RESUMO
Small nucleolar RNA (snoRNA) plays important role in various histogenesis. Whether snoRNA plays a role in adipogenesis is unknown. SNORD126 is a C/D box snoRNA. We previously demonstrated that SNORD126 promoted hepatocellular carcinoma cell growth by activating the phosphoinositide 3-kinase-protein kinase B (Akt) pathway through upregulating fibroblast growth factor receptor 2 expression. In the present study, we found that the expression of SNORD126 was downregulated in the obesity-related tissues in high-fat diet-fed rats. Overexpression of SNORD126 in 3T3-L1 cells promoted adipocytes differentiation. SNORD126 significantly increased the expression of CCAAT/enhancer-binding protein α, fatty acid-binding protein 4, peroxisome proliferative-activated receptor-γ, and the phosphorylation of Akt and p70S6K. Overexpression of SNORD126 in human adipose-derived stem cells stimulated adipogenesis and increased phosphorylation of Akt. Meanwhile, SNORD126 increased the messenger RNA and protein levels of cyclin D1 and cyclin-dependent kinase 2, which promoted mitotic clonal expansion progression during the early stage of 3T3-L1 cell differentiation. We further found that SNORD126 accelerated the growth of the groin fat pad and increased phosphorylation of Akt and p70S6K in rats. Overall, our results suggested that SNORD126 promoted adipocyte differentiation through increasing phosphorylation of Akt and p70S6K both in vitro and in vivo.
Assuntos
Adipogenia/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Nucleolar Pequeno/metabolismo , Transdução de Sinais , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Diferenciação Celular/genética , Dieta Hiperlipídica , Fase G1 , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Obesidade/genética , Ratos Sprague-Dawley , Fase S , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
Cholangiocarcinoma (CCA) still has a very unfavorable prognosis with a very high mortality, which is complicated by a lack of prognostic biomarkers. In this study, CCA patients in the Gene Expression Omnibus (GEO) cohort were categorized into two subtypes. Differentially expressed and methylated genes were identified, and the impact of DNA methylation in the trans-regulation of gene expression was investigated. Finally, a CIMP-related methylation signature specific for CCA (CMSC) was trained in GEO and validated in the Tongji cohort. A subset of patients with CIMP-H was identified, which was correlated with an unfavorable prognosis. Gene enrichment analysis implied the potential mechanism of CIMP as a promoter of carcinogenesis by regulating proliferation. The trans-regulation among differentially methylated CpG sites and genes with the same change trends was positively correlated, while the converse situation showed a negative correlation. Notably, CMSC based on four genes could significantly classify CCA patients into low- and high-risk groups in the GEO cohort, and the robustness of CMSC was validated in the Tongji cohort. The results of receiver operating characteristic analysis further indicated that CMSC was capable of highly sensitive and specific prediction of the patient outcomes in CCA. In conclusion, our work highlights the clinical significance of CMSC in the prognosis of CCA.
Assuntos
Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Adulto , Apoptose/genética , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Movimento Celular/genética , Proliferação de Células/genética , Colangiocarcinoma/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Ultrasound-guided thermal ablation (TA) has emerged as a robust therapeutic approach for treating solid tumors in multiple organs, including the thyroid. Yet, its efficacy and safety profile in the management of Graves' Disease (GD) remains to be definitively established. METHODS: A retrospective study was conducted on 50 GD patients treated with TA between October 2017 and December 2021. Key metrics like thyroid volume, volume reduction rate (VRR), thyroid hormones, and basal metabolic rate (BMR) were evaluated using paired Wilcoxon tests. RESULTS: The intervention of ultrasound-guided TA yielded a statistically significant diminution in total thyroid volume across all postoperative follow-up intervals-1, 3, 6, and 12 months-relative to pre-intervention baselines (p < 0.001). The median VRR observed at these time points were 17.5%, 26.5%, 34.4%, and 39.8%, respectively. Euthyroid status was corroborated in 96% of patients at the one-year follow-up milestone. Transient tachycardia and dysphonia were observed in three patients, while a solitary case of skin numbness was noted. Crucially, no instances of enduring injury to the recurrent laryngeal nerve (RLN) were documented. CONCLUSIONS: Our investigation substantiates ultrasound-guided TA as a pragmatic, well-tolerated, and safe therapeutic modality for GD. It effectively improves symptoms of hyperthyroidism, engenders a substantial reduction in thyroid volume, and restores thyroid hormone and BMR to physiological levels. Given its favorable safety profile, enhanced cosmetic outcomes, and minimally invasive nature, ultrasound-guided TA is a compelling alternative to thyroidectomy for GD patients.
