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BACKGROUND: Increasing evidence suggests that DXS253E is critical for cancer development and progression, but the function and potential mechanism of DXS253E in colorectal cancer (CRC) remain largely unknown. In this study, we evaluated the clinical significance and explored the underlying mechanism of DXS253E in CRC. METHODS: DXS253E expression in cancer tissues was investigated using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Kaplan-Meier plot was used to assess the prognosis of DXS253E. The cBioPortal, MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were employed to analyze the mutation profile, methylation, and immune infiltration associated with DXS253E. The biological functions of DXS253E in CRC cells were determined by CCK-8 assay, plate cloning assay, Transwell assay, flow cytometry, lactate assay, western blot, and qRT-PCR. RESULTS: DXS253E was upregulated in CRC tissues and high DXS253E expression levels were correlated with poor survival in CRC patients. Our bioinformatics analyses showed that high DXS253E gene methylation levels were associated with the favorable prognosis of CRC patients. Furthermore, DXS253E levels were linked to the expression levels of several immunomodulatory genes and an abundance of immune cells. Mechanistically, the overexpression of DXS253E enhanced proliferation, migration, invasion, and the aerobic glycolysis of CRC cells through the AKT/mTOR pathway. CONCLUSIONS: We demonstrated that DXS253E functions as a potential role in CRC progression and may serve as an indicator of outcomes and a therapeutic target for regulating the AKT/mTOR pathway in CRC.
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Anastomotic leakage (AL), one of the most severe complications in rectal surgery, is often diagnosed late because of the low specificity of the clinical symptoms and limitations of current clinical investigations. Identification of patients with early AL remains challenging. Here, we explored the protein expression profiles of AL patients to provide potential biomarkers to identify AL in patients who undergo surgery for rectal cancer. We screened differentially expressed proteins (DEPs) in drainage fluid from AL and non-AL patients using a tandem mass tag method. A total of 248 DEPs, including 98 upregulated and 150 downregulated proteins, were identified between AL and non-AL groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that DEPs were enriched in neutrophil degranulation, bacterial infection, proteolysis, hemostasis, and complement and coagulation cascades. The results of enzyme-linked immunosorbent assay validated that the expression of the top three upregulated DEPs, AMY2A, RETN, and CELA3A, was significantly increased in the drainage fluid of AL patients, compared with that of non-AL patients (AMY2A, P = 0.001; RETN, P < 0.0001; and CELA3A, P = 0.023). Thus, our findings provide several potential biomarkers for the early diagnosis of AL after rectal cancer resection.
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Fístula Anastomótica , Neoplasias Retais , Humanos , Fístula Anastomótica/diagnóstico , Fístula Anastomótica/etiologia , Fístula Anastomótica/cirurgia , Proteômica , Detecção Precoce de Câncer , Neoplasias Retais/cirurgia , Neoplasias Retais/complicações , Drenagem/efeitos adversos , Drenagem/métodos , BiomarcadoresRESUMO
Circular RNA (circRNA) is a non-coding RNA molecule that lacks polyadenylated tails and is highly stable, abundant, and conserved in human cells. CircRNAs can serve as a competing endogenous RNA (ceRNA) to sponge microRNAs (miRNA) and block their effects on target mRNA expression. CircRNAs also have possible relevance to cancer and therefore may be considered as ideal biomarkers for monitoring cancer progression. Of the about 300,000 predicted human circRNAs, only a few have validated biological functions related to cancer. To better understand the ceRNA role of circRNAs in colorectal cancer (CRC), we performed genome-wide circRNA-based RNA-sequencing (RNA-Seq) on nine CRC tumor samples and their paired histologically normal adjacent tissue samples. By profiling the mRNA expression in the same patients, we further explored the expression correlation between circRNAs and mRNAs generated from the same parental gene. Focusing on the concordant differential expression between circRNAs and mRNAs, we substantially reduced the regulatory noise. In total, we identified 694 circRNA-mRNA pairs that were consistently up or downregulated between tumor and normal tissues. These 694 circRNA-mRNA pairs are from 182 protein-coding genes associated with hormone responses and chemotaxis. Of these 182 genes, 43 are downstream targets of three highly conserved miRNAs (miR-410-3p, miR-135a, and miR-30a). Interestingly, these 43 genes are highly mutated in another cohort from eight independent CRC studies, which have significant effects on patient survival time. Focusing on miR-410-3p and its target oncogene MET, we experimentally validated the ceRNA regulatory motif of circMET. Notably, circMET is substantially upregulated in CRC cell lines and could promote cell proliferation and growth. By confirming the regulatory relationship between miR-410-3p and circMET, we propose a new mechanism for the observed sustained activation of MET in CRC. In conclusion, our work identifies a novel regulatory role of circMET and provides a potential diagnostic biomarker for CRC.
