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As cytoplasmic protein complexes that are pivotal for innate immunity, inflammasomes act primarily through the detection of pathogen- or danger-associated molecular patterns. Nucleotide oligomerisation domain-like receptor family and caspase activation recruitment domain-containing protein 4 (NLRC4) inflammasomes identify and eliminate intracellular pathogens, a process contingent on the ligand-recognition capabilities of neuronal apoptosis inhibitory proteins (NAIPs). Upon detection of specific molecules indicative of intracellular infection, NAIPs discern distinct pathogenic components and subsequently transmit signals to NLRC4, thus initiating their activation and triggering an inflammatory response. However, the mechanisms underlying NLRC4 inflammasome remain unclear. In this study, we elucidated the critical role of ATG16L2 in activating the NLRC4 inflammasome. ATG16L2-deficient macrophages exhibited reduced NLRC4 inflammasome activation, characterised by decreased oligomerisation of apoptosis-associated speck-like protein containing a CARD and attenuated cleavage of Pro-caspase-1, Pro-IL-1ß and gasdermin D. Co-immunoprecipitation assays revealed an interaction between ATG16L2 and NAIPs. Furthermore, ATG16L2 enhanced the association between NAIPs and NLRC4 by binding to NAIPs. For ATG16L2-knockout mice infected with Salmonella typhimurium, pathogen clearance and survival rates markedly decreased. Collectively, our findings suggest that ATG16L2 is a significant modulator of the innate immune system, influencing the activity of the NLRC4 inflammasome and the host's defensive response to intracellular pathogens.
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Our previous work suggested that high SIRT1 expression by cancer cells predicted a poor colorectal cancer (CRC) prognosis, but its role in the tumor microenvironment was unclear. Here, we examined tumor-infiltrating lymphocytes (TILs) in CRC expressing different levels of SIRT1. We also established a co-culture system with monocytes, CD8+ T cells and patient-derived tumor organoids (PDOs) to study the relationships between immune cells and cancer cells. The percentage of CD8+ T cells was decreased and the percentage of macrophages was increased in SIRT1-high (SIRT1-hi) CRC. Co-culture results showed that tumor-associated macrophages (TAMs) from SIRT1-hi CRC inhibited the proliferation and anti-tumor activity of CD8+ T cells. Importantly, SIRT1-hi CRC were shown to modulate the migration and the activity of TAMs. RNA sequencing revealed that CD14+ monocytes in SIRT1-hi patients expressed higher levels of CXCR4. Mechanistically, SIRT1 expression was shown to promote CXCL12 expression by inhibiting the acetylation of p53. Our findings indicate that SIRT1 in CRC induces TAM migration through the CXCR4/CXCL12 pathway, and inhibits the proliferation and activity of CD8+ T cells, resulting in promotion of CRC progression.
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Linfocitos T CD8-positivos/inmunología , Quimiocina CXCL12/metabolismo , Neoplasias Colorrectales/inmunología , Macrófagos/inmunología , Receptores CXCR4/metabolismo , Sirtuina 1/metabolismo , Diferenciación Celular/inmunología , Línea Celular Tumoral , Movimiento Celular/inmunología , Técnicas de Cocultivo , Neoplasias Colorrectales/patología , Células HT29 , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Organoides/crecimiento & desarrollo , Interferencia de ARN , ARN Interferente Pequeño/genética , Sirtuina 1/genética , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Recent theory on the "gut-brain axis" suggests a close relationship between the dysfunction of the gut and the disorders of the brain. METHODS: We performed a systemic literature search followed by a multi-step inclusion selection for all studies on the risk of Colorectal cancer (CRC) in Parkinson's disease (PD) patients using the following databases: PubMed, EMBASE and WOS. Relative risk (RR) and the 95% confidence intervals (CI) were calculated using either the random-effects model or the fixed-effects meta-analysis model, based on the assessment of heterogeneity. RESULTS: Seventeen studies involving a total of 375,964 PD patients and 879,307 cancer patients were included. Independent meta-analyses for cohort studies and case-control studies showed that the overall pooled RR of the cohort studies was 0.78 (0.66-0.91), and that of the case-control studies was 0.78 (0.65-0.94), indicating that patients with PD have a significantly decreased risk for CRC. The significant lower risk is present in both the colon and the rectum subgroups classified by tumor location. Moreover, the risk for CRC is significantly lower in America (RR = 0.58), Europe (RR = 0.82) and Asia (RR = 0.83) compared to the control population. CONCLUSION: The occurrence of CRC was significantly lower in patients with diagnosis of PD.
