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1.
Dig Dis Sci ; 69(1): 112-122, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37957408

RESUMO

BACKGROUND/AIMS: Aberrant Peroxisomal Biogenesis Factor 26 (PEX26) occurs in multiple cell process. However, the role of PEX26 in colorectal cancer (CRC) development remains unknown. We aimed to study PEX26 expression, regulation, and function in CRC cells. METHODS: Using the bioinformatic analysis, real-time quantitative PCR, and immunohistochemistry staining, we detected the expression of PEX26 in CRC and normal tissues. We performed functional experiments in vitro to elucidate the effect of PEX26 on CRC cells. We analyzed the RNA-seq data to reveal the downstream regulating network of PEX26. RESULTS: PEX26 is significantly down-regulated in CRC and its low expression correlates with the poor overall survival of CRC patients. We further demonstrated that PEX26 over-expression inhibits the ability of CRC cell migration, invasion, and epithelial-mesenchymal transition (EMT), while PEX26 knockdown promotes the malignant phenotypes of migration, invasion, and EMT via activating the Wnt pathway. CONCLUSION: Overall, our results showed that the loss of PEX26 contributes to the malignant phenotype of CRC. PEX26 may serve as a novel metastasis repressor for CRC.


Assuntos
Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Humanos , Linhagem Celular Tumoral , Células HCT116 , Fenótipo , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Metástase Neoplásica , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
2.
J Cell Biochem ; 122(12): 1781-1790, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34397105

RESUMO

The present study aimed to construct a novel methylation-related prognostic model based on microsatellite status that may enhance the prognosis of colorectal cancer (CRC) from methylation and microsatellite status perspective. DNA methylation and mRNA expression data with clinical information were downloaded from The Cancer Genome Atlas (TCGA) data set. The samples were divided into microsatellite stability and microsatellite instability group, and CIBERSORT was used to assess the immune cell infiltration characteristics. After identifying the differentially methylated genes and differentially expression genes using R packages, the methylation-driven genes were further identified. Prognostic genes that were used to establish the methylation-related risk score model were generated by the univariate and multivariate Cox regression model. Finally, we established and evaluated the methylation-related prognostic model for CRC patients. A total of 69 MDGs were obtained and three of these genes (MIOX, TH, DKFZP434K028) were selected to construct the prognostic model. Patients in the low-risk score group had a conspicuously better overall survival than those in the high-risk score group (p < .0001). The area under the receiver operating characteristic curve for this model was 0.689 at 3 years, 0.674 at 4 years, and 0.658 at 5 years. The Wilcoxon test showed that higher risk score was associated with higher T stage (p = .01), N stages (p = .0028), metastasis (p = .013), and advanced pathological stage (p = .0013). However, the more instability of microsatellite status, the lower risk score of CRC patients (p = .0048). Our constructed methylation-related prognostic model based on microsatellite status presents potential significance in assessing recurrence risk stratification, tumor staging, and immunotherapy for CRC patients.


Assuntos
Neoplasias Colorretais/metabolismo , Metilação de DNA , DNA de Neoplasias/metabolismo , Repetições de Microssatélites , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , DNA de Neoplasias/genética , Humanos , Proteínas de Neoplasias/genética , Prognóstico
3.
Biol Chem ; 402(7): 805-813, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-33984882

RESUMO

The molecular pathogenesis of colorectal cancer (CRC) has been widely investigated in recent years. Accumulating evidence has indicated that microRNA (miRNA) dysregulation participates in the processes of driving CRC initiation and progression. Aberrant expression of miR-1301 has been found in various tumor types. However, its role in CRC remains to be elucidated. In the present study, we identified miR-1301 was enriched in normal colorectal tissues and significantly down-regulated in CRC. Decreased level of miR-1301 strongly correlated with aggressive pathological characteristics, including advanced stage and metastasis. Bioinformatics and dual luciferase assay demonstrated that STAT3 is a direct target of miR-1301. Gain and loss-of-function assays showed that miR-1301 had no effect on cell proliferation. Overexpression of miR-1301 suppressed cell migration and invasion capacity of pSTAT3-positive LoVo cells, but not pSTAT3-negative SW480 cells, while inhibition of miR-1301 consistently promoted cell migration and invasion in both cell lines. Additionally, miR-1301 inhibition restored the suppressed migration and invasion of STAT3-knockdown LoVo cells. MiR-1301 functioned as a tumor suppressor to modulate the IL6/STAT3 signaling pathway. In summary, this study highlights the significant role of miR-1301/STAT3 axis in CRC metastasis.