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Neoplasias Colorretais , MicroRNAs , Proteínas Proto-Oncogênicas c-met , RNA Circular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Autophagy plays a crucial role in colorectal cancer (CRC) development. Our previous study suggested that serine/threonine protein kinase 25 (STK25) regulates aerobic glycolysis in CRC cells. Glycolysis modulates cellular autophagy during tumor growth; however, the role of STK25 in autophagy remains unclear. In this study, we found that STK25 expression was decreased in CRC tissues and CRC patients with high STK25 expression had a favorable prognosis. Functional assays suggested that STK25 inhibition promoted autophagy in CRC cells. Overexpression of STK25 exhibited the opposite effects. Moreover, the results of western blot demonstrated that silencing STK25 induced autophagy by activating the JAK2/STAT3 pathway. Therefore, STK25 could be a potential indicator for therapies targeting the JAK2/STAT3 pathway in CRC.
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Neoplasias Colorretais , Fator de Transcrição STAT3 , Autofagia/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Regulação para Baixo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Mutated KRAS promotes the activation of the MAPK pathway and the progression of colorectal cancer (CRC) cells. Aberrant activation of the PI3K pathway strongly attenuates the efficacy of MAPK suppression in KRAS-mutated CRC. The development of a novel strategy targeting a dual pathway is therefore highly essential for the therapy of KRAS-mutated CRC. In this study, a quadruple-depleting system for the KRAS, MEK1, PIK3CA, and MTOR genes based on CRISPR/SaCas9 was developed. Adenovirus serotype 5 (ADV5) was integrated with two engineered proteins, an adaptor and a protector, to form ADV-protein complex (APC) for systemic delivery of the CRISPR system. Quadruple-editing could significantly inhibit the MAPK and PI3K pathways in CRC cells with oncogenic mutations of KRAS and PIK3CA or with KRAS mutation and compensated PI3K activation. Compared with MEK and PI3K/MTOR inhibitors, quadruple-editing induced more significant survival inhibition on primary CRC cells with oncogenic mutations of KRAS and PIK3CA. The adaptor specifically targeting EpCAM and the hexon-shielding protector could dramatically enhance ADV5 infection efficiency to CRC cells and significantly reduce off-targeting tropisms to many organs except the colon. Moreover, quadruple-editing intravenously delivered by APC significantly blocked the dual pathway and tumor growth of KRAS-mutated CRC cells, without influencing normal tissues in cell- and patient-derived xenograft models. Therefore, APC-delivered quadruple-editing of the MAPK and PI3K pathways shows a promising therapeutic potential for KRAS-mutated CRC.