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Neoplasias Colorrectales , Enfermedad de Parkinson , Estudios de Cohortes , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Humanos , Incidencia , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , RiesgoRESUMEN
The transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is a single-pass transmembrane protein, and it is downregulated in human gastric cancer and levels correlate with tumor progression and time of survival. However, the mechanism of its dysregulation in gastric cancer is little known. Here we investigate its regulatory mechanism and the bidirectional regulation between TMEFF2 and STAT3 in gastric carcinogenesis. TMEFF2 expression was decreased after Helicobacter pylori (H. pylori) infection in vivo and in vitro. STAT3 directly binds to the promoter of TMEFF2 and regulates H. pylori-induced TMEFF2 downregulation in normal gastric GES-1 cells and gastric cancer AGS cells. Conversely, TMEFF2 may suppress the phosphorylation of STAT3 and TMEFF2-induced downregulation of STAT3 phosphorylation may depend on SHP-1. A highly inverse correlation between the expression of TMEFF2 and pSTAT3 was also revealed in gastric tissues. We now show the deregulation mechanism of TMEFF2 in gastric carcinogenesis and identify TMEFF2 as a new target gene of STAT3. The phosphorylation of STAT3 may be negatively regulated by TMEFF2, and the bidirectional regulation between TMEFF2 and STAT3 may contribute to H. pylori-associated gastric carcinogenesis.
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Transformación Celular Neoplásica/patología , Mucosa Gástrica/patología , Regulación Neoplásica de la Expresión Génica , Infecciones por Helicobacter/patología , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias Gástricas/patología , Animales , Transformación Celular Neoplásica/metabolismo , Inmunoprecipitación de Cromatina , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Gerbillinae , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Humanos , Técnicas para Inmunoenzimas , Masculino , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT3/genética , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiología , Células Tumorales CultivadasRESUMEN
Background: Colorectal cancer (CRC) is the third most prevalent tumor globally. The liver is the most common site for CRC metastasis, and the involvement of the liver is a common cause of death in patients with late-stage CRC. Consequently, mitigating CRC liver metastasis (CRLM) is key to improving CRC prognosis and increasing survival. Exercise has been shown to be an effective method of improving the prognosis of many tumor types. However, the ability of exercise to inhibit CRLM is yet to be thoroughly investigated. Methods: The GSE157600 and GSE97084 datasets were used for analysis. A pan-cancer dataset which was uniformly normalized was downloaded and analyzed from the UCSC database: TCGA, TARGET, GTEx (PANCAN, n = 19,131, G = 60,499). Several advanced bioinformatics analyses were conducted, including single-cell sequencing analysis, correlation algorithm, and prognostic screen. CRC tumor microarray (TMA) as well as cell/animal experiments are used to further validate the results of the analysis. Results: The greatest variability was found in epithelial cells from the tumor group. RPS4X was generally upregulated in all types of CRC, while exercise downregulated RPS4X expression. A lowered expression of RPS4X may prolong tumor survival and reduce CRC metastasis. RPS4X and tumor stemness marker-CD44 were highly positively correlated and knockdown of RPS4X expression reduced tumor stemness both in vitro and in vivo. Conclusion: RPS4X upregulation may enhance CRC stemness and increase the odds of metastasis. Exercise may reduce CRC metastasis through the regulation of RPS4X.
