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1.
Cancer Immunol Immunother ; 73(8): 156, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834869

RESUMO

BACKGROUND: Ubiquitin-specific proteases family is crucial to host immunity against pathogens. However, the correlations between USP21 and immunosurveillance and immunotherapy for colorectal cancer (CRC) have not been reported. METHODS: The differential expression of USP21 between CRC tissues and normal tissues was analyzed using multiple public databases. Validation was carried out in clinical samples through qRT-PCR and IHC. The correlation between USP21 and the prognosis, as well as clinical pathological characteristics of CRC patients, was investigated. Moreover, cell models were established to assess the influence of USP21 on CRC growth and progression, employing CCK-8 assays, colony formation assays, and wound-healing assays. Subsequently, gene set variation analysis (GSVA) was used to explore the potential biological functions of USP21 in CRC. The study also examined the impact of USP21 on cytokine levels and immune cell infiltration in the tumor microenvironment (TME). Finally, the effect of USP21 on the response to immunotherapy and chemotherapy in CRC was analyzed. RESULTS: The expression of USP21 was significantly upregulated in CRC. High USP21 is correlated with poor prognosis in CRC patients and facilitates the proliferation and migration capacities of CRC cells. GSVA indicated an association between low USP21 and immune activation. Moreover, low USP21 was linked to an immune-activated TME, characterized by high immune cell infiltration. Importantly, CRC with low USP21 exhibited higher tumor mutational burden, high PD-L1 expression, and better responsiveness to immunotherapy and chemotherapeutic drugs. CONCLUSION: This study revealed the role of USP21 in TME, response to therapy, and clinical prognosis in CRC, which provided novel insights for the therapeutic application in CRC.


Assuntos
Neoplasias Colorretais , Microambiente Tumoral , Ubiquitina Tiolesterase , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Microambiente Tumoral/imunologia , Prognóstico , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Masculino , Feminino , Proliferação de Células , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Imunoterapia/métodos
2.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 592-597, 2024 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-38825905

RESUMO

Objective: To investigate the expression of DARS2 and its clinical significance in colorectal cancer. Methods: In this study, bioinformatics tools, especially gene expression profile interactive analysis 2 (GEPIA2), were used to conduct an in-depth analysis of DARS2 expression in colorectal cancer tissues. Immunohistochemical staining was carried out in 108 colorectal cancer specimens and 30 normal colorectal tissues obtained from the First Affiliated Hospital of Nanchang University, Nanchang, China. Colorectal cancer cell lines (HCT116 and SW480) were transfected with small interfering RNA (siRNA) and DARS2 overexpression plasmid to examine the effects of DARS2 knockdown and overexpression on cell function. To assess the effects on cell function, CCK8 and transwell migration assays were used to assess proliferation and cell motility, respectively. Additionally, protein immunoblotting was employed to scrutinize the expression of proteins associated with the epithelial-mesenchymal transition of colorectal cancer cells. Results: DARS2 exhibited a pronounced upregulation in expression within colorectal cancer tissues compared to their normal epithelial counterparts. Furthermore, DARS2 expression was higher in colorectal cancer of stage Ⅲ-Ⅳ than those of stage Ⅰ-Ⅱ, exhibiting a significant correlation with N staging, M staging, and pathological staging (P<0.05). Kaplan-Meier analyses showed a decreased overall survival rate in colorectal cancer with DARS2 expression compared to those without DARS2 expression (P<0.05). In the siRNA transfection group, there was a significant reduction in cell proliferation and migration (P<0.01 and P<0.05, respectively). Conversely, the transfection of DARS2 overexpression plasmids substantially increased both cell proliferation and migration (P<0.05). Additionally, immunoblotting revealed that DARS2 knockdown led to an upregulation of E-cadherin expression and a downregulation of N-cadherin and vimentin expression. In contrast, DARS2 overexpression resulted in increased N-cadherin and vimentin expression, coupled with reduction in E-cadherin expression. Conclusions: There is a strong association between DARS2 expression and colorectal cancer progression. Silencing DARS2 inhibits cell proliferation and migration, exerting a discernible influence on the epithelial-mesenchymal transition process.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , RNA Interferente Pequeno , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , RNA Interferente Pequeno/genética , Linhagem Celular Tumoral , Vimentina/metabolismo , Vimentina/genética , Caderinas/metabolismo , Caderinas/genética , Taxa de Sobrevida , Células HCT116 , Estadiamento de Neoplasias , Regulação para Cima , Regulação Neoplásica da Expressão Gênica , Relevância Clínica
3.
BMC Cancer ; 24(1): 683, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840078