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Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Colorretais/patologia , Edição de Genes/métodos , MAP Quinase Quinase 1/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Animais , Movimento Celular/genética , Proliferação de Células/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/genética , Células HCT116 , Humanos , MAP Quinase Quinase 1/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Mutação , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transfecção , Carga Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: This study compared the long-term efficacy of different durations of adjuvant chemotherapy for patients with gastric cancer after radical gastrectomy with D2 lymphadenectomy. METHODS: We retrospectively identified 428 patients with stage II-III gastric cancer who underwent D2 gastrectomy between 2009 and 2016. Patients were divided into four groups according to the duration of adjuvant chemotherapy, including 0 week (no adjuvant, group A), 20 to 24 weeks (completed 7-8 cycles every 3 weeks or 10-12 cycles every 2 weeks, group B), and 12 to18 weeks (completed 4-6 cycles every 3 weeks or 6-9 cycles every 2 weeks, group C), and less than 12 weeks (received up to 3 cycles every 3 weeks or 5 cycles every 2 weeks, group D). The chemotherapy regimens included XELOX, SOX, and FOLFOX. 5-year overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: The 5-year OS rates for groups A, B, C, and D were 52.3, 73.7, 72.0, and 53.3%, respectively, and the 5-year DFS rates were 50.0, 68.0, 65.4, and 50.0%, respectively. OS and DFS were higher in group B than in groups A and D. Similarly, patients in group C were more likely to have higher OS and DFS than those in groups A and D. Meanwhile, there were no significant differences in OS and DFS between groups B and C. The multivariate analysis confirmed with high statistical significance the efficacy of complete courses of adjuvant chemotherapy, and, among them, the similar impact of 4-6/6-9 and 7-8/10-12 cycles, resulting in similar HRs vs Group A (0.52 and 0.42, respectively). CONCLUSIONS: To reduce toxicity and maintain efficacy, XELOX or SOX chemotherapy regimens administered for 4-6 cycles every 3 weeks or FOLFOX regimen for 6-9 cycles every 2 weeks might be a favorable option for patients with stage II-III gastric cancer after D2 gastrectomy. Prospective multicenter clinical trials with adequate sample sizes are necessary to verify these findings.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/mortalidade , Gastrectomia/mortalidade , Excisão de Linfonodo/mortalidade , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Adulto JovemRESUMO
The majority of patients with microsatellite stable (MSS) colorectal cancer (CRC) do not benefit from the immunotherapies directed at rescuing T-cell functions. Therefore, complete understanding of T-cell phenotypes and functional status in the CRC microenvironment is desirable. Here, we applied single-cell mass cytometry to mold the T-cell phenotype in 18 patients with MSS CRC for better understanding of CRC as a systemic disease and to search for tumor-driven T-cell profile changes. We show interpatient and intrapatient phenotypic diversity of T-cell subsets. We revealed increased immunosuppressive/exhausted T-cell phenotypes at tumor lesions. CD8+ CD28- immunosenescent T cells with impaired proliferation capacity dominate the T-cell compartment. As per the transcriptome and quantitative real time-PCR analysis, the accumulation of immunosuppressive cells is driven by the tumor microenvironment. T-cell profiles are similar between patients at early and late stages, indicating that the immunosuppressive microenvironment is formulated early during CRC development. Mapping of T-cell infiltration and understanding of the mechanisms underlying their regulation may provide valuable information to boost the immune response in patients with MSS CRC.
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Neoplasias Colorretais/imunologia , Linfócitos T/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Humanos , Tolerância Imunológica , Fenótipo , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Linfócitos T/patologia , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Metastasis is a major cause of failed colorectal cancer (CRC) treatment. While lung metastasis (LM) is observed in 10-15% of patients with CRC, the genetic mechanisms that cause CRC to metastasize to the lung remain unclear. METHODS: In this study, we employed whole exome sequencing (WES) of primary CRC tumors and matched isolated LM lesions to compare their genomic profiles. Comprehensive genomic analyses of five freshly frozen primary tumor lesions, five paired LM lesions, and matched non-cancerous tissues was achieved by WES. RESULTS: An integrated analysis of somatic mutations, somatic copy number alterations, and clonal structures revealed that genomic alterations were present in primary and metastatic CRCs with various levels of discordance, indicating substantial levels of intertumor heterogeneity. Moreover, our results suggest that the founder clone of the primary tumor was responsible for the formation of the metastatic lesion. Additionally, only a few metastasis-specific mutations were identified, suggesting that LM-promoting mutations might be pre-existing in primary tumors. CONCLUSIONS: Primary and metastatic CRC show intertumor heterogeneity; however, both lesions were founded by the same clone. These results indicate that malignant clones contributing to disease progression should be identified during the genetic prognosis of cancer metastasis.
