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NTRK (neurotrophic tyrosine receptor kinase) gene fusions that encode chimeric proteins exhibiting constitutive activity of tropomyosin receptor kinases (TRK), are oncogenic drivers in multiple cancer types. However, the underlying mechanisms in oncogenesis that involve various N-terminal fusion partners of NTRK fusions remain elusive. Here, we show that NTRK fusion proteins form liquid-like condensates driven by their N-terminal fusion partners. The kinase reactions are accelerated in these condensates where the complexes for downstream signaling activation are also concentrated. Our work demonstrates that the phase separation driven by NTRK fusions is not only critical for TRK activation, but the condensates formed through phase separation serve as organizational hubs for oncogenic signaling.
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Neoplasias , Proteínas de Fusión Oncogénica , Humanos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal/genética , Neoplasias/genética , Neoplasias/metabolismo , Fusión Génica , Receptor trkA/genética , Receptor trkA/metabolismo , Inhibidores de Proteínas QuinasasRESUMEN
The Wnt/ß-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the ß-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of ß-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the ß-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3ß and CK1α were unsuccessfully recruited, preventing ß-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of ß-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.
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Complejo de Señalización de la Axina , beta Catenina , Humanos , Complejo de Señalización de la Axina/genética , Proteína Axina/genética , Proteína Axina/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Separación de Fases , Mutación/genética , Vía de Señalización Wnt/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismoRESUMEN
The flicker frequency of incident light constitutes a critical determinant in biology. Nevertheless, the exploration of methods to simulate external light stimuli with varying frequencies and develop artificial retinal neurons capable of responsive behavior remains an open question. This study presents an artificial neuron comprising organic phototransistors. The triggering properties of neurons are modulated by optical input, enabling them to execute rudimentary synaptic functions, emulating the biological characteristics of retinal neurons. The artificial retinal neuron exhibits varying responses to incoming light frequencies, allowing it to replicate the persistent visual behavior of the human eye and facilitating image discrimination. Additionally, through seamless integration with circuitry, it can execute motion recognition on a machine cart, preventing collisions with high-speed obstacles. The artificial retinal neuron offers a cost-effective and energy-efficient route for future mobile robot processors.
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Retina , Visión Ocular , Humanos , Neuronas/fisiologíaRESUMEN
Salmonella is a zoonotic pathogen posing a serious risk to the farming industry and public health due to food animals serving as reservoirs for future contamination and spread of Salmonella. The present study is designed to monitor the contamination status of Salmonella in duck farms and the main control points during breeding. 160 strains of duck-derived Salmonella were isolated from the 736 samples (cloacal swabs, feces, water, feed, soil, and air and dead duck embryos) collected in southwest Shandong Province and the province's surrounding area. The percentage of Salmonella-positive samples collected was 21.74% (160/736), and the greatest prevalence from duck embryo samples (40.00%, 36/90). These Salmonella were classified into 23 serotypes depending on their O and H antigens, in which S. Typhimurium (30.15%), S. Kottbus (13.97%) and S. Enteritidis (10.29%) were the prevailing serotypes. Subsequently, the molecular subtyping was done. Clustered regularly interspaced short palindromic repeats (CRISPR) analysis showed that 41 strains of S. Typhimurium and 14 strains of S. Enteritidis were classified into 13 and 3 genotypes, respectively. 19 S. Kottbus isolates from different sources featured ST1546, ST198, ST321, and ST1690 by multilocus sequence typing (MLST) analysis, among which ST1546 belongs to S. Kottbus was a new ST. The minimum spanning tree analysis based on the two CRISPR loci and seven MLST loci from all S. Typhimurium, S. Enteritidis and S. Kottbus isolates revealed that duck embryos, feed and water were key control points to the spread of Salmonella along the breeding chain. Meanwhile, the emergence of S. Kottbus in duck flocks was considered a potential public health hazard.