Assuntos
Neoplasias Colorretais/metabolismo , MicroRNAs/metabolismo , Fator de Transcrição STAT3/metabolismo , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , MicroRNAs/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas
4.
Life Sci ; 266: 118872, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309715

RESUMO

AIMS: Colorectal cancer (CRC) is a leading cause of cancer-related death globally. Thus, in this study, we aimed to investigate chromosome 8 open reading frame 48 (C8orf48) as a biomarker for early detection of CRC. MAIN METHODS: RNA expression and methylation profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Cell proliferation, migration and invasion assays were performed to confirm the function of C8orf48 in CRC cells. Dual-luciferase reporter assay was used to identify that C8orf48 was the direct target of miR-556. Genomics of Drug Sensitivity in Cancer (GDSC) database, gene set enrichment analysis (GSEA) and western blot analysis were performed to explore the mechanism of C8orf48. KEY FINDINGS: we found that C8orf48 is down-regulated in clinical samples of CRC tissues. Enrichment analysis showed that C8orf48 is associated with methylation biomarkers in CRC, and TCGA database confirmed that the methylation of C8orf48 is up-regulated in the early stage of CRC. We further revealed that the overexpression of C8orf48 decreased CRC cell proliferation, migration and invasion. Luciferase reporter indicated that C8orf48 was the direct target of the oncogene miR-556. Additionally, we used GDSC database, GSEA database and western blot analysis to demonstrate that C8orf48 plays a suppressor role in CRC by inhibiting MAPK signaling pathway. SIGNIFICANCE: C8orf48 was identified as a biomarker for early detection of CRC for the first time, and might provide novel information for CRC prediction and therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Proteínas de Neoplasias/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Prognóstico , Células Tumorais Cultivadas
5.
Int J Mol Sci ; 21(24)2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33302562

RESUMO

Colorectal cancer (CRC) is one of the most common malignant carcinomas in the world, and metastasis is the main cause of CRC-related death. However, the molecular network involved in CRC metastasis remains poorly understood. Long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and may act as a competing endogenous RNA (ceRNA) to affect the expression of mRNA by suppressing miRNA function. In this study, we identified 628 mRNAs, 144 lncRNAs, and 25 miRNAs that are differentially expressed (DE) in metastatic CRC patients compared with nonmetastatic CRC patients from the Cancer Genome Atlas (TCGA) database. Functional enrichment analyses confirmed that the identified DE mRNAs are extensively involved in CRC tumorigenesis and migration. By bioinformatics analysis, we constructed a metastasis-associated ceRNA network for CRC that includes 28 mRNAs, 12 lncRNAs, and 15 miRNAs. We then performed multivariate Cox regression analysis on the ceRNA-related DE lncRNAs and identified a 3-lncRNA signature (LINC00114, LINC00261, and HOTAIR) with the greatest prognostic value for CRC. Clinical feature analysis and functional enrichment analysis further proved that these three lncRNAs are involved in CRC tumorigenesis. Finally, we used Transwell, Cell Counting Kit (CCK)-8, and colony formation assays to clarify that the inhibition of LINC00114 promotes the migratory, invasive, and proliferative abilities of CRC cells. The results of the luciferase assay suggest that LINC00114 is the direct target of miR-135a, which also verified the ceRNA network. In summary, this study provides a metastasis-associated ceRNA network for CRC and suggests that the 3-lncRNA signature may be a useful candidate for the diagnosis and prognosis of CRC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , RNA Longo não Codificante/genética , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Redes Reguladoras de Genes , Células HCT116 , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Análise de Sobrevida , Transcriptoma
6.
Int J Mol Sci ; 21(18)2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32899503

RESUMO

Metastasis is a well-known poor prognostic factor and primary cause of mortality in patients with colorectal cancer (CRC). Recently, with the progress of high through-put sequencing, aberrantly expressed non-coding RNAs (ncRNAs) were found to participate in the initiation and development of cancer. However, the mechanisms of ncRNA-mediated regulation of metastasis in CRC remain largely unknown. In this study, we systematically analyzed the expression network of microRNAs (miRNAs) and genes in CRC metastasis using bioinformatics, and discovered that the miR-581/SMAD7 axis could be a potential factor that drives CRC metastasis. A dual luciferase report assay and protein analysis confirmed the binding relationship between miR-581 and SMAD7. Further functional assays revealed that miR-581 inhibition could suppress cell proliferation and induce apoptosis in SW480 cells. Up-regulation or down-regulation of miR-581 could both affect cell invasion capacity and modulate epithelial to mesenchymal transition (EMT) via a SMAD7/TGFß signaling pathway. In conclusion, our findings elucidated that miR-581/SMAD7 could be essential for CRC metastasis, and may serve as a potential therapeutic target for CRC patients.


Assuntos
Neoplasias Colorretais/genética , MicroRNAs/genética , Proteína Smad7/genética , Bancos de Espécimes Biológicos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/patologia , Biologia Computacional/métodos , Bases de Dados Genéticas , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Proteína Smad7/metabolismo
7.
Cancer Cell Int ; 20: 208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32518519

