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The oncogene c-Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c-Myc is significantly up-regulated by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/- mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. Second, the K63-linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c-Myc and promotes c-Myc protein acetylation, which thereby enhances c-Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70-kDa-interacting protein-mediated c-Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c-Myc signaling is also primed in hepatitis B virus-transgenic mice, unveiling a critical role for a mechanism in inflammation-cancer transition. In clinical specimens, TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c-Myc to promote human hepatocarcinogenesis. Consistently, curbing c-Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c-Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c-Myc signaling, with potential implications for HCC therapy.
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Carcinogênese , Carcinoma Hepatocelular/genética , Genes myc/fisiologia , Histona Desacetilases/fisiologia , Neoplasias Hepáticas/genética , Fator 6 Associado a Receptor de TNF/fisiologia , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Estabilidade Proteica , Células Tumorais CultivadasRESUMO
PURPOSE: To investigate the clinical performance, pathological characteristics, treatment and prognosis of salivary gland malignant tumor (SGMT) with skull base metastasis. METHODS: Five SGMT patients with skull base metastasis were retrospectively studied. Major clinical symptoms included headache, facial paralysis, and ear hearing loss. Three patients had previous history of SGMT resection. All patients underwent preoperative computed tomography (CT) and magnetic resonance imaging (MRI). Craniotomy was performed in three patients, and all the five patients underwent radiotherapy and chemotherapy. RESULTS: Two patients were confirmed as having adenocarcinoma, one patient was pathologically confirmed to have squamous cell carcinoma, one patient had ductal carcinoma, and one patient had acinar cell carcinoma. One patient died after 2 years of treatment, and the remaining 4 patients were followed up for 6 â¼ 24 months, suggesting that the tumor size was not enlarged or showed no local recurrence. CONCLUSION: SGMT with skull base metastasis is extremely rare, and due to similar imaging characteristics, it can be easily misdiagnosed as meningioma or schwannoma. Early diagnosis, extent of invasion, surgery and combination of chemotherapy and radiotherapy are the prognostic factors of the disease.
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BACKGROUND: To explore the clinical value of texture analysis of MR images (multiphase Gd-EOB-DTPA-enhanced MRI and T2 weighted imaging (T2WI) to identify the differentiated degree of hepatocellular carcinoma (HCC). METHOD: One hundred four participants were enrolled in this retrospective study. Each participant performed preoperative Gd-EOB-DTPA-enhanced MR scanning. Texture features were analyzed by MaZda, and B11 program was used for data analysis and classification. The diagnosis efficiencies of texture features and conventional imaging features in identifying the differentiated degree of HCC were assessed by receiver operating characteristic analysis. The relationship between texture features and differentiated degree of HCC was evaluated by Spearman's correlation coefficient. RESULTS: The grey-level co-occurrence matrix -based texture features were most frequently extracted and the nonlinear discriminant analysis was excellent with the misclassification rate ranging from 3.33 to 14.93%. The area under the curve (AUC) of the combined texture features between poorly- and well-differentiated HCC, poorly- and moderately-differentiated HCC, moderately- and well-differentiated HCC was 0.812, 0.879 and 0.808 respectively, while the AUC of tumor size was 0.649, 0.660 and 0.517 respectively. The tumor size was significantly different between poorly- and moderately-HCC (p = 0.014). The COMBINE AUC values were not increased with tumor size combined. CONCLUSIONS: Texture analysis of Gd-EOB-DTPA-enhanced MRI and T2WI was valuable and might be a promising method in identifying the differentiated degree of HCC. The poorly-differentiated HCC was more heterogeneous than well- and moderately-differentiated HCC.