RESUMO

BACKGROUND: MicroRNAs (miRNAs) emerge in various organisms, ranging from viruses to humans, and play crucial regulatory roles within cells, participating in a variety of biological processes. In numerous prediction methods for miRNA-disease associations, the issue of over-dependence on both similarity measurement data and the association matrix still hasn't been improved. In this paper, a miRNA-Disease association prediction model (called TP-MDA) based on tree path global feature extraction and fully connected artificial neural network (FANN) with multi-head self-attention mechanism is proposed. The TP-MDA model utilizes an association tree structure to represent the data relationships, multi-head self-attention mechanism for extracting feature vectors, and fully connected artificial neural network with 5-fold cross-validation for model training. RESULTS: The experimental results indicate that the TP-MDA model outperforms the other comparative models, AUC is 0.9714. In the case studies of miRNAs associated with colorectal cancer and lung cancer, among the top 15 miRNAs predicted by the model, 12 in colorectal cancer and 15 in lung cancer were validated respectively, the accuracy is as high as 0.9227. CONCLUSIONS: The model proposed in this paper can accurately predict the miRNA-disease association, and can serve as a valuable reference for data mining and association prediction in the fields of life sciences, biology, and disease genetics, among others.


Assuntos
MicroRNAs , Redes Neurais de Computação , Humanos , MicroRNAs/genética , Predisposição Genética para Doença , Biologia Computacional/métodos , Neoplasias Colorretais/genética , Neoplasias Pulmonares/genética , Algoritmos
4.
Genome Med ; 16(1): 77, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38840170

RESUMO

BACKGROUND: Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. METHODS: Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. RESULTS: Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. CONCLUSIONS: This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.


Assuntos
Neoplasias Colorretais , Metilação de DNA , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/genética , Feminino , Masculino , Pessoa de Meia-Idade , Epigênese Genética , Idoso , Ilhas de CpG , Metagenômica/métodos , Metagenoma , Microbiota/genética , Fezes/microbiologia , RNA Ribossômico 16S/genética
5.
Cell Mol Biol (Noisy-le-grand) ; 70(6): 187-191, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38836661

RESUMO

In this study, we investigated the role of LINC00520 in colorectal cancer (CRC) progression. We analyzed LINC00520 expression in 15 pairs of CRC tissues and adjacent tissues using qRT-PCR, revealing significantly elevated levels in CRC tissues and cell lines. Lentivirus-mediated up/down-regulation of LINC00520 in CRC cell lines demonstrated that increased LINC00520 expression enhanced cell invasiveness, as confirmed by transwell and wound healing assays. Bioinformatics analysis identified a regulatory axis involving LINC00520, microRNA-195-3p, and NAT2. Luciferase assays confirmed direct binding between LINC00520 and microRNA-195-3p, as well as microRNA-195-3p and NAT2. Overexpression of NAT2 reversed the inhibitory effects on invasion and migration induced by LINC00520 silencing. This suggests that LINC00520, highly expressed in CRC tissues, may modulate tumor biological functions through the microRNA-195-3p/NAT2 axis. Our findings provide insights into the mechanism underlying CRC progression, highlighting the potential of LINC00520 as a therapeutic target.


Assuntos
Arilamina N-Acetiltransferase , Movimento Celular , Neoplasias Colorretais , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Linhagem Celular Tumoral , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Movimento Celular/genética , Invasividade Neoplásica/genética , Proliferação de Células/genética
6.
Cell Mol Biol (Noisy-le-grand) ; 70(6): 14-20, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38836687