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Patients with metachronous colorectal cancer (CRC) have been diagnosed with primary CRC more than once. Given that the genetic and microenvironment is the same in these cases, metachronous CRC is an important model for studying colorectal tumorigenesis. We performed whole exome sequencing of seven freshly frozen tumors from three patients with metachronous CRC and compared their genetic profiles. In patients with metachronous tumors of distinct genetic origins, 3.74% and 0.20% of genes were ubiquitously mutated and candidate cancer genes mutated at different sites. Tumors from the same patients were clonally unrelated, and thus druggable genes differed. In contrast, in a patient with metachronous tumors of a common genetic origin, the ubiquitously mutated genes were 61.02%, with ubiquitously mutated genes and candidate cancer genes all mutated at the same sites, tumors were clonally related, and some druggable genes were the same. Therefore, two different clonal relationships between metachronous tumors exist in CRC, one is monoclonal and the other is polyclonal. Our findings may help to advance understanding of the differences in metachronous CRCs and the genetic mechanisms of which they originate, and provide new avenues for CRC treatment.
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Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Heterogeneidade Genética , Mutação , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/patologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sequenciamento do Exoma/métodosRESUMO
Sporadic synchronous colorectal cancer (CRC) refers to more than one primary tumor detected in a single patient at the time of the first diagnosis without predisposition of cancer development. Given the same genetic and microenvironment they raise, sporadic synchronous CRC is a unique model to study CRC tumorigenesis. We performed whole exome sequencing in 32 fresh frozen tumor lesions from 15 patients with sporadic synchronous CRC to compare their genetic alterations. This approach identified ubiquitously mutated genes in the range from 0.34% to 4.22% and from 0.8% to 7.0% in non-hypermutated tumors and hypermutated tumors, respectively, in a single patient. We show that both ubiquitously mutated genes and candidate cancer genes from different tumors in the same patient mutated at different sites. Consistently, obvious differences in somatic copy number variations (SCNV) were found in most patients with non-hypermutated tumor lesions, which had ubiquitous copy number amplification rates ranging from 0% to 8.8% and ubiquitous copy number deletion rates ranging from 0% to 8.2%. Hypermutated lesions were nearly diploid with 0% to 18.8% common copy number aberrations. Accordingly, clonal structures, altered signaling pathways and druggable genes in a single patient with synchronous CRC varied significantly. Taken together, the disparate SCNVs and mutations in synchronous CRC supported the field effect theory of tumorigenesis. Moreover, the intertumor heterogeneity of synchronous CRCs implies that analysis of all tumor lesions from the same patient is necessary for appropriate clinical treatment decisions.
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Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Sequenciamento do Exoma/métodos , Exoma , Mutação , Predisposição Genética para Doença , HumanosRESUMO
BACKGROUND: Colorectal cancer is a heterogeneous group of malignancies with complex molecular subtypes. While colon cancer has been widely investigated, studies on rectal cancer are very limited. Here, we performed multi-region whole-exome sequencing and single-cell whole-genome sequencing to examine the genomic intratumor heterogeneity (ITH) of rectal tumors. METHODS: We sequenced nine tumor regions and 88 single cells from two rectal cancer patients with tumors of the same molecular classification and characterized their mutation profiles and somatic copy number alterations (SCNAs) at the multi-region and the single-cell levels. RESULTS: A variable extent of genomic heterogeneity was observed between the two patients, and the degree of ITH increased when analyzed on the single-cell level. We found that major SCNAs were early events in cancer development and inherited steadily. Single-cell sequencing revealed mutations and SCNAs which were hidden in bulk sequencing. In summary, we studied the ITH of rectal cancer at regional and single-cell resolution and demonstrated that variable heterogeneity existed in two patients. The mutational scenarios and SCNA profiles of two patients with treatment naïve from the same molecular subtype are quite different. CONCLUSIONS: Our results suggest each tumor possesses its own architecture, which may result in different diagnosis, prognosis, and drug responses. Remarkable ITH exists in the two patients we have studied, providing a preliminary impression of ITH in rectal cancer.
