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1.
PLoS One ; 17(9): e0274463, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36129940

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is a rare blood cancer with poor prognosis. Overexpression of the proto-oncogene TCL1A and missense mutations of the tumor suppressor ATM are putative main drivers of T-PLL development, but so far only little is known about the existence of T-PLL gene expression subtypes. We performed an in-depth computational reanalysis of 68 gene expression profiles of one of the largest currently existing T-PLL patient cohorts. Hierarchical clustering combined with bootstrapping revealed three robust T-PLL gene expression subgroups. Additional comparative analyses revealed similarities and differences of these subgroups at the level of individual genes, signaling and metabolic pathways, and associated gene regulatory networks. Differences were mainly reflected at the transcriptomic level, whereas gene copy number profiles of the three subgroups were much more similar to each other, except for few characteristic differences like duplications of parts of the chromosomes 7, 8, 14, and 22. At the network level, most of the 41 predicted potential major regulators showed subgroup-specific expression levels that differed at least in comparison to one other subgroup. Functional annotations suggest that these regulators contribute to differences between the subgroups by altering processes like immune responses, angiogenesis, cellular respiration, cell proliferation, apoptosis, or migration. Most of these regulators are known from other cancers and several of them have been reported in relation to leukemia (e.g. AHSP, CXCL8, CXCR2, ELANE, FFAR2, G0S2, GIMAP2, IL1RN, LCN2, MBTD1, PPP1R15A). The existence of the three revealed T-PLL subgroups was further validated by a classification of T-PLL patients from two other smaller cohorts. Overall, our study contributes to an improved stratification of T-PLL and the observed subgroup-specific molecular characteristics could help to develop urgently needed targeted treatment strategies.


Assuntos
Leucemia Prolinfocítica de Células T , Leucemia Prolinfocítica , Proteínas Sanguíneas/genética , Proteínas Cromossômicas não Histona/genética , GTP Fosfo-Hidrolases/genética , Genes Supressores de Tumor , Humanos , Leucemia Prolinfocítica/genética , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/patologia , Proteínas de Membrana/genética , Chaperonas Moleculares/genética , Proteínas/genética , Transdução de Sinais , Transcriptoma
2.
Int J Mol Sci ; 23(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36077026

RESUMO

Tumor suppressor genes (TSGs) are essential genes in the development of cancer. While they have many roles in normal cells, mutation and dysregulation of the TSGs result in aberrant molecular processes in cancer cells. Therefore, understanding TSGs and their roles in the oncogenic process is crucial for prevention and treatment of cancer. In this research, multi-omics breast cancer data were used to identify molecular mechanisms of TSGs in breast cancer. Differentially expressed genes and differentially coexpressed genes were identified in four large-scale transcriptomics data from public repositories and multi-omics data analyses of copy number, methylation and gene expression were performed. The results of the analyses were integrated using enrichment analysis and meta-analysis of a p-value summation method. The integrative analysis revealed that TSGs have a significant relationship with genes of gene ontology terms that are related to cell cycle, genome stability, RNA processing and metastasis, indicating the regulatory mechanisms of TSGs on cancer cells. The analysis frame and research results will provide valuable information for the further identification of TSGs in different types of cancers.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Carcinogênese/genética , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Genes Supressores de Tumor , Humanos , Oncogenes
3.
Int J Mol Sci ; 23(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36077295