RESUMO

BACKGROUND: Lung cancer is the most common cancer worldwide, and metastasis is the leading cause of lung cancer related death. However, the molecular network involved in lung cancer metastasis remains incompletely described. Here, we aimed to construct a metastasis-associated ceRNA network and identify a lncRNA prognostic signature in lung cancer. METHODS: RNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and gene set enrichment analysis (GSEA) were performed to investigate the function of these genes. Using Cox regression analysis, we found that a 6 lncRNA signature may serve as a candidate prognostic factor in lung cancer. Finally, we used Transwell assays with lung cancer cell lines to verify that LINC01010 acts as a tumor suppressor. RESULTS: We identified 1249 differentially expressed (DE) mRNAs, 440 DE lncRNAs and 26 DE miRNAs between nonmetastatic and metastatic lung cancer tissues. GO and KEGG analyses confirmed that the identified DE mRNAs are involved in lung cancer metastasis. Using bioinformatics tools, we constructed a metastasis-associated ceRNA network for lung cancer that includes 117 mRNAs, 23 lncRNAs and 22 miRNAs. We then identified a 6 lncRNA signature (LINC01287, SNAP25-AS1, LINC00470, AC104809.2, LINC00645 and LINC01010) that had the greatest prognostic value for lung cancer. Furthermore, we found that suppression of LINC01010 promoted lung cancer cell migration and invasion. CONCLUSIONS: This study might provide insight into the identification of potential lncRNA biomarkers for diagnosis and prognosis in lung cancer.

8.
J Cell Physiol ; 235(2): 1469-1479, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31273789

RESUMO

Aberrant loss of tumor-suppressor genes plays a crucial role in tumorigenesis and development of colorectal cancer (CRC). Extensive studies have reported tha hypermethylation of Ras association domain family member 6 (RASSF6) is common in various solid tumors. Another important mode of epigenetic regulation, microRNA (miRNA) regulation of RASSF6, is far from clear. The aim of the present work was to screen out novel miRNA regulating RASSF6, and to explore its underlying mechanism in CRC. With the use of bioinformatics, clinical sample data, and luciferase binding assay, we determined that microRNA-496 (miR-496) could be a novel oncomiR that directly binds to RASSF6. Next, a series of miR-496 mimics or inhibitor, or RASSF6 small interfering RNA (siRNA) introduced into CRC cells were applied to examine the effect of miR-496 on CRC cell viability, migration, and epithelial-mesenchymal transition (EMT). The results demonstrated that miR-496/RASSF6 could promote cell migration and EMT via Wnt signaling activation, but had no effect on cell viability. Our results confirmed that the miR-496/RASSF6 axis is involved in Wnt pathway-mediated tumor metastasis, highlighting its potential as a therapeutic target for CRC.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Movimento Celular/genética , Neoplasias Colorretais/genética , Metilação de DNA/genética , Humanos , Via de Sinalização Wnt/fisiologia
9.
Apoptosis ; 24(7-8): 662-672, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31134446

RESUMO

Mutations in the DNA damage repair (DDR) pathway are frequently detected in colorectal cancer (CRC). The dysregulation of miRNAs, such as oncogenes or tumor suppressors, participates in CRC tumorigenesis. A previous study showed that low miR-3607 expression correlated with poor survival in prostate cancer patients, but its role in CRC remains unclear. In this study, we analyzed miR-3607 expression Pan-Cancer data from the NCI's Genomic Data Commons (GDC) and found that miR-3607 was downregulated in lymphatic invasion patients and in recurrent cancer and correlated with Pan-Cancer patient survival. Functional studies indicated that the overexpression of miR-3607 decreased CRC cell proliferation, migration and invasion. Additionally, we used gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and a protein-protein interaction network to demonstrate that miR-3607 affects the DDR pathway. Luciferase reporter and apoptosis assays confirmed that DNA damage inducible 1 homolog 2 (DDI2) is the functional target of miR-3607. Therefore, miR-3607 inhibits the tumorigenesis of CRC probably by suppressing the oncogene DDI2, and it might serve as a novel target for CRC prediction and therapy.


Assuntos
Ácido Aspártico Proteases/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Dano ao DNA/genética , MicroRNAs/genética , Apoptose , Ácido Aspártico Proteases/antagonistas & inibidores , Ácido Aspártico Proteases/metabolismo , Sítios de Ligação , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Células HT29 , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Mutação , Invasividade Neoplásica , Mapas de Interação de Proteínas
10.
Mol Carcinog ; 58(6): 957-966, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30693981

RESUMO

Sporadic colorectal cancer (sCRC) is one of the leading causes of cancer death worldwide. As a highly heterogeneous complex disease, the currently reported classical genetic markers for sCRC, including APC, KRAS, BRAF, and TP53 gene mutations and epigenetic alterations, can explain only some sCRC patients. Here, we first reported a deleterious c.551C>T mutation in SARDH in sCRC. SARDH was identified as a novel tumor suppressor gene and was abnormally decreased in sCRC at both the transcriptional and the translational level. SARDH mRNA levels were also down-regulated in oesophageal cancer, lung cancer, liver cancer, and pancreatic cancer in the TCGA database. SARDH overexpression inhibited the proliferation, migration, and invasion of CRC cell lines, whereas its depletion improved these processes. SARDH overexpression was down-regulated in multiple pathways, especially in the chemokine pathway. The SARDH transcript level was positively correlated with the methylation states of CXCL1 and CCL20. Therefore, we concluded that SARDH depletion is involved in the development of sCRC.


Assuntos
Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica/métodos , Mutação Puntual , Sarcosina Desidrogenase/genética , Sarcosina Desidrogenase/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CCL20/genética , Quimiocina CXCL1/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Metilação de DNA , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Splicing de RNA , Sequenciamento do Exoma
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