RESUMO
Lenvatinib is a standard therapy option for advanced hepatocellular carcinoma (HCC), but resistance limits clinical benefits. In this study, we identified inhibition of ROS levels and reduced redox status in Lenvatinib-resistant HCC. Integrating RNA-seq with unbiased whole-genome CRISPR-Cas9 screen analysis indicated LINC01607 regulated the P62 to enhance drug resistance by affecting mitophagy and antioxidant pathways. Underlying mechanisms were investigated both in vitro and in vivo. We initially confirmed that LINC01607, as a competing endogenous RNA (ceRNA) competing with mirRNA-892b, triggered protective mitophagy by upregulating P62, which reduced ROS levels and promoted drug resistance. Furthermore, LINC01607 was proved to resist oxidative stress by regulating the P62-Nrf2 axis, which transcriptionally regulated the expression of LINC01607 to form a positive feedback loop. Finally, silencing LINC01607 combined with Lenvatinib reversed resistance in animal and patient-derived organoid models. In conclusion, we proposed a novel mechanism of Lenvatinib resistance involving ROS homeostasis. This work contributed to understanding redox homeostasis-related drug resistance and provided new therapeutic targets and strategies for HCC patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Mitofagia , Espécies Reativas de Oxigênio , Linhagem Celular TumoralRESUMO
Hypoxia is an important feature of the tumor microenvironment(TME) and is closely associated with cancer metastasis, immune evasion, and drug resistance. However, the precise role of hypoxia in hepatocellular carcinoma(HCC), as well as its influence on the TME, and drug sensitivity remains unclear. We found the excellent survival prediction value of Hypoxia_DEGs_Score model. In hypoxic HCC, somatic mutation, copy number variation, and DNA methylation were closely related to hypoxic changes and affected tumorigenesis, progression, metastasis, and drug resistance. In HCC, aggravated hypoxic stress was found to be accompanied by an immune exclusion phenotype and increased infiltration of immunosuppressive cells. In the validation cohort, patients with high Hypoxia_DEGs_Score were found to have worse immunotherapeutic outcomes and prognoses, and may benefit from drugs against cell cycle signaling pathways rather than those inhibiting the PI3K/mTOR pathway. Hypoxia_DEGs_Score has an excellent predictive capability of changes in the TME, the efficacy of immunotherapy, and the response of drugs. Therefore, Hypoxia_DEGs_Score can help develop personalized immunotherapy regimens and improve the prognosis of HCC patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Variações do Número de Cópias de DNA , Humanos , Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Prognóstico , Microambiente TumoralRESUMO
Recent evidence suggests that small nucleolar RNAs (snoRNAs) are involved in the progression of various cancers, but their precise roles in hepatocellular carcinoma (HCC) remain largely unclear. Here, we report that SNORD17 promotes the progression of HCC through a positive feedback loop with p53. HCC-related microarray datasets from the Gene Expression Omnibus (GEO) database and clinical HCC samples were used to identify clinically relevant snoRNAs in HCC. SNORD17 was found upregulated in HCC tissues compared with normal liver tissues, and the higher expression of SNORD17 predicted poor outcomes in patients with HCC, especially in those with wild-type p53. SNORD17 promoted the growth and tumorigenicity of HCC cells in vitro and in vivo by inhibiting p53-mediated cell cycle arrest and apoptosis. Mechanistically, SNORD17 anchored nucleophosmin 1 (NPM1) and MYB binding protein 1a (MYBBP1A) in the nucleolus by binding them simultaneously. Loss of SNORD17 promoted the translocation of NPM1 and MYBBP1A into the nucleoplasm, leading to NPM1/MDM2-mediated stability and MYBBP1A/p300-mediated activation of p53. Interestingly, p300-mediated acetylation of p53 inhibited SNORD17 expression by binding to the promoter of SNORD17 in turn, forming a positive