RESUMO

This study concerns the analysis of the modulation of Chronic Myeloid Leukemia (CML) cell model K562 transcriptome following transfection with the tumor suppressor gene encoding for Protein Tyrosine Phosphatase Receptor Type G (PTPRG) and treatment with the tyrosine kinase inhibitor (TKI) Imatinib. Specifically, we aimed at identifying genes whose level of expression is altered by PTPRG modulation and Imatinib concentration. Statistical tests as differential expression analysis (DEA) supported by gene set enrichment analysis (GSEA) and modern methods of ontological term analysis are presented along with some results of current interest for forthcoming experimental research in the field of the transcriptomic landscape of CML. In particular, we present two methods that differ in the order of the analysis steps. After a gene selection based on fold-change value thresholding, we applied statistical tests to select differentially expressed genes. Therefore, we applied two different methods on the set of differentially expressed genes. With the first method (Method 1), we implemented GSEA, followed by the identification of transcription factors. With the second method (Method 2), we first selected the transcription factors from the set of differentially expressed genes and implemented GSEA on this set. Method 1 is a standard method commonly used in this type of analysis, while Method 2 is unconventional and is motivated by the intention to identify transcription factors more specifically involved in biological processes relevant to the CML condition. Both methods have been equipped in ontological knowledge mining and word cloud analysis, as elements of novelty in our analytical procedure. Data analysis identified RARG and CD36 as a potential PTPRG up-regulated genes, suggesting a possible induction of cell differentiation toward an erithromyeloid phenotype. The prediction was confirmed at the mRNA and protein level, further validating the approach and identifying a new molecular mechanism of tumor suppression governed by PTPRG in a CML context.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Monoéster Fosfórico Hidrolases , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Genes Supressores de Tumor , Humanos , Mesilato de Imatinib/farmacologia , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Monoéster Fosfórico Hidrolases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Fatores de Transcrição/genética
4.
Front Endocrinol (Lausanne) ; 13: 950326, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060966

RESUMO

Neuroblastoma breakpoint family, member 1 (NBPF1), appears to be a double-edged sword with regard to its role in carcinogenesis. On the one hand, the tumor-suppressing functions of NBPF1 have been definitively observed in neuroblastoma, prostate cancer, cutaneous squamous cell carcinoma, and cervical cancer. On the other hand, there is evidence that NBPF1 regulates the colony formation, invasion, and maintenance of liver cancer cells and hence functions as an oncogene. The roles of NBPF1 are strictly dependent on the biological context and type of organization. However, a systematic pan-cancer analysis has thus far not been undertaken, and the significance of NBPF1 in the occurrence and progression of many malignancies is uncertain. In this paper, bioinformatics techniques were employed to analyze NBPF1 expression across different cancers and investigate the relationship between NBPF1 and clinical features, prognosis, genetic alteration, and tumor immune microenvironment, respectively. Our results show that NBPF1 is variably expressed in distinct tumor tissues and is also closely linked to clinical outcomes. In particular, compared to other tumor types, there was a strong negative correlation between NBPF1 expression and various components of the tumor microenvironment in adrenocortical carcinoma (ACC). We thus developed an NBPF1-derived immune risk model based on NBPF1-related immune genes; ACC patients with a high-risk score tended to have a poorer prognosis, accompanied by immune hyporesponsiveness. NBPF1 can be used as a prognostic biomarker for multiple cancers. Moreover, anti-NBPF1 immunotherapy may be suitable for treating ACC patients.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Genes Supressores de Tumor , Oncogenes , Microambiente Tumoral , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Carcinoma de Células Escamosas/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Genes Supressores de Tumor/fisiologia , Humanos , Neuroblastoma/genética , Oncogenes/genética , Neoplasias Cutâneas/genética , Microambiente Tumoral/genética
5.
Nat Commun ; 13(1): 5033, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028493

RESUMO

DAXX and ATRX are tumor suppressor proteins that form a histone H3.3 chaperone complex and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT). Here, we show that DAXX and ATRX knock-out (KO) U87-T cells that have acquired ALT-like features have defects in p53 chromatin binding and DNA damage response. RNA-seq analysis revealed that p53 pathway is among the most perturbed. ChIP-seq and ATAC-seq revealed a genome-wide reduction in p53 DNA-binding and corresponding loss of chromatin accessibility at many p53 response elements across the genome. Both DAXX and ATRX null cells showed a depletion of histone H3.3 and accumulation of γH2AX at many p53 sites, including subtelomeres. These findings indicate that loss of DAXX or ATRX can compromise p53 chromatin binding and p53 DNA damage response in ALT-like cells, providing a link between histone composition, chromatin accessibility and tumor suppressor function of p53.