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Carcinoma Hepatocelular/diagnóstico , Processamento de Imagem Assistida por Computador , Neoplasias Hepáticas/diagnóstico , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Meios de Contraste/administração & dosagem , Feminino , Gadolínio DTPA/administração & dosagem , Hepatectomia , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , SoftwareRESUMO
Previously, we identified UBE2L3 as a susceptibility gene for chronic hepatitis B virus (HBV) infection through genome-wide association study. Here, we analysed the association between genetic variants of UBE2L3 and the susceptibility to HBV-related hepatocellular carcinoma (HCC) and further explored its role in HCC. This case-control study included 1344 subjects who cleared HBV, 1560 HBV carriers and 1057 HBV-related HCC patients. Two single nucleotide polymorphisms (SNPs) were genotyped, including rs2266959 and rs4821116. Logistic regression analysis was performed to compute the odds ratio (OR) and 95% confidence interval (CI). We further analysed the expression of UBE2L3 and its association with pathological features based on The Cancer Genome Atlas (TCGA) data and our tissue microarray. Proliferation and migration assays were performed in hepatoma cell lines with or without UBE2L3 knockdown. Further RNA-seq analysis was performed to explore the underlying oncogenic mechanism. The variant genotypes of rs4821116 in UBE2L3 were associated with decreased risk for HCC and chronic HBV infection. Moreover, based on both TCGA and our tissue microarray data, higher levels of UBE2L3 expression were correlated with higher tumour grade, advanced tumour stage and poor survival. In vitro analysis revealed that UBE2L3 may promote hepatocyte proliferation and migration. RNA-seq analysis showed that UBE2L3 was inversely correlated with CDKN2B, a negative regulator of cell cycle, and CLDN1, loss of which may promote cancer metastasis. In conclusion, UBE2L3 may also be a susceptibility gene in HBV-related HCC, and it may promote HCC proliferation and migration by negatively regulating CDKN2B and CLDN1.
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Carcinoma Hepatocelular/genética , Predisposição Genética para Doença/genética , Hepatite B Crônica/complicações , Neoplasias Hepáticas/genética , Enzimas de Conjugação de Ubiquitina/genética , Animais , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China/epidemiologia , Progressão da Doença , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Vírus da Hepatite B/genética , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Camundongos , Camundongos Transgênicos , Polimorfismo de Nucleotídeo Único , Regulação para Cima/genéticaRESUMO
BACKGROUND & AIMS: Aberrant estrogen receptor-α (ERα) expression and signaling are implicated in the development of hepatocellular carcinoma (HCC), but its regulation in HCC remains enigmatic. Herein, we aimed to identify a new mechanism by which ERα signaling is regulated in HCC, which may lead to a potential new strategy for HCC therapy. METHODS: Expression levels of Erbin and ERα in human HCC samples were evaluated by immunohistochemistry. In vitro and in vivo experiments were used to assess the effect of Erbin and ERα signaling on HCC cell growth. Crosstalk between Erbin and ERα signaling was analyzed by molecular methods. Animal models of diethylnitrosamine (DEN) or DEN/CCl4-induced HCC in wild-type Erbin+/+ and mutant ErbinΔC/ΔC mice were observed. The regulatory effects of Erbin on tamoxifen treatment of HCC were evaluated in vitro and in vivo. RESULTS: Erbin inactivated ERα signaling to drive tumorigenesis of HCC, acting to enhance binding of Chip to ERα via its interaction with ERα and thereby promoting ubiquitination and degradation of ERα. Deletion of the PDZ domain of Erbin in ErbinΔC/ΔC mice, disrupted the interaction of Chip and ERα, increased the stability of ERα protein, and thus inhibited tumorigenesis of HCC. Silencing of Erbin effectively sensitized the response of HCC after tamoxifen treatment in vitro and in vivo. CONCLUSIONS: Our data uncovered an important role of Erbin in regulating HCC tumorigenesis through inactivating ERα-mediated tumor-suppressive signaling, suggesting a new strategy for tamoxifen therapy in HCC by targeting Erbin/ERα signaling axis. LAY SUMMARY: Erbin expression is significantly elevated in human hepatocellular carcinoma (HCC) tissue. This elevated expression of Erbin contributes to tumorigenesis of HCC by negatively regulating ERα signaling. However, restoring ERα signaling by inhibiting Erbin expression enhances the sensitivity of HCC cells to tamoxifen treatment, providing a new approach for tamoxifen treatment in HCC.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Receptor alfa de Estrogênio/genética , Feminino , Inativação Gênica , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Estabilidade Proteica , Fatores Sexuais , Tamoxifeno/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Regulação para CimaRESUMO
Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD.