RESUMO

Colorectal cancer (CRC) poses a significant global health challenge with high morbidity and mortality rates. This study investigates the role of LY6G6D, a member of the LY6/uPAR superfamily, in CRC. Employing a bioinformatic approach, we analyzed LY6G6D expression across different cancer types, compared it with known oncogenes in CRC, explored the involved genomic alterations, and assessed associated clinicopathological characteristics. LY6G6D exhibited aberrant expression, particularly elevated in CRC adenocarcinoma and highly specific to tumor tissues when compared with other oncogenes, despite its comparatively low frequency of genomic alteration. Subsequently, tumor immune infiltration analysis revealed distinct associations, primarily indicating a negative correlation, suggesting immune down-regulation. Survival analysis in context of LY6G6D was conducted with Kaplan-Meier (KM) curves, indicating a 10% risk of disease recurrence in the case of elevated expression. Additionally, we constructed a 3D protein model of LY6G6D through ab-inito approach. The protein model was validated, followed by conservation analysis and active site identification. Active site identification of LY6G6D's final predicted model revealed some similar sites that were estimated to be conserved. Target-guided drug molecules were collected and molecular docking was executed, proposing Cardigin (Digitoxin) and Manzamine A as potential therapeutic candidates. In conclusion, LY6G6D emerges as a significant biomarker for diagnostic and therapeutic applications in CRC, highlighting its multifaceted role in tumorigenesis. The proposed drugs present avenues for further investigations.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Humanos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Simulação de Acoplamento Molecular , Antígenos Ly/metabolismo , Antígenos Ly/genética , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/genética
7.
Mol Biomed ; 5(1): 21, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38844562

RESUMO

Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.


Assuntos
Neoplasias Colorretais , Terapia de Alvo Molecular , Transdução de Sinais , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/terapia , Neoplasias Colorretais/imunologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia
8.
Sci Rep ; 14(1): 13037, 2024 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844605

RESUMO

The proteasome-associated deubiquitinase USP14 is a potential drug target. Using an inducible USP14 knockout system in colon cancer cells, we found that USP14 depletion impedes cellular proliferation, induces cell cycle arrest, and leads to a senescence-like phenotype. Transcriptomic analysis revealed altered gene expression related to cell division and cellular differentiation. USP14 knockout cells also exhibited changes in morphology, actin distribution, and expression of actin cytoskeletal components. Increased ubiquitin turnover was observed, offset by upregulation of polyubiquitin genes UBB and UBC. Pharmacological inhibition of USP14 with IU1 increased ubiquitin turnover but did not affect cellular growth or morphology. BioGRID data identified USP14 interactors linked to actin cytoskeleton remodeling, DNA damage repair, mRNA splicing, and translation. In conclusion, USP14 loss in colon cancer cells induces a transient quiescent cancer phenotype not replicated by pharmacologic inhibition of its deubiquitinating activity.


Assuntos
Proliferação de Células , Senescência Celular , Neoplasias Colorretais , Ubiquitina Tiolesterase , Humanos , Senescência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Linhagem Celular Tumoral , Fenótipo , Complexo de Endopeptidases do Proteassoma/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Ubiquitina/metabolismo
9.
J Transl Med ; 22(1): 544, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844980

RESUMO

BACKGROUND: Several studies have demonstrated a strong correlation between impaired Succinate dehydrogenase (SDH) function and the advancement of tumors. As a subunit of SDH, succinate dehydrogenase complex subunit C (SDHC) has been revealed to play tumor suppressive roles in several cancers, while its specific role in colorectal cancer (CRC) still needs further investigation. METHODS: Online database were utilized to investigate the expression of SDHC in colorectal cancer and to assess its correlation with patient prognosis. Cell metastasis was assessed using transwell and wound healing assays, while tumor metastasis was studied in a nude mice model in vivo. Drug screening and RNA sequencing were carried out to reveal the tumor suppressor mechanism of SDHC. Triglycerides, neutral lipids and fatty acid oxidation were measured using the Triglyceride Assay Kit, BODIPY 493/503 and Colorimetric Fatty Acid Oxidation Rate Assay Kit, respectively. The expression levels of enzymes involved in fatty acid metabolism and the PI3K/AKT signaling pathway were determined by quantitative real-time PCR and western blot. RESULTS: Downregulation of SDHC was found to be closely associated with a poor prognosis in CRC. SDHC knockdown promoted CRC metastasis both in vitro and in vivo. Through drug screening and Gene set enrichment analysis, it was discovered that SDHC downregulation was positively associated with the fatty acid metabolism pathways significantly. The effects of SDHC silencing on metastasis were reversed when fatty acid synthesis was blocked. Subsequent experiments revealed that SDHC silencing activated the PI3K/AKT signaling axis, leading to lipid accumulation by upregulating the expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) and reduction of fatty acid oxidation rate by suppressing the expression of acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1A (CPT1A). CONCLUSIONS: SDHC deficiency could potentially enhance CRC metastasis by modulating the PI3K/AKT pathways and reprogramming lipid metabolism.