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The natural bulk Van der Waals heterostructure compound 6R-TaS_{2} consists of alternate stacking 1T- and 1H-TaS_{2} monolayers, creating a unique system that incorporates charge-density-wave (CDW) order and superconductivity (SC) in distinct monolayers. Here, after confirming that the 2D nature of the lattice is preserved up to 8 GPa in 6R-TaS_{2}, we documented an unusual evolution of CDW and SC by conducting high-pressure electronic transport measurements. Upon compression, we observe a gradual suppression of CDW within the 1T layers, while the SC exhibits a dome-shaped behavior that terminates at a critical pressure P_{c} around 2.9 GPa. By taking account of the fact that the substantial suppression of SC is concomitant with the complete collapse of CDW order at P_{c}, we argue that the 6R-TaS_{2} behaves like a stack of Josephson junctions and thus the suppressed superconductivity can be attributed to the weakening of Josephson coupling associated with the presence of CDW fluctuations in the 1T layers. Furthermore, the SC reversely enhances above P_{c}, implying the development of emergent superconductivity in the 1T layers after the melting of T-layer CDW orders. These results show that the 6R-TaS_{2} not only provides a promising platform to explore emergent phenomena but also serves as a model system to study the complex interactions between competing electronic states.
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The bladder cancer-associated protein (BLCAP) gene is a tumor-suppressor gene as its encoded protein can inhibit cell proliferation by stimulating apoptosis in many malignant tumors. It is also a novel site of adenosine-to-inosine (A-to-I) RNA editing by ADAR (adenosine deaminase acting on RNA). In this study, we found by exome and transcriptome sequencing that there was an abnormal RNA editing event of the BLCAP gene in colorectal cancer (CRC) tissues compared to adjacent normal tissues. The editing of BLCAP transcripts promoted the degradation of BLCAP by ubiquitination, so BLCAP could not maintain its function as a tumor suppressor gene in CRC. Moreover, our further studies revealed that BLCAP could interact with Rb1 and inhibit its phosphorylation, while the loss of repressive effect due to reduced BLCAP protein levels caused by A-to-I RNA editing facilitates the transition from G1 to S phase of the cell cycle, leading to increased cell proliferation and reduced apoptosis. Thus, A-to-I RNA editing events tend to play an essential role in CRC carcinogenesis.
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Neoplasias Colorrectales , Edición de ARN , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Humanos , Proteínas de Neoplasias/genética , ARN/metabolismo , Edición de ARN/genética , Proteínas de Unión a Retinoblastoma/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The application of artificial neural network algorithm in pathological diagnosis of gastrointestinal malignant tumors has become a research hotspot. In the previous studies, the algorithm research mainly focused on the model development based on convolutional neural networks, while only a few studies used the combination of convolutional neural networks and recurrent neural networks. The research contents included classical histopathological diagnosis and molecular typing of malignant tumors, and the prediction of patient prognosis by utilizing artificial neural networks. This article reviews the research progress on artificial neural network algorithm in the pathological diagnosis and prognosis prediction of digestive tract malignant tumors.
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Neoplasias Gastrointestinales , Redes Neurales de la Computación , Humanos , Algoritmos , Pronóstico , Neoplasias Gastrointestinales/diagnósticoRESUMEN
Achieving tough and stable tissue adhesion under a physiological environment is of great significance for the clinical applications of hydrogel adhesives. The current tough hydrogel adhesives face challenges in the preservation of the maximal adhesion for a long time due to swelling. Here, we propose a double-network strategy for tough tissue adhesion by a hydrogel with long-term stability under a physiological environment. A double-network hydrogel consisting of a covalently crosslinked primary network with tunable hydrophilicity and a non-covalently crosslinked secondary network with functional groups is designed. The primary network exhibited hydrophobicity in the physiological environment, which could constrict the secondary network and limit the swelling of the entire hydrogel. The secondary network could form strong interlinks with tissue and provide large energy dissipation through the unzipping of its noncovalent crosslinks when separated by a force. The combination of the two networks resulted in a tough and stable tissue adhesion. A poly(N-isopropylacrylamide)/calcium alginate hydrogel synthesized based on this strategy realized an adhesion energy of 300-500 J m-2 with porcine tissues, and the maximal adhesion could be maintained for over 1000 min after submerging in a PBS solution at 37 °C. The swelling behavior of the hydrogel and changes in mechanical properties under the physiological environment are studied, and its application in repairing the aorta wound is demonstrated.