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Heterogeneidade Genética , Genômica , Neoplasias Retais/genética , Análise por Conglomerados , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Genômica/métodos , Humanos , Mutação , Especificidade de Órgãos/genética , Análise de Sequência de DNA , Análise de Célula Única , Sequenciamento do ExomaRESUMO
PURPOSE: Many studies revealed that the recurrence rate of stage II colon cancer was up to 2540 %. Regrettably, the risk factors for recurrence of stage II colon cancer remain ambiguous. So, we conducted this study to identify the clinicopathological factors associated with prognosis of stage II colon cancer. METHODS: We enrolled 452 stage II colon cancer patients who underwent radical resection at Peking University Cancer Hospital between January 2007 and December 2010, and 162 patients who received adjuvant treatment were excluded. RESULTS: The 5-year recurrence rate and overall survival of this cohort were 19.3 (56/290) and 75.9 % (220/290), respectively. In univariate analysis, the following variables were significantly associated with tumor recurrence:male patients (P<0.001), tumor size >5 cm (P=0.048), and preoperative carcinoembryonic antigen (CEA) level ≥ 5 ng/ml (P=0.004); the following factors were significantly associated with adverse 5-year overall survival:male patients (P<0.001), age ≥60 years old (P=0.004), less than 12 lymph nodes (P=0.006), and preoperative CEA level ≥5 ng/ml (P=0.011). In multivariate analysis,the preoperative CEA level ≥5 ng/ml (P=0.003) and male (P<0.001) were adverse variables significantly associated with tumor recurrence, and the preoperative CEA level ≥ 5 ng/ml (P=0.016), male (P<0.001), and age ≥60 years old (P=0.008) were independent prognostic factors for the 5-year overall survival rate, respectively. CONCLUSIONS: The preoperative CEA level ≥5 ng/ml and male were undesirable factors significantly associated with tumor recurrence. The preoperative CEA level ≥5 ng/ml, male, and age ≥60 years old were adverse factors significantly associated with poor prognosis.
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Neoplasias do Colo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Adulto JovemRESUMO
Angiogenesis is a prerequisite of tumor growth and metastasis and, thus, anti-angiogenesis treatment has become an important part of cancer therapy. A 15-amino acid peptide of the fibrinogen α chain, fibrinostatin, was previously found in serum samples of gastric cancer patients. Herein we demonstrated that fibrinostatin has anti-angiogenesis activity in several angiogenesis models and it reduces tumor growth in mouse xenografts and allografts. Increased tumor necrosis and reduced microvessel density in tumors were observed in mouse xenograft models. Fibrinostatin inhibited proliferation and induced apoptosis in HUVEC, but not in cancer cells. In addition, fibrinostatin specifically entered HUVEC. Fibrinostatin also prevented migration, adhesion and tubule formation of HUVEC in vitro. A single-dose acute toxicity testing and a repeated-dose chronic toxicity study in the mouse, rat and monkey indicated that fibrinostatin had a wide margin of safety. Taken together, fibrinostatin shows promise as a potential anti-angiogenesis therapeutic agent.
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Inibidores da Angiogênese/farmacologia , Proliferação de Células/efeitos dos fármacos , Fibrinogênio/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Western Blotting , Movimento Celular/efeitos dos fármacos , Embrião de Galinha , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
BACKGROUND: Colon cancer nomogram designed by Memorial Sloan-Kettering Cancer Center (MSKCC) is an online prediction tool to predict overall survival for individual patient after curative resection. However, this model was never externally validated. We evaluated the accuracy of this nomogram in an independent external Chinese cohort. METHODS: Clinical data from 1005 patients who underwent primary curative-intent surgery at Peking University Cancer Hospital & Institute between 1996 and 2008 were used for external validation. Clinicopathologic characteristics and the performance of the MSKCC nomogram for prediction of overall survival were evaluated for 985 patients with complete data by using concordance index (C-index) and calibration plot. RESULTS: The C-index for the MSKCC nomogram was 0.71 in the Chinese cohort, compared with 0.67 for American Joint Committee on Cancer (AJCC) stage (P < .0001). This suggests that the nomogram discriminates overall survival better than AJCC staging system. Calibration plot showed a good calibration of the nomogram in the validation cohort. Furthermore, the MSKCC nomogram prediction illustrated the heterogeneity for survival of Chinese patients within each AJCC stage. CONCLUSIONS: The MSKCC nomogram for colon cancer provides more accurate survival predictions than the AJCC staging system when applied to an external Chinese cohort. The MSKCC nomogram improved individualized prediction of survival and may aid in more accurate patient counseling, selection of various treatment options, and follow-up scheduling.