Assuntos
Cromatina , Histonas , Proteínas Correpressoras , Dano ao DNA , DNA Helicases , Genes Supressores de Tumor , Chaperonas Moleculares , Proteínas Nucleares , Proteína Supressora de Tumor p53 , Proteína Nuclear Ligada ao X
6.
Annu Rev Genomics Hum Genet ; 23: 331-361, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36044908

RESUMO

A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes-NF1, NF2, TSC1, TSC2, PTEN, VHL, RB1, and TP53-and their related genetic syndromes/entities. We compare and discuss approaches for comprehensive diagnostic genetic testing, the spectrum of variant allele frequency, and disease severity. We also review affected individuals who have no mutation identified after conventional genetic analysis, as well as genotype-phenotype correlations and transmission risk for each tumor suppressor gene in full heterozygous and mosaic patients. This review provides new insight into similarities as well as marked differences regarding the appreciation of mosaicism in these tumor suppressor syndromes.


Assuntos
Genes Supressores de Tumor , Mosaicismo , Humanos , Mutação , Fenótipo , Prevalência
7.
J Immunol Res ; 2022: 4472509, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935578

RESUMO

Ovarian cancer (OC) causes more deaths than any other cancer of the female reproductive system due to its late presentation and malignant nature. Although significant progress has been made in the diagnosis and treatment of OC over the last decade, chemotherapeutic drug resistance and cancer recurrence remain serious challenges in OC management. In the field of cancer therapy, traditional Chinese herbal medicines and their active compounds have been widely reported to have favorable therapeutic effects on cancer. Recent studies have also revealed the protective effect of puerarin in cancer, but the exact role and underlying mechanism of puerarin in OC remain unclear. Here, we established in vivo and in vitro OC models to evaluate the anticancer effect of puerarin. It was found that puerarin significantly inhibited OC cell viability and proliferation and induced cell apoptosis. In OC model mice, puerarin treatment suppressed tumor formation and modulated the gut microbiome. In addition, the expression of tumor suppressor genes was activated by puerarin in vitro and in vivo. These findings add to the existing knowledge on the usefulness of herbal active ingredients for the prevention and treatment of OC and provide a new perspective regarding the therapeutic potential of puerarin in cancer.


Assuntos
Microbioma Gastrointestinal , Neoplasias Ovarianas , Animais , Carcinoma Epitelial do Ovário , Feminino , Genes Supressores de Tumor , Humanos , Isoflavonas , Camundongos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/tratamento farmacológico
8.
Int J Mol Sci ; 23(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35955652

RESUMO

Lung cancer is the leading cause of cancer death worldwide. miR-199a, which has two mature molecules: miR-199a-3p and miR-199a-5p, plays an important biological role in the genesis and development of tumors. We collected recent research results on lung cancer and miR-199a from Google Scholar and PubMed databases. The biological functions of miR-199a in lung cancer are reviewed in detail, and its potential roles in lung cancer diagnosis and treatment are discussed. With miR-199a as the core point and a divergence outward, the interplay between miR-199a and other ncRNAs is reviewed, and a regulatory network covering various cancers is depicted, which can help us to better understand the mechanism of cancer occurrence and provide a means for developing novel therapeutic strategies. In addition, the current methods of diagnosis and treatment of lung cancer are reviewed. Finally, a conclusion was drawn: miR-199a inhibits the development of lung cancer, especially by inhibiting the proliferation, infiltration, and migration of lung cancer cells, inhibiting tumor angiogenesis, increasing the apoptosis of lung cancer cells, and affecting the drug resistance of lung cancer cells. This review aims to provide new insights into lung cancer therapy and prevention.