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Colite Ulcerativa/genética , Doença de Crohn/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Receptores de Interleucina-1/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Receptores Toll-Like/metabolismo , Adulto , Idoso , Animais , Colo/metabolismo , Sulfato de Dextrana/farmacologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Fenilacetatos/farmacologia , Estudos Prospectivos , Transdução de Sinais/fisiologiaRESUMO
OBJECTIVE: To investigate the feasibility of tissue similarity map (TSM)-based relative cerebral blood volume (rCBV) assessment in evaluating the hemodynamic characteristics of gliomas and in differentiating high-grade gliomas from low-grade ones without concentration time curve (CTC). MATERIALS AND METHODS: TSM-based rCBV (rCBV TSM ) and conventional rCBV (rCBV PWI ) maps were generated (n = 35). The differences in percentage and concordance correlation coefficient (CCC) of the rCBV TSM and rCBV PWI ratios were calculated. The Mann-Whitney test and the receiver operating characteristic (ROC) curve analysis were also performed to examine the relationships of rCBV ratios between high- and low-grade gliomas. The improvement factors of signal to noise ratio (SNR) of rCBV TSM maps were also calculated. RESULTS: The mean difference in percentage between rCBV TSM and rCBV PWI ratios was 4.29 ± 2.62%. The CCC of rCBV TSM and rCBV PWI ratios was 0.9974, with 95% confidence interval of 0.9948, 0.9987, which implied a high agreement between them. The Mann-Whitney test suggested that the rCBV TSM and rCBV PWI ratios of high-grade gliomas were significantly different from those of low-grade gliomas (P < 0.001). The improvement factors of SNR of the rCBV TSM map were 1.31 ± 0.24 for glioma and 1.28 ± 0.24 for normal white matter. CONCLUSION: It is feasible to use rCBV TSM in the evaluation of hemodynamic characteristics of gliomas and differentiation of high- and low-grade gliomas without CTC. Moreover, rCBV TSM maps possess a higher SNR, which allows potentially more accurate diagnosis compared with the conventional ones.
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Nur77, an orphan member of the nuclear receptor superfamily, has been implicated in tumorigenesis. However, its contributions to colorectal cancer (CRC) invasion and metastasis are largely under characterized. Here, we present the first evidence that the invasion and metastasis of CRC is regulated by Nur77. High expression of Nur77 was observed in clinical CRC tissues, and this elevated expression was significantly associated with advanced tumor, lymph nodes, distant metastasis stage (P = 0.003), lymph node metastasis (P = 0.001) and poor survival (P = 0.03). Overexpression of Nur77 in CRC cells enhanced cell invasion in vitro, whereas knockdown of Nur77 diminished cell invasion and metastasis both in vitro and in vivo. In studying the possible mechanism by which overexpression of Nur77 contributes to CRC invasion and metastasis, we observed that the nuclear protein Nur77 promoted the expression of matrix metalloproteinase (MMP)-9, a novel downstream target of Nur77, and subsequently decreased the expression of E-cadherin. Examination of clinical samples further showed that Nur77 expression is positively correlated with MMP-9, whereas negatively correlated with E-cadherin. Interestingly, Nur77-mediated CRC invasion via MMP-9 and E-cadherin could be mimicked by some metastasis-inducible factors including hypoxia and prostaglandin E2. Collectively, our study demonstrated that Nur77 could promote the invasion and metastasis of CRC cells through regulation of MMP-9/E-cadherin signaling. These observations provide a possible new strategy for potentially treating or preventing the metastasis of CRC through targeting of Nur77.