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Colectomia/mortalidade , Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Nomogramas , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Técnicas de Apoio para a Decisão , Feminino , Previsões/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Adulto JovemRESUMO
N-α-Acetyltransferase 10 protein (Naa10p, also called arrest-defective 1), the catalytic subunit of N-acetyltransferase A, is a critical regulator of cell death and proliferation. Naa10p is also shown to regulate cancer metastasis by inhibiting cell motility; however, its role in cancer metastasis is not fully understood. In this study, we found that high expression of Naa10p is positively correlated with the survival of patients with breast cancer, whereas negatively correlated with lymph node metastasis. Naa10p inhibits breast cancer cell migration and invasion in vitro and decreases the xenograft growth and metastasis in nude mice. Microarray screening revealed that Naa10p downregulates inhibitors of differentiation 1 (ID1) expression. Naa10p binds to signal transducer and activator of transcription 5a (STAT5a) and decreases STAT5a-stimulated ID1 expression in an acetyltransferase-independent manner. Moreover, Naa10p antagonizes Janus kinase 2-STAT5a signaling by lowering p65-activated interleukin-1ß expression. Our results demonstrate a novel mechanism through which Naa10p inhibits the metastasis of breast cancer cells by targeting STAT5a.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Proteína 1 Inibidora de Diferenciação/metabolismo , Interleucina-1beta/metabolismo , Janus Quinase 2/metabolismo , Metástase Linfática/patologia , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos BALB C , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , NF-kappa B/metabolismo , Fator de Transcrição STAT5/genética , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Golgi phosphoprotein 3 (GOLPH3) has been validated as a potent oncogene involved in the progression of many types of solid tumors, and its overexpression is associated with poor clinical outcome in many cancers. However, it is still unknown the association of GOLPH3 expression with the prognosis of colorectal cancer (CRC) patients who received 5-fluorouracil (5-FU)-based adjuvant chemotherapy. METHODS: The expression of GOLPH3 was determined by qRT-PCR and immunohistochemistry in colorectal tissues from CRC patients treated with 5-FU based adjuvant chemotherapy after surgery. The association of GOLPH3 with clinicopathologic features and prognosis was analysed. The effects of GOLPH3 on 5-FU sensitivity were examined in CRC cell lines. RESULTS: GOLPH3 expression was elevated in CRC tissues compared with matched adjacent noncancerous tissues. Kaplan-Meier survival curves indicated that high GOLPH3 expression was significantly associated with prolonged disease-free survival (DFS, P = 0.002) and overall survival (OS, P = 0.011) in patients who received 5-FU-based adjuvant chemotherapy. Moreover, multivariate analysis showed that GOLPH3 expression was an independent prognostic factor for DFS in CRC patients treated with 5-FU-based chemotherapy (HR, 0.468; 95%CI, 0.222-0.987; P = 0.046). In vitro, overexpression of GOLPH3 facilitated the 5-FU chemosensitivity in CRC cells; while siRNA-mediated knockdown of GOLPH3 reduced the sensitivity of CRC cells to 5-FU-induced apoptosis. CONCLUSIONS: Our results suggest that GOLPH3 is associated with prognosis in CRC patients treated with postoperative 5-FU-based adjuvant chemotherapy, and may serve as a potential indicator to predict 5-FU chemosensitivity.
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Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fluoruracila/uso terapêutico , Proteínas de Membrana/metabolismo , Idoso , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Análise Multivariada , Poli(ADP-Ribose) Polimerases/metabolismo , Prognóstico , RNA Interferente Pequeno/metabolismoRESUMO
microRNAs (miRNAs) are a class of endogenous, single-stranded non-coding RNAs of 20-23 nucleotides in length, functioning as negative regulators of gene expression at the post-transcriptional level. The dysregulation of miRNAs has been demonstrated to play critical roles in tumorigenesis, either through inhibiting tumor suppressor genes or activating oncogenes inappropriately. Besides their promising clinical applications in cancer diagnosis and treatment, recent studies have uncovered that miRNAs could act as a regulatory language, through which messenger RNAs, transcribed pseudogenes, and long noncoding RNAs crosstalk with each other and form a novel regulatory network. RNA transcripts involved in this network have been termed as competing endogenous RNAs (ceRNAs), since they influence each other's level by competing for the same pool of miRNAs through miRNA response elements (MREs) on their target transcripts. The discovery of miRNA-ceRNA network not only provides the possibility of an additional level of post-transcriptional regulation, but also dictates a reassessment of the existing regulatory pathways involved in cancer initiation and progression.