Assuntos
Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , MicroRNAs/genética , RNA não Traduzido
9.
DNA Cell Biol ; 41(9): 810-823, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35914029

RESUMO

MicroRNAs (miRNAs) are short non-coding RNAs that bind to the 3' untranslated region (3'' UTR) of target mRNAs to control gene expression post-transcriptionally. Recent indications have highlighted their important roles in a variety of pathophysiological conditions as well as human malignancies. Dysregulated miRNAs act as tumor suppressor genes or oncogenes in a variety of cancers. MiR-491 has been shown to have a major effect on tumorigenesis in multiple malignancies through binding to specific genes and signaling cascades, thereby preventing cancer progression. This review provides an overview of miR-491 expression in regulatory mechanisms and biological procedures of tumor cells, as well as the prospective possible treatment effects of various types of human cancers.


Assuntos
MicroRNAs , Neoplasias , Regiões 3' não Traduzidas , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Estudos Prospectivos
10.
Cancer Rep (Hoboken) ; 5(9): e1694, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35976177

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are a class of short non-coding RNAs with a length of approximate 22 nuclei acids that can be expressed both as an oncogene and tumor suppressor gene in human cancers. MiRNAs can participate in the post- transcriptional regulation of gene expression, and regulate the several cancer-related processes, including proliferation, apoptosis, metastasis, etc. RECENT FINDINGS: Expression of miRNA-433 has been reported to vary in different tumors and affected by various factors. We have summarized the different previous studies and found that miRNA-433 can significantly inhibit the growth of the cancer cells not only in malignant tumors of the digestive tract, but also in lung cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, renal carcinoma, glioma, retinoblastoma and osteosarcoma. CONCLUSION: When the expression of miRNA-433 was up-regulated, the proliferation, metastasis and invasion abilities of the malignant tumor cells were significantly inhibited. At the same time, the potential mechanisms through which miRNA-433 can suppress the growth and metastasis of the cancer cells were found to be basically the same, and involved modulation of the specific signaling pathways or target genes in the malignant tumors. Overall, it can be concluded that miRNA-433 can serve as potential and valuable therapeutic target.


Assuntos
Neoplasias da Mama , Neoplasias Renais , MicroRNAs , Neoplasias da Mama/patologia , Feminino , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Renais/genética , MicroRNAs/genética
11.
Int J Mol Sci ; 23(15)2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35955624

RESUMO

The chromodomain helicase DNA binding domain 5 (CHD5) is required for neural development and plays an important role in the regulation of gene expression. Although CHD5 exerts a broad tumor suppressor effect in many tumor types, its specific functions regarding its expression levels, and impact on immune cell infiltration, proliferation and migration in glioma remain unclear. Here, we evaluated the role of CHD5 in tumor immunity in a pan-cancer multi-database using the R language. The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), and Cancer Cell Lines Encyclopedia (CCLE) datasets were utilized to determine the role of CHD5 in 33 types of cancers, including the expression level, prognosis, tumor progression, and immune microenvironment. Furthermore, we explored the effect of CHD5 on glioma proliferation and migration using the cell counting kit 8 (CCK-8) assay, transwell assays and western blot analysis. The findings from our pan-cancer analysis showed that CHD5 was differentially expressed in the tumor tissues as compared to the normal tissues. Survival analysis showed that CHD5 was generally associated with the prognosis of glioblastoma (GBM), low Grade Glioma (LGG) and neuroblastoma, where the low expression of CHD5 was associated with a worse prognosis in glioma patients. Then, we confirmed that the expression level of CHD5 was associated with tumor immune infiltration and tumor microenvironment, especially in glioma. Moreover, si-RNA mediated knockdown of CHD5 promoted the proliferation and migration of glioma cells in vitro. In conclusion, CHD5 was found to be differentially expressed in the pan-cancer analysis and might play an important role in antitumor immunity. CHD5 is expected to be a potential tumor prognostic marker, especially in glioma.