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Caderinas/biossíntese , Carcinogênese/genética , Neoplasias Colorretais/genética , Metaloproteinase 9 da Matriz/biossíntese , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Caderinas/genética , Movimento Celular/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Transdução de Sinais/genéticaRESUMO
BACKGROUND: The intra- and inter-tumoral heterogeneity of gliomas and the complex tumor microenvironment make accurate treatment of gliomas challenging. At present, research on gliomas mainly relies on cell lines, stem cell tumor spheres, and xenotransplantation models. The similarity between traditional tumor models and patients with glioma is very low. AIMS: In this study, we aimed to address the limitations of traditional tumor models by generating patient-derived glioma organoids using two methods that summarized the cell diversity, histological features, gene expression, and mutant profiles of their respective parent tumors and assess the feasibility of organoids for personalized treatment. MATERIALS AND METHODS: We compared the organoids generated using two methods through growth analysis, immunohistological analysis, genetic testing, and the establishment of xenograft models. RESULTS: Both types of organoids exhibited rapid infiltration when transplanted into the brains of adult immunodeficient mice. However, organoids formed using the microtumor method demonstrated more similar cellular characteristics and tissue structures to the parent tumors. Furthermore, the microtumor method allowed for faster culture times and more convenient operational procedures compared to the Matrigel method. DISCUSSION: Patient-derived glioma organoids, especially those generated through the microtumor method, present a promising avenue for personalized treatment strategies. Their capacity to faithfully mimic the cellular and molecular characteristics of gliomas provides a valuable platform for elucidating tumor biology and evaluating therapeutic modalities. CONCLUSION: The success rates of the Matrigel and microtumor methods were 45.5% and 60.5%, respectively. The microtumor method had a higher success rate, shorter establishment time, more convenient passage and cryopreservation methods, better simulation of the cellular and histological characteristics of the parent tumor, and a high genetic guarantee.
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Glioma , Adulto , Humanos , Animais , Camundongos , Glioma/patologia , Técnicas de Cultura de Células/métodos , Organoides/metabolismo , Organoides/patologia , Células-Tronco Neoplásicas , Microambiente TumoralRESUMO
Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.
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Neoplasias Colorretais , Interleucina-6 , Humanos , Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/patologia , Histonas/metabolismo , Interleucina-6/metabolismo , Lactatos/metabolismo , Macrófagos/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Microambiente TumoralRESUMO
The Wnt/ß-catenin signaling pathway is a growth control pathway involved in various biological processes as well as the development and progression of cancer. Colorectal cancer (CRC) is one of the most common malignancies in the world. The hyperactivation of Wnt signaling is observed in almost all CRC and plays a crucial role in cancer-related processes such as cancer stem cell (CSC) propagation, angiogenesis, epithelial-mesenchymal transition (EMT), chemoresistance, and metastasis. This review will discuss how the Wnt/ß-catenin signaling pathway is involved in the carcinogenesis and progression of CRC and related therapeutic approaches.
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OBJECTIVE: To explore the intrinsic mechanism of the mammalian target of rapamycin (mTOR) pathway activation and promotion of neuronal axon growth. METHODS: Human neuroblastoma cells, SH-SY5Y, were induced with all-trans retinoic acid (ATRA; 10 µM for three days) which differentiated the cell line into a neuronal-like state. Immunohistochemical staining was used to detect the differentiation status of the neuronal-like cells. Phosphatase and tensin homolog (PTEN) RNA interference (RNAi) experiments were performed on the differentiated cells; reverse transcription-polymerase chain reaction (RT-PCR) detected transcriptional levels of PTEN following 24 h of interference. After 36 h, western blot assay was used to detect expression levels of ribosomal protein S6 kinase (pS6k) and mTOR. To downregulate the expression of PTEN and cluster of differentiation 44 (CD44), a cell-surface glycoprotein, simultaneously, PTEN siRNA and CD44 siRNA sequences were mixed in equal proportions in co-interference experiments. RT-PCR detected the transcription level of CD44, and the relationship between the CD44 and axonal growth was observed after 48 h of interference. RESULTS: Microtubule-associated protein 2 (MAP2) expression was enhanced after three days of induction in SH-SY5Y cells. RT-PCR showed the transcription level of PTEN was significantly downregulated after 24 h of PTEN knockdown. mTOR and pS6k protein expression levels were significantly upregulated after 36 h of interference. CD44 transcription levels were upregulated after PTEN gene interference. The neurite length of the cells in the experimental interference group was significantly longer than that in the control group, and the expression level of CD44 was positively correlated with neurite growth. The neurite length of the PTEN-only interference group was significantly greater than that of the co-interference and ATRA groups. CONCLUSION: Activation of the mTOR pathway promoted neurite growth through upregulation of CD44 expression, thus promoting neuronal regeneration.