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Alginatos , Hidrogeles , Animales , Interacciones Hidrofóbicas e Hidrofílicas , Fenómenos Mecánicos , Porcinos , Adherencias TisularesRESUMEN
BACKGROUND: Salmonella as an important food-borne zoonotic bacterial pathogen, infection in ducks is a recessive infection, however, it can also cause high mortality and threat to food safety. Preventing and controlling the infection and transmission of Salmonella in ducks critically require rapid and sensitive detection method. Full-length Salmonella-specific protein PagN was induced and expressed in E.coil BL21 and was purified as an antigen to establish an indirect enzyme-linked immunosorbent assays (iELSA) detection kit. RESULTS: The recombinant PagN protein has a molecular weight of 43 kDa containing a His-tag, was recognized by an anti-Salmonella positive serum by Western blot assay. The optimal concentration of PagN as a coating antigen in the iELISA was 1 µg/mL, and the optimal dilution of enzyme-labeled secondary antibody was 1:4000 (0.025 µg/mL). The cutoff OD450 value was established at 0.268. The iELISA kit showed high selectivity since no cross-reaction with E. coli, Staphylococcus aureus and Streptococcus was observed. iELISA method and Dot-blot test were performed on 100 clinical sera samples collected from duck farms, and the actual coincidence rate was 89% (89/100). 613 duck serum samples from 3 different farms were tested using established method and commercial ELISA kit. The concordance between the two methods was 94.1%. CONCLUSION: Anti-PagN based iELISA can serve as a useful tool for diagnosis of Salmonella infection.
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Patos , Escherichia coli , Animales , Sensibilidad y Especificidad , Ensayo de Inmunoadsorción Enzimática/veterinaria , Ensayo de Inmunoadsorción Enzimática/métodos , Proteínas Recombinantes , Anticuerpos Antibacterianos , Anticuerpos AntiviralesRESUMEN
Osmotic stress is one of the main stresses seriously affects the growth and development of plants. Hydrogen sulfide (H2S) emerges as the third gaseous signal molecule to involve in the complex network of signaling events. Phospholipase Dδ (PLDδ), as signal enzyme, responds to many biotic or abiotic stress responses. In this study, the functions and the relationship of PLDδ and H2S in stomatal closure induced by osmotic stress were explored. Using the seedlings of ecotype (WT), PLDδ deficient mutant (pldδ), L-cysteine desulfhydrase (LCD) deficient mutant (lcd) and pldδlcd double mutant as materials, the Real-time quantitative PCR (RT-qPCR) and the stomatal aperture were analyzed. Osmotic stress induced the expressions of PLDδ and LCD. The H2S content and the activities of PLD and LCD ascended in WT under osmotic stress. The phenotypes of pldδ, lcd and pldδlcd were more sensitive to osmotic stress than WT. Compared with pldδ, the stomatal of lcd showed lower sensitivity to osmotic stress, and the stomatal aperture of pldδlcd was similar to that of lcd. Simultaneous application of PA and NaHS resulted in tighter closure of stomatal than application of either PA or NaHS alone. These results suggested that osmotic stress-triggered stomatal closure requires PLDδ and H2S in A. thaliana. LCD acted downstream of PLDδ to regulate the stomatal closure induced by osmotic stress.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiología , Sulfuro de Hidrógeno/metabolismo , Fosfolipasa D/metabolismo , Estomas de Plantas/fisiología , Presión OsmóticaRESUMEN
Chorispora bungeana (C. bungeana) is a rare alpine subnival species that is highly tolerant to low temperature stress. Phospholipase D (PLD) is a key enzyme involved in membrane phospholipid catabolism during plant growth and the stress response. In this study, one member of CbPLD gene family, CbPLDδ, was cloned from C. bungeana and was introduced into tobacco. This gene encodes an 864-amino acid protein with two catalytic HxKxxxxD motifs which are essential for phospholipase D activity. After the CbPLDδ gene is fused with the vector containing the GFP tag, subcellular localization showed that CbPLDδ was predominately located in the cell membrane. RT-qPCR and histochemical GUS assays showed that CbPLDδ gene was induced by low temperature and expressed predominantly in leaf and root. Compared with wild-type tobacco, CbPLDδ transgenic tobacco showed higher activities of antioxidant enzymes, and lower levels of malonidiadehyde and electrolyte leakage under low temperature stress. These results reflected that CbPLDδ is involved in the response to low temperature stress, and has the potential to improve the low temperature tolerance of plants.