Assuntos
Glioma , Proteínas do Tecido Nervoso , Biomarcadores Tumorais/genética , DNA Helicases/genética , DNA Helicases/metabolismo , Genes Supressores de Tumor , Glioma/genética , Humanos , Proteínas do Tecido Nervoso/metabolismo , Microambiente Tumoral/genética
12.
Adv Cancer Res ; 156: 227-248, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35961701

RESUMO

Despite progress in treating or preventing viral hepatitis, a leading cause of liver cancer, hepatocellular cancer (HCC) continues to be a major cause of cancer-related deaths globally. HCC is a highly heterogeneous cancer with many genetic alterations common within a patient's tumor and between different patients. This complicates therapeutic strategies. In this review, we highlight the critical role that the Smad-mediated transforming growth factor ß (TGF-ß) pathway plays both in liver homeostasis and in the development and progression of HCC. We summarize the mouse models that have enabled the exploration of the dual nature of this pathway as both a tumor suppressor and a tumor promoter. Finally, we highlight how the insights gained from evaluating pathway activity using transcriptional profiling can be used to stratify HCC patients toward rational therapeutic regimens based on the differences in patients with early or late TGF-ß pathway activity or activated, normal, or inactivated profiles of this key pathway.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/patologia , Genes Supressores de Tumor , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
13.
Sci Rep ; 12(1): 13722, 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35962012

RESUMO

The diagnosis and treatment of non-small cell lung cancer (NSCLC) are not ideal. We identified NSCLC-related has_circ_0006423 in database. qRT-PCR was used to measure expression levels of hsa_circ_0006423 and miR-492 in the plasma and tissue samples, and 3 NSCLC cell lines, respectively. We analyzed the relationship between expression levels of hsa_circ_0006423 and clinicopathological factors and miR-492 expression in plasma and tissue samples. Assess the diagnostic value of hsa_circ_0006423 and miR-492 in NSCLC. Cell function vitro experiment to explore the effect of has_circ_0006423 on NSCLC. We found has_circ_0006423 is lower expressed in NSCLC and miR-492 is opposite, has_circ_0006423 and miR-492 has diagnostic value in NSCLC. In A549 and NCI-H1299 cells, hsa_circ_0006423 inhibited the proliferation, migration, and invasion of NSCLC cells by sponging miR-492 and accelerating NSCLC cell apoptosis. This effect may be due to the combination of has_circ_0006423 and miR-492 affecting the progression of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
14.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36012339

RESUMO

Ovarian cancer represents one of the most malignant gynecological cancers worldwide, with an overall 5-year survival rate, being locked in the 25-30% range in the last decade. Cancer immunotherapy is currently one of the most intensively investigated and promising therapeutic strategy and as such, is expected to provide in the incoming years significant benefits for ovarian cancer treatment as well. Here, we provide a detailed survey on the highly pleiotropic oncosuppressive roles played by the human RNASET2 gene, whose protein product has been consistently reported to establish a functional crosstalk between ovarian cancer cells and key cellular effectors of the innate immune system (the monocyte/macrophages lineage), which is in turn able to promote the recruitment to the cancer tissue of M1-polarized, antitumoral macrophages. This feature, coupled with the ability of T2 ribonucleases to negatively affect several cancer-related parameters in a cell-autonomous manner on a wide range of ovarian cancer experimental models, makes human RNASET2 a very promising candidate to develop a "multitasking" therapeutic approach for innovative future applications for ovarian cancer treatment.


Assuntos
Neoplasias Ovarianas , Ribonucleases , Proteínas Supressoras de Tumor , Feminino , Genes Supressores de Tumor , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ribonucleases/genética , Ribonucleases/metabolismo , Proteínas Supressoras de Tumor/genética
15.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36012357

RESUMO

miRNAs are non-coding RNA sequences of approximately 22 nucleotides that interact with genes by inhibiting their translation through binding to their 3' or 5' UTR regions. Following their discovery, the role they play in the development of various pathologies, particularly cancer, has been studied. In this context, miR-7 is described as an important factor in the development of cancer because of its role as a tumor suppressor, regulating a large number of genes involved in the development and progression of cancer. Recent data support the function of miR-7 as a prognostic biomarker in cancer, and miR-7 has been proposed as a strategy in cancer therapy. In this work, the role of miR-7 in various types of cancer is reviewed, illustrating its regulation, direct targets, and effects, as well as its possible relationship to the clinical outcome of cancer patients.