Assuntos
Neoplasias Colorretais , Ácidos Graxos , Camundongos Nus , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-akt , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Humanos , Ácidos Graxos/metabolismo , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Transdução de Sinais , Masculino , Feminino , Regulação para Baixo/genética , Técnicas de Silenciamento de Genes , Camundongos , Metabolismo dos Lipídeos/genética , Camundongos Endogâmicos BALB C
10.
Cancer Rep (Hoboken) ; 7(6): e2085, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38837682

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. Long noncoding RNA (lncRNA) is involved in many malignant tumors. This study aimed to clarify the role of the lncRNA plasmacytoma variant translocation 1 (PVT1) in CRC growth and metastasis. METHODS: Differentially expressed lncRNAs in CRC were analyzed using the Cancer Genome Atlas. Gene expression profiling interactive analysis and a comprehensive resource for lncRNAs from cancer arrays databases were used to analyze lncRNA PVT1 expression and CRC prognosis, respectively. Cell counting kit-8, wound healing, colony formation, Transwell, and immunofluorescence assays were used to evaluate CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), respectively. Tumor growth and metastasis models were used to explore the PVT1 effect on the growth and metastasis of CRC in vivo. RESULTS: PVT1 was highly expressed in CRC, associated with a poor prognosis of CRC, and showed good diagnostic value. Transfection of sh-PVT1 or pcDNA3.1-PVT1 reduced or increased the proliferation, wound healing rate, colony formation, invasion, and EMT of CRC cells. PVT1 and miR-3619-5p were co-expressed in CRC cytoplasm, and PVT1 acted as a competitive endogenous RNA (ceRNA) by sponging miR-3619-5p to up-regulate tripartite motif containing 29 (TRIM29) expression. MiR-3619-5p overexpression and TRIM29 knockdown reduced proliferation, wound healing rate, invasion, and EMT of CRC cells. However, simultaneous PVT1 and miR-3619-5p overexpression or knockdown of miR-3619-5p and TRIM29 knockdown rescued the malignant phenotype of CRC cells. CONCLUSIONS: We first clarified the ceRNA mechanism of PVT1 in CRC, which induced growth and metastasis by sponging with miR-3619-5p to regulate TRIM29.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , MicroRNAs , RNA Longo não Codificante , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , RNA Longo não Codificante/genética , MicroRNAs/genética , Proliferação de Células/genética , Camundongos , Animais , Prognóstico , Transição Epitelial-Mesenquimal/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Masculino , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos Nus , Feminino , Linhagem Celular Tumoral , Metástase Neoplásica , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Eur J Med Res ; 29(1): 310, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38840262

RESUMO

KDM6A (lysine demethylase 6A) has been reported to undergo inactivating mutations in colorectal cancer, but its function in the progression of colorectal cancer has not been evaluated using animal models of colorectal cancer. In this study, we found that knocking out KDM6A expression in mouse intestinal epithelium increased the length of villus and crypt, promoting the development of AOM (azoxymethane)/DSS (dextran sulfate sodium salt)-induced colorectal cancer. On the other hand, knocking down KDM6A expression promoted the growth of colorectal cancer cells. In molecular mechanism studies, we found that KDM6A interacts with HIF-1α; knocking down KDM6A promotes the binding of HIF-1α to the LDHA promoter, thereby promoting LDHA expression and lactate production, enhancing glycolysis. Knocking down LDHA reversed the malignant phenotype caused by KDM6A expression loss. In summary, this study using animal models revealed that KDM6A loss promotes the progression of colorectal cancer through reprogramming the metabolism of the colorectal cancer cells, suggesting that restoring the function of KDM6A is likely to be one of the strategies for colorectal cancer treatment.


