ribosomal RNA (rRNA) processing in tumour cells, extracellular vesicle-mediated delivery of 18S rRNA and subsequent M2 macrophage polarisation. A cell-penetrating peptide blocking phase separation and interaction of CNBP with SMARCC2 inhibited ribosome biogenesis and NB progression. High KPNB1, CNBP, SMARCC1 or SMARCA4 expression or low SMARCC2 levels were associated with poor survival of NB patients. CONCLUSIONS: These findings suggest that CNBP phase separation is a target for inhibiting ribosome biogenesis and tumour progression in NB via modulating SWI/SNF complex activity.

Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study.

Neuroblastoma is the most common extracranial solid malignancy in children. This study was undertaken to determine the long-term survival of neuroblastoma patients receiving conventional therapeutics (surgery, chemotherapy, and radiotherapy). The neuroblastoma patients examined were registered in the Surveillance, Epidemiology and End Results (SEER) database (1975-2016). Using propensity score matching analysis, the patients were paired by record depending on whether they received surgery, chemotherapy, or radiotherapy. Univariate and multivariate analyses of the disease-specific survival of the paired patients were performed by the log-rank test and Cox regression assay. A total of 4568 neuroblastoma patients were included in this study. During 1975-2016, the proportion of histopathological grade III/IV cases receiving surgery gradually increased, while the number of patients with tumors of grade I to IV undergoing chemotherapy or radiotherapy was stable or even decreased. After propensity score analysis, for Grade I + II and Grade III tumors, surgery obviously improved the disease-specific survival of patients, while chemotherapy was unfavorable for patient prognosis, and radiotherapy exerted no obvious effect on the patients. However, no matter what treatment was chosen, the patients with advanced-histopathological-grade tumors had a poor prognosis. Meanwhile, for all histopathological grades, the patients receiving surgery and subsequent chemotherapy or radiotherapy suffered from worsen disease-specific survival than those simply undergoing surgery. Fortunately, the negative effects of surgery, chemotherapy, or radiotherapy improved gradually over time. Surgery improved the long-term survival of the neuroblastoma patients, while chemotherapy and radiotherapy exerted an unfavorable impact on patient outcome. These results provide an important reference for the clinical treatment of neuroblastoma.

Surgery-first for a patient with mild hemifacial microsomia: A case report and review of literature.

BACKGROUND: Hemifacial microsomia (HFM) is the second most common craniofacial congenital anomaly following cleft lip and palate. Because of the various phenotypic spectra and the severity of the deformity, a wide range of treatment approaches have been proposed. Recently, the surgery-first approach (SFA) was introduced to treat mild to moderate HFM, and it yielded a balanced facial appearance. The SFA not only promotes rapid improvement in facial aesthetics but also considerably reduces the overall treatment time. CASE SUMMARY: A female patient, aged 25 years old, sought orthodontic treatment with the chief complaint of dental and facial asymmetry. After a comprehensive physical examination and imaging analysis were performed, the patient was diagnosed with mild HFM that was primarily attributed to unilateral abnormal development of the maxilla-mandibular. The SFA was carried out to correct the skeletal deformity. The palatal suture was used as the midline of the maxilla in the surgical plan to center the maxilla, and the chin was also properly positioned to obtain a relatively symmetrical facial appearance. Four weeks after the surgery, the patient was referred for postsurgical orthodontics to decompensate the dentition and stabilize the occlusion. After 20 mo of treatment, all orthodontic appliances were removed. The posttreatment photographs of the patient and her smile confirmed good aesthetic and occlusal results. CONCLUSION: Mild HFM can be corrected by SFA, which not only promotes rapid improvement in facial aesthetics but also considerably reduces the overall treatment time.