Assuntos
MicroRNAs , Neoplasias , Regiões 5' não Traduzidas , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias/genética
16.
BMC Cancer ; 22(1): 922, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028821

RESUMO

BACKGROUND: Lymph node metastasis (LNM) is a critical event during the colorectal cancer (CRC) development and is indicative of poor prognosis. Identification of molecular markers of LNM may facilitate better therapeutic decision-making. METHODS: Six pairs of CRC tissues and corresponding adjacent tissues [3 pairs diagnosed as pT1N0M0 (M_Low group) and 3 pairs diagnosed as pT4N2M0 (M_High group)] collected from CRC patients who underwent surgical resection were used. MicroRNA sequencing was performed to screen differential microRNAs involved in CRC LNM. The selected microRNAs were validated in CRC tissues and cell lines using qRT-PCR. The functions of candidate hsa-miR-1248 were evaluated by CCK-8, colony formation, and Transwell assay. The binding of hsa-miR-1248 with its target PSMD10 was confirmed by luciferase activity assay, and the expression of PSMD10 in tissues was detected by droplet digital polymerase chain reaction. RESULTS: Ninety-five miRNAs were downregulated in carcinoma tissues (M_Low and M_high groups) compared with the normal group. Their expression in M_High group was significantly lower compared with M_Low group. The top 3 were hsa-miR-635, hsa-miR-1248, and hsa-miR-668-3p. After validation in tissues/cell lines, only hsa- hsa-miR-1248 was decreased in high metastatic tissues or SW620 cells compared to low metastatic tissues or SW480 cells. Hsa-miR-1248 was found to inhibit CRC cell viability, proliferation, invasion, and migration. The tumor suppressor effect of has-miR-1248 in CRC cells was attenuated or enhanced by up-regulating or down-regulating PSMD10, respectively. CONCLUSION: Hsa-miR-1248 may act as a tumor suppressor gene in CRC by targeting and inhibiting PSMD10, which provides a clue for CRC treatment.


Assuntos
Neoplasias Colorretais , MicroRNAs , Complexo de Endopeptidases do Proteassoma , Proteínas Proto-Oncogênicas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Metástase Linfática , MicroRNAs/genética , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas/genética
17.
Sci Rep ; 12(1): 12208, 2022 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-35842463

RESUMO

Localized in the mitochondria, SIRT4 is a nicotinamide adenine dinucleotide (NAD +) -dependent adenosine diphosphate (ADP) -ribosyltransferase and is one of the least characterized members of the sirtuin family. Although it is well known that it shows deacetylase activity for energy metabolism, little is understood about its function in tumorigenesis. Recent research suggests that SIRT4 may work as both a tumor suppressor gene and an oncogene. However, the clinical significance of SIRT4 in prostate cancer remains unknown. In this study, we evaluated SIRT4 protein levels in cancerous prostate tissue and corresponding non-tumor prostate tissue via immunohistochemical staining on a tissue microarray including tissues from 89 prostate cancer patients. The association between SIRT4 expression and Gleason score was also determined. Further, shSIRT4 or stable prostate cancer cell lines (22RV1) overexpressing SIRT4 were constructed via lentiviral infection. Using Cell-Counting Kit-8 (CCK-8) assay, wound healing assay, migration, and invasion and apoptosis assays, the effects of SIRT4 on the migration, invasion ability, and proliferation of prostate cancer cells were investigated. We also determined the effect of SIRT4 on glutamine metabolism in 22RV1 cells. We found the protein levels of SIRT4 in prostate cancer tissues were significantly lower than those in their non-neoplastic tissue counterparts (P < 0.01); a lower SIRT4 level was also significantly associated with a higher Gleason score (P < 0.01). SIRT4 suppressed the migration, invasion capabilities, and proliferation of prostate cancer cells and induced cellular apoptosis. Furthermore, the invasion and migration of 22RV1 cells were mechanistically inhibited by SIRT4 via glutamine metabolism inhibition. In conclusion, the present study's findings showed that SIRT4 protein levels are significantly associated with the Gleason score in patients with prostate cancer, and SIRT4 exerts a tumor-suppressive effect on prostate cancer cells by inhibiting glutamine metabolism. Thus, SIRT4 may serve as a potential novel therapeutic target for prostate cancer.