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Temperature is one of the seven fundamental physical quantities. The ability to measure temperatures approaching absolute zero has driven numerous advances in low-temperature physics and quantum physics. Currently, millikelvin temperatures and below are measured through the characterization of a certain thermal state of the system as there is no traditional thermometer capable of measuring temperatures at such low levels. In this study, we develop a kind of diamond with sp2-sp3 composite phase to tackle this problem. The synthesized composite phase diamond (CPD) exhibits a negative temperature coefficient, providing an excellent fit across a broad temperature range, and reaching a temperature measurement limit of 1 mK. Additionally, the CPD demonstrates low magnetic field sensitivity and excellent thermal stability, and can be fabricated into probes down to 1 micron in diameter, making it a promising candidate for the manufacture of next-generation cryogenic temperature sensors. This development is significant for the low-temperature physics researches, and can help facilitate the transition of quantum computing, quantum simulation, and other related technologies from research to practical applications.
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Autophagy has been associated with tumor progression, prognosis, and treatment response. However, an autophagy-related model and their clinical significance have not yet been fully elucidated. In the present study, through the integrative analysis of bulk RNA sequencing and single-cell RNA sequencing, an autophagy-related risk model was identified. The model was capable of distinguishing the worse prognosis of patients with gastric cancer (GC), which was validated in TCGA and two independent Gene Expression Omnibus cohorts utilizing the survival analysis, and was also independent of other clinical covariates evaluated by multivariable Cox regression. The clinical value of this model was further assessed using a receiver operating characteristic (ROC) and nomogram analysis. Investigation of single-cell RNA sequencing uncovered that this model might act as an indicator of the dysfunctional characteristics of T cells in the high-risk group. Moreover, the high-risk group exhibited the lower expression of immune checkpoint markers (PDCD1 and CTLA4) than the low-risk group, which indicated the potential predictive power to the current immunotherapy response in patients with GC. In conclusion, this autophagy-associated risk model may be a useful tool for prognostic evaluation and will facilitate the potential application of this model as an indicator of the predictive immune checkpoint biomarkers.
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BACKGROUND AND PURPOSE: To evaluate longitudinal patient-reported distress in cervical cancer patients treated with definitive chemoradiation (CRT). MATERIALS AND METHODS: Between 2011 and 2016, consenting cervical cancer patients treated with definitive CRT who completed ≥ 2 revised Edmonton Symptom Assessment System (ESAS-r) questionnaires at clinical visits, including baseline, were included. A linear mixed model was used to assess the longitudinal trend in ESAS-r. A minimal clinically important difference (MCID) for total ESAS-r score was defined as a change of 3-points for improvement and 4-points for deterioration. The proportion of patients with an MCID over time was described using moving averages. To test for changes, mixed effects logistic models were fitted, each of which included patient-specific random intercepts and random slopes. RESULTS: 67 patients were eligible for analysis (736 ESAS-r assessments). Median (range) follow-up was 24 months (range: 15-45) and compliance at 12 months was 60% (40/67). There was a significant decrease in ESAS-r scores over time. Baseline ESAS-r was strongly predictive of ESAS-r at follow-up (p < 0.001). The proportion of patients with an MCID for improvement from baseline significantly increased over time (p < 0.001) and the proportion with an MCID for deterioration significantly decreased over time (p < 0.001). No predictors for distress were found. CONCLUSIONS: Long-term cervical cancer survivors experience distress that significantly improves over time to an extent expected to be clinically meaningful for patients. Implementing cervical cancer specific patient-reported outcome tools into practice could better inform patient needs.
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Multidrug resistance (MDR) of cancer cells is a significant challenge in chemotherapy, highlighting the urgent medical need for simple and reproducible strategies to reverse this process. Here, we report the development of an active tumor-targeting and redox-responsive nanoplatform (PA-ss-NP) using hyaluronic acid-g-cystamine dihydrochloride-poly-ε-(benzyloxycarbonyl)-L-lysine (HA-ss-PLLZ) to co-deliver paclitaxel (PTX) and apatinib (APA) for effective reversal of MDR. This smart nanoplatform specifically bound to CD44 receptors, leading to selective accumulation at the tumor site and uptake by MCF-7/ADR cells. Under high concentrations of cellular glutathione (GSH), the nanocarrier was degraded rapidly with complete release of its encapsulated drugs. Released APA effectively inhibited the function of the P-glycoprotein (P-gp) drug pump and improved the sensitivity of MDR cells to chemotherapeutic agents, leading to the recovery of PTX chemosensitivity in MDR cells. As expected, this newly developed intelligent drug delivery system could effectively control MDR, both in vitro and in vivo.