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Brassicaceae , Criopreservación , Brassicaceae/genética , Clonación Molecular , Frío , Criopreservación/métodos , Proteínas de Plantas/genética , Estrés Fisiológico , TemperaturaRESUMEN
BACKGROUND: Accumulating evidence indicates that circular RNAs (circRNAs) act as microRNA (miRNA) sponges to directly inhibit specific miRNAs and alter their ability to regulate gene expression at the post-transcriptional level; this mechanism is believed to occur in various cancers. However, the expression level, precise function and mechanism of circ_001680 in colorectal carcinoma (CRC) are largely unknown. METHODS: qRT-PCR was used to detect the expression of circ_001680 and miR-340 in human CRC tissues and their matched normal tissues. Bioinformatics analyses and dual-fluorescence reporter assays were used to evaluate whether circ_001680 could bind to miR-340. Circ_001680 overexpression and knockdown cell lines were constructed to investigate the proliferation and migration abilities in vivo and in vitro through function-based experiments, including CCK8, plate clone formation, transwell, and wounding healing assays. The relationships among circ_001680, miR-340 and BMI1 were investigated by bioinformatics analyses, dual-fluorescence reporter system, FISH, RIP and RNA pull down assays. Sphere forming assays and flow cytometry analyses were used to assess the effect of circ_001680 on the stemness characteristics of CRC cells. RESULTS: Circ_001680 was more highly expressed in of CRC tissue than in matched adjacent normal tissues from the same patients. Circ_001680 was observed to enhance the proliferation and migration capacity of CRC cells. Furthermore, dual-fluorescence reporter assays confirmed that circ_001680 affects the expression of BMI1 by targeting miR-340. More importantly, we also found that circ_001680 could promote the cancer stem cell (CSC) population in CRC and induce irinotecan therapeutic resistance by regulating the miR-340 target gene BMI1. CONCLUSIONS: Our results demonstrated that circ_001680 is a part of a novel strategy to induce chemotherapy resistance in CRC through BMI1 upregulation. Moreover, circ_001680 may be a promising diagnostic and prognostic marker to determine the success of irinotecan-based chemotherapy.
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Biomarcadores de Tumor/metabolismo , Movimiento Celular , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , MicroARNs/genética , Complejo Represivo Polycomb 1/metabolismo , ARN Circular/genética , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Irinotecán/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Complejo Represivo Polycomb 1/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Siah E3 ubiquitin protein ligase 1 (Siah1) has been identified as a tumor suppressor gene and plays an important role in the development of malignant tumors. However, the potential role and molecular mechanism of Siah1 in the development and progression of CRC is still unclear. METHODS: To explore the role and molecular mechanism of Siah1 in the development and progression of CRC, we examined the expression of Siah1 in CRC tissue samples and analyzed its association with progression and prognosis in CRC. In addition, overexpression and knockdown of Siah1 was used to investigate its activity in CRC cells. We also use bioinformatics to analyze and verify the significant roles of Siah1 in critical signaling pathways of CRC. RESULTS: We found that the expression of Siah1 was significantly downregulated in CRC tissues, and low expression of Siah1 was associated with aggressive TNM staging and poor survival of CRC patients. Moreover, we revealed that overexpression of Siah1 in CRC cells markedly inhibited CRC cell proliferation and invasion in vitro and in vivo, while knockdown of Siah1 enhanced CRC cell proliferation and invasion. Furthermore, we found that Siah1 prohibited cell proliferation and invasion in CRC partially through promoting AKT (the serine-threonine protein kinase) and YAP (yes associated protein) ubiquitylation and proteasome degradation to regulate the activity of MAPK(mitogen-activated protein kinase 1), PI3K-AKT (phosphatidylinositol 3-kinase-the serine-threonine protein kinase) and Hippo signaling pathways. CONCLUSIONS: These findings suggested that Siah1 is a novel potential prognostic biomarker and plays a tumor suppressor role in the development and progression of CRC.