Assuntos
Neoplasias da Próstata , Sirtuínas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Genes Supressores de Tumor , Glutamina/metabolismo , Humanos , Masculino , Proteínas Mitocondriais/metabolismo , NAD/metabolismo , Neoplasias da Próstata/genética , Sirtuínas/genética , Sirtuínas/metabolismo
18.
Int J Biol Sci ; 18(10): 4233-4244, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844785

RESUMO

High frequent metastasis is the major cause of breast cancer (BC) mortality among women. However, the molecular mechanisms underlying BC metastasis remain largely unknown. Here, we identified six hub BC metastasis driver genes (BEND5, HSD11B1, NEDD9, SAA2, SH2D2A and TNFSF4) through bioinformatics analysis, among which BEND5 is the most significant gene. Low BEND5 expression predicted advanced stage and shorter overall survival in BC patients. Functional experiments showed that BEND5 could suppress BC growth and metastasis in vitro and in vivo. Mechanistically, BEND5 inhibits Notch signaling via directly interacting with transcription factor RBPJ/CSL. BEN domain of BEND5 interacts with the N-terminal domain (NTD) domain of RBPJ, thus preventing mastermind like transcriptional coactivator (MAML) from forming a transcription activation complex with RBPJ. Our study provides a novel insight into regulatory mechanisms underlying Notch signaling and suggests that BEND5 may become a promising target for BC therapy.


Assuntos
Neoplasias da Mama , Receptores Notch , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Ligante OX40/genética , Ligante OX40/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Int J Biol Sci ; 18(10): 3918-3933, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35844798

RESUMO

Objective: The treatment and prognosis of patients with advanced colorectal cancer (CRC) remain a difficult problem. Herein, we investigated the role of DEAD (Asp-Glu-Ala-Asp) box helicase 3 (DDX3) in CRC and proposed potential therapeutic targets for advanced CRC. Methods: The expression of DDX3 in CRC and its effect on prognosis were explored by databases and CRC tissue microarrays. Stable DDX3 knockdown and overexpression cell lines were established with lentiviral vectors. The effects of DDX3 on CRC were investigated by functional experiments in vitro and in vivo. The molecular mechanism of DDX3 in CRC was explored by western blotting. Molecular-specific inhibitors were further used to explore potential therapeutic targets for advanced CRC. Results: The expression of DDX3 was decreased in advanced CRC, and patients with low DDX3 expression had a poor prognosis. In vitro and in vivo experiments showed that low DDX3 expression promoted the proliferation, migration and invasion of CRC. DDX3 loss regulated E-cadherin and ß-catenin signaling through the mitogen-activated protein kinase (MAPK) pathway as shown by western blotting. In addition, the MEK inhibitor, PD98059, significantly reduced the increased cell proliferation, migration and invasion caused by knockdown of DDX3. Conclusions: DDX3 acts as a tumor suppressor gene in CRC. DDX3 loss in advanced cancer promotes cancer progression by regulating E-cadherin and ß-catenin signaling through the MAPK pathway, and targeting the MAPK pathway may be a therapeutic approach for advanced CRC.


Assuntos
Neoplasias Colorretais , RNA Helicases DEAD-box/metabolismo , beta Catenina , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Via de Sinalização Wnt , beta Catenina/metabolismo
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