Assuntos
Neoplasias Colorretais , Progressão da Doença , Glicólise , Histona Desmetilases , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Animais , Camundongos , Humanos , Histona Desmetilases/metabolismo , Histona Desmetilases/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética
12.
BMC Cancer ; 24(1): 671, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38824581

RESUMO

BACKGROUND: The role of novel circular RNAs (circRNAs) in colorectal cancer (CRC) remains to be determined. This study aimed to identify a novel circRNA involved in CRC pathogenesis, assess its diagnostic value, and construct a regulatory network. METHODS: Differential expression analysis was conducted using circRNA datasets to screen for differentially expressed circRNAs. The expression of selected circRNAs was validated in external datasets and clinical samples. Diagnostic value of plasma circRNA levels in CRC was assessed. A competing endogenous RNA (ceRNA) network was constructed for the circRNA using TCGA dataset. RESULTS: Analysis of datasets revealed that hsa_circ_101303 was significantly overexpressed in CRC tissues compared to normal tissues. The upregulation of hsa_circ_101303 in CRC tissues was further confirmed through the GSE138589 dataset and clinical samples. High expression of hsa_circ_101303 was associated with advanced N stage, M stage, and tumor stage in CRC. Plasma levels of hsa_circ_101303 were markedly elevated in CRC patients and exhibited moderate diagnostic ability for CRC (AUC = 0.738). The host gene of hsa_circ_101303 was also found to be related to the TNM stage of CRC. Nine miRNAs were identified as target miRNAs for hsa_circ_101303, and 27 genes were identified as targets of these miRNAs. Subsequently, a ceRNA network for hsa_circ_101303 was constructed to illustrate the interactions between the nine miRNAs and 27 genes. CONCLUSIONS: The study identifies hsa_circ_101303 as a highly expressed circRNA in CRC, which is associated with the progression of the disease. Plasma levels of hsa_circ_101303 show promising diagnostic potential for CRC. The ceRNA network for hsa_circ_101303 provides valuable insights into the regulatory mechanisms underlying CRC.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs , RNA Circular , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , RNA Circular/genética , RNA Circular/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Masculino , Feminino , MicroRNAs/genética , MicroRNAs/sangue , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Estadiamento de Neoplasias
14.
Sci Rep ; 14(1): 10539, 2024 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719941

RESUMO

Abnormal angiogenesis leads to tumor progression and metastasis in colorectal cancer (CRC). This study aimed to elucidate the association between angiogenesis-related genes, including VEGF-A, ANGPT-1, and ANGPT-2 with both metastatic and microsatellite alterations at selected tetranucleotide repeats (EMAST) subtypes of CRC. We conducted a thorough assessment of the ANGPT-1, ANGPT-2, and VEGF-A gene expression utilizing publicly available RNA sequencing and microarray datasets. Then, the experimental validation was performed in 122 CRC patients, considering their disease metastasis and EMAST+/- profile by using reverse transcription polymerase chain reaction (RT-PCR). Subsequently, a competing endogenous RNA (ceRNA) network associated with these angiogenesis-related genes was constructed and analyzed. The expression level of VEGF-A and ANGPT-2 genes were significantly higher in tumor tissues as compared with normal adjacent tissues (P-value < 0.001). Nevertheless, ANGPT-1 had a significantly lower expression in tumor samples than in normal colon tissue (P-value < 0.01). We identified a significantly increased VEGF-A (P-value = 0.002) and decreased ANGPT-1 (P-value = 0.04) expression in EMAST+ colorectal tumors. Regarding metastasis, a significantly increased VEGF-A and ANGPT-2 expression (P-value = 0.001) and decreased ANGPT-1 expression (P-value < 0.05) were established in metastatic CRC patients. Remarkably, co-expression analysis also showed a strong correlation between ANGPT-2 and VEGF-A gene expressions. The ceRNA network was constructed by ANGPT-1, ANGPT-2, VEGF-A, and experimentally validated miRNAs (hsa-miR-190a-3p, hsa-miR-374c-5p, hsa-miR-452-5p, and hsa-miR-889-3p), lncRNAs (AFAP1-AS1, KCNQ1OT1 and MALAT1), and TFs (Sp1, E2F1, and STAT3). Network analysis revealed that colorectal cancer is amongst the 82 significant pathways. We demonstrated a significant differential expression of VEGF-A and ANGPT-1 in colorectal cancer patients exhibiting the EMAST+ phenotype. This finding provides novel insights into the molecular pathogenesis of colorectal cancer, specifically in EMAST subtypes. Yet, the generalization of in silico findings to EMAST+ colorectal cancer warrants future experimental investigations. In the end, this study proposes that the EMAST biomarker could serve as an additional perspective on CMS4 biology which is well-defined by activated angiogenesis and worse overall survival.