feedback loop between SNORD17 and p53. Administration of SNORD17 antisense oligonucleotides (ASOs) significantly suppressed the growth of xenograft tumors in mice. In summary, this study suggests that SNORD17 drives cancer progression by constitutively inhibiting p53 signaling in HCC and may represent a potential therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Nucleolar Pequeno , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Ligação a DNA/metabolismo , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Nucleofosmina/metabolismo , RNA Nucleolar Pequeno/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
The differential expression of chromosome 12 open reading frame 75 (C12orf75) is closely related with cancer progression. Here, we studied the expression levels of C12orf75 and investigated its prognostic value in various cancers across distinct datasets including ONCOMINE, PrognoScan, GEPIA, and TCGA. The correlation between genetic alteration of C12orf75 and immune infiltration was investigated using the cBioPortal and TIMER databases. RNA interference was used to verify the influence of C12orf75 knockdown on the biological phenotype of hepatocellular carcinoma cells. C12orf75 showed increased expression in most tested human cancers. The increased expression of C12orf75 was related with a poor prognosis in urothelial bladder carcinoma and hepatocellular liver carcinoma, but it was surprisingly converse in renal papillary cell carcinoma. In urothelial bladder carcinoma and hepatocellular liver carcinoma, we observed positive correlations between the expression of C12orf75 and the infiltration of immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The knockdown of C12orf75 in hepatocellular carcinoma cells suppressed the proliferation, migration, and invasion and arrested the cell cycle. This is the first report C12orf75 has potential as a prognostic biomarker and therapeutic target for molecularly targeted drugs in urothelial bladder carcinoma, hepatocellular liver carcinoma, and renal papillary cell carcinoma.
Assuntos
Mineração de Dados , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Linfócitos do Interstício Tumoral/imunologia , Mutação/genética , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Prognóstico , Regiões Promotoras Genéticas/genética , Análise de Sobrevida , Regulação para Cima/genéticaRESUMO
Objective: APBB1IP is a Rap1-binding protein that mainly acts as a regulator of leukocyte recruitment and pathogen clearance through complement-mediated phagocytosis. However, the role of APBB1IP in tumor immunity remains unclear. This study was carried out to evaluate the prognostic landscape of APBB1IP in pan-cancer analysis and investigate the relationship between APBB1IP expression and immune infiltration. Methods: We explored the expression pattern and prognostic value of APBB1IP in pan-cancer analysis through Kaplan-Meier Plotter and multiple databases, including TCGA, Oncomine. We then assessed the correlation between APBB1IP expression and immune cell infiltration using the TIMER database. Furthermore, we identified the proteins that interact with APBB1IP and performed epigenetic and transcriptional analyses. Multivariate Cox regression analyses were applied to construct a prognostic model, which consisted of APBB1IP and its interacting proteins, based on the lung cancer cohorts from the Gene Expression Omnibus (GEO) database. Results: The expression of APBB1IP was correlated with the prognosis of several types of cancer. APBB1IP upregulation was found to be associated with increased immune cell infiltration, especially for CD8+ T cells, natural killer (NK) cells, and immune regulators. A link was found between APBB1IP and immune-related proteins including RAP1A/B, TLN1/2 and VCL in the interaction network. Conclusion: APBB1IP can serve as a prognostic biomarker in pan-cancer analysis. APBB1IP upregulation was correlated with increased immune-cell infiltration, and the expression APBB1IP in different tumors might be related to the tumor immune microenvironment.