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Neuritos , Neuroblastoma , Humanos , Regulação para Cima , Neuritos/metabolismo , Sirolimo , Neuroblastoma/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Interferente Pequeno/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Hialuronatos/genéticaRESUMO
The p53 tumor suppressor exerts antitumor functions through its ability to regulate the transcription of its downstream targets. Long noncoding RNAs (lncRNAs) act as oncogenes or tumor suppressors implicated in tumorigenesis and tumor progression. Here, we identify the lncRNA LINC00324 (long intergenic noncoding RNA 00324) as a direct p53 transcriptional target. Knockdown of LINC00324 expression promotes tumor growth by reducing p53 transcriptional activity, whereas ectopic LINC00324 expression demonstrates a reverse effect. Notably, LINC00324 is present in the endogenous p53 complex in tumor cells and directly binds to the C-terminal domain of p53 in vitro. Mechanistically, LINC00324 enables p53 transactivation by competitively disrupting the p53-SET interaction, resulting in an increase of p300/CBP-mediated H3K18 and H3K27 acetylation on the p53 target promoters. Lower LINC00324 expression is associated with more aggressive disease status and predicts worse overall survival of patients with cancer. Our study identifies a p53/LINC00324 positive feedback loop that suppresses tumor growth by counteracting SET-mediated transcriptional repression.
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Neoplasias , RNA Longo não Codificante , Humanos , Retroalimentação , Expressão Gênica , Neoplasias/genética , Oncogenes , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.
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Neoplasias Colorretais , Transdução de Sinais , Animais , Camundongos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Fosforilação , Ubiquitinação , Cloridrato de Vilazodona/farmacologiaRESUMO
BACKGROUND: TRIP6 is a zyxin family member that serves as an adaptor protein to regulate diverse biological processes. In prior reports, TRIP6 was shown to play a role in regulating inflammation. However, its in vivo roles and mechanistic importance in colitis remain largely elusive. Herein, we therefore employed TRIP6-deficient (TRIP6-/-) mice in order to explore the mechanistic importance of TRIP6 in a dextran sodium sulfate (DSS)-induced model of murine colitis. FINDINGS: Wild-type (TRIP6+/+) mice developed more severe colitis following DSS-mediated disease induction relative to TRIP6-/- mice, as evidenced by more severe colonic inflammation and associated crypt damage. TRIP6 expression in wild-type mice was significantly elevated following DSS treatment. Mechanistically, TRIP6 binds to TRAF6 and enhances oligomerization and autoubiquitination of TRAF6. This leads to the activation of NF-κB signaling and the expression of pro-inflammatory cytokines such as TNFα and IL-6, in the in vivo mouse model of colitis. CONCLUSIONS: These in vivo data demonstrate that TRIP6 serves as a positive regulator of DSS-induced colitis through interactions with TRAF6 resulting in the activation of inflammatory TRAF6 signaling, highlighting its therapeutic promise as a protein that theoretically can be targeted to prevent or treat colitis.