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Sistemas de Liberación de Medicamentos/métodos , Resistencia a Antineoplásicos , Ácido Hialurónico/farmacología , Paclitaxel/farmacología , Piridinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adyuvantes Inmunológicos/farmacología , Transporte Biológico Activo/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Humanos , Receptores de Hialuranos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Micelas , Polímeros/farmacologíaRESUMEN
Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic ß-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release ex vivo. GLP-1 is exclusively produced in approximately 50% of α-cells in lean mouse islets and 70% of α-cells in human islets, suggesting a paracrine α to ß-cell signaling through the ß-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human ß-cell function.
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Colecistoquinina/fisiología , Péptido 1 Similar al Glucagón/fisiología , Secreción de Insulina , Células Secretoras de Insulina/citología , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.
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Biomarcadores de Tumor/metabolismo , Cromosomas Humanos Par 16/genética , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteínas Represoras/metabolismo , Proteínas Represoras/fisiología , Alelos , Animales , Antígenos CD/genética , Apoptosis , Biomarcadores de Tumor/genética , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Cadherinas/genética , Proliferación Celular , Estudios de Cohortes , Neoplasias Colorrectales/patología , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Sitios de Carácter Cuantitativo , Proteínas Represoras/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Long noncoding RNAs (lncRNAs) contribute to many steps in carcinogenesis and often serve as biomarkers or therapeutic targets for tumor diagnosis and therapy. Although the role of lncRNAs in tumor formation is becoming clear, whether lncRNAs mediate gut microbiota-induced colorectal cancer (CRC) is largely unknown. Enterotoxigenic Bacteroides fragilis (ETBF) is a well-known tumor-inducing bacterium in the human gut; however, its tumorigenic effect remains to be explored. In the present study, we revealed the mechanism by which a lncRNA participates in gut bacteria-induced carcinogenesis: Bacteroides fragilis-associated lncRNA1 (BFAL1) in CRC tissues mediates ETBF carcinogenesis. BFAL1 was highly expressed in CRC tissues compared with that in adjacent normal tissues. In vitro, BFAL1 was upregulated in ETBF-treated CRC cells. Mechanistically, ETBF promoted tumor growth via BFAL1 by activating the Ras homolog, which is the MTORC1 binding/mammalian target of the rapamycin (RHEB/mTOR) pathway. Furthermore, BFAL1 regulated RHEB expression by competitively sponging microRNAs miR-155-5p and miR-200a-3p. Clinically, both high expression of BFAL1 and high abundance of ETBF in CRC tissues predicted poor outcomes for patients with CRC. Thus, BFAL1 is a mediator of ETBF-induced carcinogenesis and may be a potential therapeutic target for ETBF-induced CRC.
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Bacteroides fragilis/patogenicidad , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/microbiología , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Proteína Homóloga de Ras Enriquecida en el Cerebro/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Western Blotting , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Biología Computacional , Humanos , ARN Largo no Codificante/genética , ARN Interferente Pequeño/genética , Proteína Homóloga de Ras Enriquecida en el Cerebro/genética , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Long non-coding RNAs (lncRNAs) contribute to colorectal cancer (CRC). However, the role of lncRNAs in CRC metabolism, especially glucose metabolism remains largely unknown. In this study, we identify a lncRNA, GLCC1, which is significantly upregulated under glucose starvation in CRC cells, supporting cell survival and proliferation by enhancing glycolysis. Mechanistically, GLCC1 stabilizes c-Myc transcriptional factor from ubiquitination by direct interaction with HSP90 chaperon and further specifies the transcriptional modification pattern on c-Myc target genes, such as LDHA, consequently reprogram glycolytic metabolism for CRC proliferation. Clinically, GLCC1 is associated with tumorigenesis, tumor size and predicts poor prognosis. Thus, GLCC1 is mechanistically, functionally, and clinically oncogenic in colorectal cancer. Targeting GLCC1 and its pathway may be meaningful for treating patients with colorectal cancer.