Assuntos
Angiopoietina-1 , Angiopoietina-2 , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica , Fator A de Crescimento do Endotélio Vascular , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Angiopoietina-2/genética , Angiopoietina-2/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Metástase Neoplásica , Idoso , Repetições de Microssatélites/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Angiogênese
15.
Commun Biol ; 7(1): 551, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720110

RESUMO

Fusobacterium nucleatum, a gram-negative oral bacterium, has been consistently validated as a strong contributor to the progression of several types of cancer, including colorectal (CRC) and pancreatic cancer. While previous in vitro studies have shown that intracellular F. nucleatum enhances malignant phenotypes such as cell migration, the dependence of this regulation on features of the tumor microenvironment (TME) such as oxygen levels are wholly uncharacterized. Here we examine the influence of hypoxia in facilitating F. nucleatum invasion and its effects on host responses focusing on changes in the global epigenome and transcriptome. Using a multiomic approach, we analyze epigenomic alterations of H3K27ac and global transcriptomic alterations sustained within a hypoxia and normoxia conditioned CRC cell line HCT116 at 24 h following initial infection with F. nucleatum. Our findings reveal that intracellular F. nucleatum activates signaling pathways and biological processes in host cells similar to those induced upon hypoxia conditioning in the absence of infection. Furthermore, we show that a hypoxic TME favors F. nucleatum invasion and persistence and therefore infection under hypoxia may amplify malignant transformation by exacerbating the effects induced by hypoxia alone. These results motivate future studies to investigate host-microbe interactions in tumor tissue relevant conditions that more accurately define parameters for targeted cancer therapies.


Assuntos
Neoplasias Colorretais , Epigenoma , Infecções por Fusobacterium , Fusobacterium nucleatum , Oxigênio , Transcriptoma , Humanos , Fusobacterium nucleatum/genética , Fusobacterium nucleatum/fisiologia , Fusobacterium nucleatum/patogenicidade , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Células HCT116 , Infecções por Fusobacterium/genética , Infecções por Fusobacterium/microbiologia , Infecções por Fusobacterium/metabolismo , Oxigênio/metabolismo , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica
16.
Int J Biol Sci ; 20(7): 2388-2402, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725844

RESUMO

Metastasis is the leading cause of death in colorectal cancer (CRC) patients. By mediating intercellular communication, exosomes exhibit considerable value in regulating tumor metastasis. Long non-coding RNAs (lncRNAs) are abundant in exosomes and participate in regulating tumor progression. However, it is poorly understood how the cancer-secreted exosomal lncRNAs affect CRC proliferation and metastasis. Here, by analyzing the public databases we identified a lncRNA SNHG3 and demonstrated that SNHG3 was delivered through CRC cells-derived exosomes to promote metastasis in CRC. Mechanistically, exosomal SNHG3 was internalized by CRC cells and afterward upregulated the expression of ß-catenin by facilitating the intranuclear transport of hnRNPC. Consequently, the RNA stability of ß-catenin was enhanced which led to the activation of EMT and metastasis of CRC cells. Our findings expand the oncogenic mechanisms of exosomal SNHG3 and identify it as a diagnostic marker for CRC.


Assuntos
Neoplasias Colorretais , Exossomos , RNA Longo não Codificante , beta Catenina , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , beta Catenina/metabolismo , Exossomos/metabolismo , Linhagem Celular Tumoral , Estabilidade de RNA/genética , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Animais , Camundongos , Proliferação de Células/genética , Camundongos Nus
17.
Int J Epidemiol ; 53(3)2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38725300

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.


Assuntos
Índice de Massa Corporal , Neoplasias Colorretais , Análise da Randomização Mendeliana , Obesidade , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/epidemiologia , Fatores de Risco , Obesidade/genética , Obesidade/epidemiologia , Fator de Crescimento Insulin-Like I/metabolismo , Consumo de Bebidas Alcoólicas/epidemiologia
18.
Biol Direct ; 19(1): 36, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715141

RESUMO

Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.