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Macrophages plays a vital role in the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), but the polarization of macrophages was not consistent in previous reports and the contribution of hepatocytes to macrophage polarization is not clear. Here, we show that in clinical NASH and HCC samples, impaired Dicer activity was common and correlated with increased M1-like macrophages. Mice with Dicer deletion in hepatocytes could induce macrophages M1 polarization either in the development of NASH under high fat diet feeding, or in the carcinogenesis of HCC after DEN treatment. In hepatic cells, Dicer deletion delivered distinct lipid profile and increased lipid oxidation. Mechanically, Dicer deletion caused declined miR-192-3p and increased IGF2 in hepatocytes. Restoring miR-192-3p could suppress IGF2 and inhibit macrophage infiltration in the liver tissue, as well as reduce the lipid de novo synthesis and peroxidation. Overall, our data highlights the central role of Dicer-associated miR-192-3p in the etiopathogenesis of macrophage M1 polarization in NASH and HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Hepatócitos , Lipídeos , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
BEST4 is a member of the bestrophin protein family that plays a critical role in human intestinal epithelial cells. However, its role and mechanism in colorectal cancer (CRC) remain largely elusive. Here, we investigated the role and clinical significance of BEST4 in CRC. Our results demonstrate that BEST4 expression is upregulated in clinical CRC samples and its high-level expression correlates with advanced TNM (tumor, lymph nodes, distant metastasis) stage, LNM (lymph node metastasis), and poor survival. Functional studies revealed that ectopic expression of BEST4 promoted CRC cell proliferation and metastasis, whereas the depletion of BEST4 had the opposite effect both in vitro and in vivo. Mechanistically, BEST4 binds to the p85α regulatory subunit of phosphatidylinositol-3-kinase (PI3K) and promotes p110 kinase activity; this leads to activation of Akt signaling and expression of MYC and CCND1, which are critical regulators of cell proliferation and metastasis. In clinical samples, the expression of BEST4 is positively associated with the expression of phosphorylated Akt, MYC and CCND1. Pharmacological inhibition of Akt activity markedly repressed BEST4-mediated Akt signaling and proliferation and metastasis of CRC cells. Importantly, the interaction between BEST4 and p85α was also enhanced by epidermal growth factor (EGF) in CRC cells. Therapeutically, BEST4 suppression effectively sensitized CRC cells to gefitinib treatment in vivo. Taken together, our findings indicate the oncogenic potential of BEST4 in colorectal carcinogenesis and metastasis by modulating BEST4/PI3K/Akt signaling, highlighting a potential strategy for CRC therapy.
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Proteínas Proto-Oncogênicas c-aktRESUMO
The structural engineering is subject to various subjective and objective factors, the deformation is usually inevitable, the deformation monitoring data usually are nonstationary and nonlinear, and the deformation prediction is a difficult problem in the field of structural monitoring. Aiming at the problems of the traditional structural deformation prediction methods, a structural deformation prediction model is proposed based on temporal convolutional networks (TCNs) in this study. The proposed model uses a one-dimensional dilated causal convolution to reduce the model parameters, expand the receptive field, and prevent future information leakage. By obtaining the long-term memory of time series, the internal time characteristics of structural deformation data can be effectively mined. The network hyperparameters of the TCN model are optimized by the orthogonal experiment, which determines the optimal combination of model parameters. The experimental results show that the predicted values of the proposed model are highly consistent with the actual monitored values. The average RMSE, MAPE, and MAE with the optimized model parameters reduce 44.15%, 82.03%, and 66.48%, respectively, and the average running time is reduced by 45.41% compared with the results without optimization parameters. The average RMSE, MAE, and MAPE reduce by 26.88%, 62.16%, and 40.83%, respectively, compared with WNN, DBN-SVR, GRU, and LSTM models.
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Aprendizado Profundo , Redes Neurais de Computação , Engenharia , PrevisõesRESUMO
OBJECTIVES: Recurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6â¯months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma. PATIENTS AND METHODS: Eighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500â¯mg/day) and TMZ (50â¯mg/m2/day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions. RESULTS: From the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4â¯months and 9.1â¯months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%). CONCLUSION: Apatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piridinas/uso terapêutico , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Quimioterapia Combinada , Feminino , Glioma/mortalidade , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Qualidade de Vida , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The transforming growth factor-ß (TGF-ß) signaling pathway mediates various biological functions, and its dysregulation is closely related to the occurrence of malignant tumors. However, the role of TGF-ß signaling in tumorigenesis and development is complex and contradictory. On the one hand, TGF-ß signaling can exert antitumor effects by inhibiting proliferation or inducing apoptosis of cancer cells. On the other hand, TGF-ß signaling may mediate oncogene effects by promoting metastasis, angiogenesis, and immune escape. This review summarizes the recent findings on molecular mechanisms of TGF-ß signaling. Specifically, this review evaluates TGF-ß's therapeutic potential as a target by the following perspectives: ligands, receptors, and downstream signaling. We hope this review can trigger new ideas to improve the current clinical strategies to treat tumors related to the TGF-ß signaling pathway.