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Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Largo no Codificante/metabolismo , Anciano , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Femenino , Glucólisis/genética , Proteínas HSP90 de Choque Térmico/genética , Humanos , Estimación de Kaplan-Meier , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Pronóstico , Ubiquitinación/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
TEAD4 (TEA domain family member 4) was recently revealed as an oncogenic character in tumorigenesis. However, its role remains unclear in colorectal tumorigenesis. Here, we firstly found that the expression level of TEAD4 was significantly elevated in clinical samples of colorectal adenomas (CRA) and correlated with the size and histological type of CRA. Moreover, patients with higher TEAD4 expression in normal colon mucosa are more prone to be recurrent after polypectomy. TEAD4 knockdown significantly inhibited colorectal cell proliferation in vitro and suppressed tumor growth in vivo. RNA-seq and GSEA analysis reveals TEAD4 can probably regulate Hippo pathway and further experiment confirm the downstream target gene YAP1. The subsequent ChIP-qPCR and luciferase report assay indicated that TEAD4 regulated YAP1 by direct binding and transcriptional activation. In summary, our study reveals that TEAD4 plays an important tumor-promoting role in colorectal cancer by directly targeting the YAP1, thus we suggests TEAD4 may be used as a novel biomarker in colorectal tumorigenesis and provides TEAD4/YAP1 axis as a potential therapeutic option for colorectal cancer.
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Proteínas Adaptadoras Transductoras de Señales/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/metabolismo , Proteínas Musculares/metabolismo , Fosfoproteínas/genética , Factores de Transcripción/metabolismo , Transcripción Genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenoma/genética , Adenoma/patología , Animales , Secuencia de Bases , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Fosfoproteínas/metabolismo , Unión Proteica , Transducción de Señal , Factores de Transcripción de Dominio TEA , Activación Transcripcional/genética , Proteínas Señalizadoras YAPRESUMEN
The abnormal expression of microRNAs (miRNAs) in colorectal cancer (CRC) progression has been widely investigated. It was reported that the same hairpin RNA structure could generate mature products from each strand, termed 5p and 3p, which binds different target mRNAs. Here, we explored the expression, functions, and mechanisms of miR-514b-3p and miR-514b-5p in CRC cells and tissues. We found that miR-514b-3p was significantly down-regulated in CRC samples, and the ratio of miR-514b-3p/miR-514b-5p increased from advanced CRC, early CRC to matched normal colorectal tissues. Follow-up functional experiments illustrated that miR-514b-3p and miR-514b-5p had distinct effects through interacting with different target genes: MiR-514b-3p reduced CRC cell migration, invasion and drug resistance through increasing epithelial marker and decreasing mesenchymal marker expressions, conversely, miR-514b-5p exerted its pro-metastatic properties in CRC by promoting EMT progression. MiR-514b-3p overexpressing CRC cells developed tumors more slowly in mice compared with control cells, however, miR-514b-5p accelerated tumor metastasis. Overall, our data indicated that though miR-514b-3p and miR-514b-5p were transcribed from the same RNA hairpin, each microRNA has distinct effect on CRC metastasis.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , MicroARNs/metabolismo , Animales , Secuencia de Bases , Línea Celular Tumoral , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Desnudos , MicroARNs/genética , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment.Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751-65. ©2018 AACR.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/genética , Células Madre Mesenquimatosas/citología , MicroARNs/genética , Animales , Antígenos CD/biosíntesis , Células CACO-2 , Cadherinas/biosíntesis , Línea Celular Tumoral , Movimiento Celular/genética , Células HCT116 , Células HT29 , Humanos , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Invasividad Neoplásica/genética , Trasplante de Neoplasias , Complejo Represivo Polycomb 1/biosíntesis , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genética , Factores de Transcripción/biosíntesis , Trasplante Heterólogo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/biosíntesisRESUMEN