Assuntos
Cetuximab , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Cetuximab/farmacologia , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Linhagem Celular Tumoral , Camundongos , Animais , RNA Circular/genética , RNA Circular/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Antineoplásicos Imunológicos/farmacologia , Glicólise , Proliferação de Células/efeitos dos fármacos
19.
Klin Onkol ; 38(2): 110-117, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38697819

RESUMO

BACKGROUND: With the aim to show the feasibility of early tumor shrinkage (ETS) concept implementation into daily clinical practice in the Czech Republic, a non-interventional, multicentric, single arm, prospective study in real world set-up was performed. MATERIAL AND METHODS: The study objectives were to explore the time interval from the treatment starting date to the date of the first radiographic control (TFRC) and evaluate the proportion of patients who achieved ≥ 20% tumor regression within the first 8 weeks of first-line therapy, in the real-world settings. RESULTS: The medians of TFRC in all individual participating centers were > 12 weeks (range 14.0-36.4 weeks). TFRC ≤ 8 weeks was reported for only 3% of patients in the cohort with first-line therapy, and there were only 3 patients (1%) who achieved tumor regression of ≥ 20% by day 60 (8.6 weeks). CONCLUSION: These findings indicate that the basic time parameter of ETS could not realistically be employed in routine oncology care of patients with metastatic colorectal cancer (mCRC) in the Czech Republic, unless there would be a strict request to perform TRFC by week 8 since the initiation of the therapy. In addition, the frequency of objective tumor response to first-line therapy with cetuximab + chemotherapy was evaluated. Based on the relative regression in the sum of diameters of measurable metastatic lesions, unconfirmed partial responses were achieved in 42.4 % and unconfirmed complete response in 8.6% of patients, altogether corresponding to the overall response rate of 51% with first-line therapy. The frequency of responses was higher among patients with left than right sided primary tumors. It seems that the regimen of cetuximab/FOLFOX might be more active in frontline therapy of right sided RAS wild type mCRC than cetuximab/FOLFIRI.


Assuntos
Cetuximab , Neoplasias Colorretais , Estudos de Viabilidade , Humanos , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Estudos Prospectivos , República Tcheca , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucovorina/uso terapêutico
20.
Mol Biol Rep ; 51(1): 603, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38698270

RESUMO

BACKGROUND: Drug combination studies help to improve new treatment approaches for colon cancer. Tumor spheroids (3D) are better models than traditional 2-dimensional cultures (2D) to evaluate cellular responses to chemotherapy drugs. The cultivation of cancer cells in 2D and 3D cultures affects the apoptotic process, which is a major factor influencing the response of cancer cells to chemotherapeutic drugs. In this study, the antiproliferative effects of 5-fluorouracil (5-FU) and doxorubicin (DOX) were investigated separately and in combination using 2D and 3D cell culture models on two different colon cancer cell lines, HT-29 (apoptosis-resistant cells) and Caco-2 2 (apoptosis-susceptible cells). METHODS: The effect of the drugs on the proliferation of both colon cancer cells was determined by performing an MTT assay in 2D culture. The apoptotic effect of 5-FU and DOX, both as single agents and in combination, was assessed in 2D and 3D cultures through quantitative real-time polymerase chain reaction analysis. The expression of apoptotic genes, such as caspases, p53, Bax, and Bcl-2, was quantified. RESULTS: It was found that the mRNA expression of proapoptotic genes was significantly upregulated, whereas the mRNA expression of the antiapoptotic Bcl-2 gene was significantly downregulated in both colon cancer models treated with 5-FU, DOX, and 5-FU + DOX. CONCLUSION: The results indicated that the 5-FU + DOX combination therapy induces apoptosis and renders 5-FU and DOX more effective at lower concentrations compared to their alone use. This study reveals promising results in reducing the potential side effects of treatment by enabling the use of lower drug doses.


Assuntos
Apoptose , Proliferação de Células , Neoplasias Colorretais , Doxorrubicina , Fluoruracila , Esferoides Celulares , Humanos , Fluoruracila/farmacologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Doxorrubicina/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HT29 , Proliferação de Células/efeitos dos fármacos , Células CACO-2 , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linhagem Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/genética
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