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Screening cancer genomes has provided an in-depth characterization of genetic variants such as copy number variations (CNVs) and gene expression changes of non-coding transcripts. Single-dimensional experiments are often designed to differentiate a patient cohort into various sets with the aim of identifying molecular changes among groups; however, this may be inadequate to decipher the causal relationship between molecular signatures in individual patients. To overcome this challenge with respect to personalized medicine, we implemented a patient-specific multi-dimensional integrative approach to uncover coherent signals from multiple independent platforms. In particular, we focused on the consistent gene dosage effects of CNVs for both mRNA and long non-coding RNA (lncRNA) expression in nine colorectal cancer patients. We identified 511 CNV-lncRNA-mRNA regulatory triplets associated with CNVs and aberrant expression of both mRNAs and lncRNAs. By filtering out inconsistent changes among CNVs, mRNAs, and lncRNAs, we further characterized 165 coherent motifs associated with 56 genes. In total, 108 motifs were linked with 31 copy number gains, 44 upregulated lncRNAs, and 45 upregulated mRNAs. Another 57 coherent downregulated motifs were also collected. We discuss how for many of these CNV-lncRNA-mRNA regulatory triplets, their clinical impact remains to be explored, including survival time, microsatellite instability, tumor stage, and primary tumor sites. By validating two example CNV-lncRNA-mRNA triplets with up- and down-regulation, we confirmed that individual variations in multiple dimensions are a robust tool to identify reliable molecular signals for personalized medicine. In summary, we utilized a patient-specific computational pipeline to explore the consistent CNV-driven motifs consisting of lncRNAs and mRNAs. We also identified LSM14B as a potential promoter in colorectal cancer progression, suggesting that it may serve as a target for colorectal cancer treatment.
Assuntos
Neoplasias Colorretais , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Variações do Número de Cópias de DNA/genética , Transcriptoma , RNA Mensageiro/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Redes Reguladoras de GenesRESUMO
Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor ß (ERß). However, clinical strategies for CRC therapy associated with ERß are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERß/TGFBR1 signaling axis. WFDC3 interacts with ERß and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERß-mediated transcription. Blocking TGFß signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERß pathway in CRC patients.
Assuntos
Neoplasias Colorretais , Receptor beta de Estrogênio , Humanos , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Expressão Gênica , Estrogênios , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Linhagem Celular TumoralRESUMO
N-α-Acetyltransferase 10 protein (Naa10p/ARD1), the catalytic subunit of N-acetyltransferase A, catalyzes both N-α-acetylation and ε-acetylation, as well as autoacetylation. Naa10p is involved in controlling cell proliferation, apoptosis, autophagy and neuronal development. Our group and others had reported prognostic value of Naa10p expression in various types of cancer. Despite the efforts to elucidate the biological function of Naa10p, it remains controversial regarding its roles in tumor development. Herein, we report that depletion of Naa10p inhibited the growth of xenograft tumors in nude mice. Microarray analysis identified MCL1 gene as one of targets downstream of Naa10p. Naa10p positively regulated MCL1 expression, as exogenous Naa10p promoted MCL1 expression, whereas Naa10p silencing decreased MCL1 expression. Ablation of Naa10p sensitized cancer cells to stimuli-induced apoptosis, and the anti-apoptotic function of Naa10p was, at least in part, mediated by MCL1. Mechanistically, we found a physical interaction between Naa10p and RelA/p65. Transcriptional activation of the MCL1 gene required the recruitment of Naa10p-RelA/p65 complex to the p65-binding site of MCL1 promoter region. We also demonstrated a positive correlation between MCL1 and Naa10p messenger RNA levels in both colon cancer and lung cancer tissues. These results indicate that Naa10p inhibits apoptosis through Naa10p-RelA/p65-dependent MCL1 transcriptional activation.