Objective: The E3 ubiquitin ligase RNF6 (RING-finger protein 6) plays a crucial role in carcinogenesis. However, the copy number and expression of RNF6 were rarely reported in colorectal cancer. We aimed to explore the mechanical, biological, and clinical role of RNF6 in colorectal cancer initiation and progression.Design: The copy number and expression of RNF6 were analyzed from Tumorscape and The Cancer Genome Atlas (TCGA) datasets. Gene expressions were examined by real-time PCR, Western blot, and immunohistochemical staining. Gene expression profiling studies were performed to identify pivotal genes regulated by RNF6. Biological function of RNF6 on tumor growth and metastasis was detected in vivo and in vitro Role of RNF6 in modulating SHP-1 expression was examined by coimmunoprecipitation and confocal microscopy, respectively.Results: The copy number of RNF6 was significantly amplified in colorectal cancer, and the amplification was associated with RNF6 expression level. Amplification and overexpression of RNF6 positively correlated with patients with colorectal cancer with poor prognosis. The gene set enrichment analysis (GSEA) revealed cell proliferation, and invasion-related genes were enriched in RNF6 high-expressed colorectal cancer cells as well as in patients from TCGA dataset. Downregulation of RNF6 impaired the colorectal cancer cell proliferation and invasion in vitro and in vivo RNF6 may activate the JAK/STAT3 pathway and increase pSTAT3 levels by inducing the ubiquitination and degradation of SHP-1.Conclusions: Genomic amplification drives RNF6 overexpression in colorectal cancer. RNF6 may be a novel biomarker in colorectal carcinogenesis, and RNF6 may increase pSTAT3 level via promoting SHP-1 ubiquitylation and degradation. Targeting the RNF6/SHP-1/STAT3 axis provides a potential therapeutic option for RNF6-amplified tumors. Clin Cancer Res; 24(6); 1473-85. ©2017 AACR.
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Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Quinasas Janus/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Factor de Transcripción STAT3/genética , Animales , Células CACO-2 , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/metabolismo , Amplificación de Genes , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HT29 , Humanos , Quinasas Janus/metabolismo , Estimación de Kaplan-Meier , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/genética , Trasplante Heterólogo , UbiquitinaciónRESUMEN
Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread, and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative therapeutic approaches. Here we demonstrate a critical role of ASAP3 in regulating the microvilli structure of parietal cells in vivo, and reveal the feasibility of controlling gastric acidity by targeting ASAP3. Conditional knockout of ASAP3 in mice caused elongation and stacking of microvilli in parietal cells, and substantially decreased gastric acid secretion. These were associated with active assembly of F-actin caused by a higher level of GTP-bound Arf6 GTPase. Consistently, a small molecular compound QS11 inhibited ASAP3 function and significantly reduced gastric acidity in vivo. Of note, the expression of ASAP3 was positively correlated with gastric acid secretion in 90 human cases, and high expression of ASAP3 was associated with reflux disease and peptic ulcer. These results reveal for the first time that ASAP3 regulates the microvilli structures in parietal cells. Our data also suggest ASAP3 as a feasible and drugable therapeutic target for gastric acidity-associated diseases.
RESUMEN
UNLABELLED: Long noncoding RNAs (lncRNA) play a role in carcinogenesis. However, the function of lncRNAs in human gastric cancer remains largely unknown. In this study, we identified a novel lncRNA, GClnc1, which was upregulated and associated with tumorigenesis, tumor size, metastasis, and poor prognosis in gastric cancer. GClnc1 affected gastric cancer cell proliferation, invasiveness, and metastasis in multiple gastric cancer models. Mechanistically, GClnc1 bound WDR5 (a key component of histone methyltransferase complex) and KAT2A histone acetyltransferase, acted as a modular scaffold of WDR5 and KAT2A complexes, coordinated their localization, specified the histone modification pattern on the target genes, including SOD2, and consequently altered gastric cancer cell biology. Thus, GClnc1 is mechanistically, functionally, and clinically oncogenic in gastric cancer. Targeting GClnc1 and its pathway may be meaningful for treating patients with gastric cancer. SIGNIFICANCE: This report documents a novel lncRNA, GClnc1, which may act as a scaffold to recruit the WDR5 and KAT2A complex and modify the transcription of target genes. This study reveals that GClnc1 is an oncogenic lncRNA in human gastric cancer. Cancer Discov; 6(7); 784-801. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.