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BACKGROUND: Ubinuclein-2 (UBN2) is a nuclear protein that interacts with many transcription factors. The molecular role and mechanism of UBN2 in the development and progression of cancers, including colorectal cancer (CRC), is not well understood. The current study explored the role of UBN2 in the development and progression CRC. METHODS: Oncomine network and The Cancer Genome Atlas (TCGA) database were downloaded and Gene Set Enrichment Analysis (GSEA) was performed to compare the UBN2's expression between normal and tumor tissues, as well as the potential correlation of UBN2 expression with signaling pathways. Immunohistochemistry (IHC), qRT-PCR and Western blotting were performed to determine the expression of UBN2 in CRC tissues or cell lines. In vitro proliferation and invasion assays, and orthotopic mouse metastatic model were used to analyze the effect of UBN2 on the development and progression of CRC. RESULTS: The analysis of UBN2 expression using Oncomine network showed that UBN2 was upregulated in CRC tissues compared to matched adjacent normal intestinal epithelial tissues. IHC, qRT-PCR and Western blotting confirmed that UBN2 expression is higher in CRC tissues compared with matched adjacent normal intestinal epithelial tissues. In addition, analyses of TCGA data revealed that high UBN2 expression was associated with advanced stages of lymph node metastasis, distant metastasis, and short survival time in CRC patients. IHC showed that high UBN2 expression is correlated with advanced stages of CRC. Moreover, UBN2 is highly expressed in the liver metastatic lesions. Furthermore, knockdown of UBN2 inhibited the growth, invasiveness and metastasis of CRC cells via regulation of the Ras/MAPK signaling pathway. CONCLUSION: The current study demonstrates that UBN2 promotes tumor progression in CRC. UBN2 may be used as a promising biomarker for predicting the prognosis of CRC patients.
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BACKGROUND/AIMS: It is well established that many non-trophoblastic tumors secrete HCG (human chorionic gonadotropin) and that such secretion is correlated with the poor prognosis of tumor patients. This study aims to analyze the correlation between ß-HCG expression and outcome of colorectal cancer (CRC) and understand its role in CRC pathology Methods: We detected the mRNA and protein expression of ß-HCG in human CRC tissues with RT-qPCR and immunohistochemistry, and we compared the clinical-pathological characteristics, prognosis and progression between the ß-HCG positive and negative groups. We also generated CRC cell lines with ß-HCG over-expression as well as ß-HCG stable knockout, and evaluated cell function and mechanism in vitro and in vivo. RESULTS: Fifty out of 136 CRC patients (37%) expressed ß-HCG at the invasive front. Clinical-pathological data showed that ß-HCG was positively correlated with Dukes staging (P=0.031) and lymph node metastasis (P=0.012). Survival analysis suggested that the patients with high expression of ß-HCG had poorer prognosis than those with low ß-HCG expression (P=0.0289). ß-HCG expression level was also positively correlated with tumor invasion in early-stage CRC patient tissues (P=0.0227). Additionally ß-HCG promoted the migration and invasion of CRC in vitro and in vivo but had no effect on the proliferation of tumor cells. CONCLUSION: Our study demonstrated that ß-HCG was ectopically expressed in the CRC patients and its high expression correlated with poor prognosis of early-stage CRC. Additionally it worked as an oncogene that promotes the migration and invasion of CRC by epithelial-mesenchymal transition (EMT).
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Gonadotropina Coriónica Humana de Subunidad beta/metabolismo , Neoplasias Colorrectales/diagnóstico , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Gonadotropina Coriónica Humana de Subunidad beta/deficiencia , Gonadotropina Coriónica Humana de Subunidad beta/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Índice de Severidad de la Enfermedad , Trasplante HeterólogoRESUMEN
PURPOSE: The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression. METHODS: We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources. RESULTS: Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS. CONCLUSIONS: We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.
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Biomarcadores de Tumor , Expresión Génica , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/mortalidad , Adulto , Anciano , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Vigilancia de la Población , Pronóstico , Sistema de Registros , Análisis de Supervivencia , Neoplasias de la Mama Triple Negativas/epidemiología , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: miRNAs are regarded as molecular biomarkers and therapeutic targets for colorectal cancer (CRC), a series of miRNAs have been proven to involve into CRC carcinogenesis, invasion and metastasis. Aberrant miR-422a expression and its roles have been reported in some cancers. However, the function and underlying mechanism of miR-422a in the progression of CRC remain largely unknown. METHODS: Real-time PCR were used to quantify miR-422a expression in CRC tissues. Both vivo and vitro functional assays showed miR-422a inhibits CRC cell proliferation. Target prediction program (miRBase) and luciferase reporter assays were conducted to confirm the target genes AKT1 and MAPK1 of miR-422a. Specimens from 50 patients with CRC were analyzed for the correlation between the expression of miR-422a and the expression of the target genes AKT1 and MAPK1 by real-time PCR. RESULTS: MiR-422a was downregulated in CRC tissues and cell lines. Ectopic expression of miR-422a inhibited cell proliferation and tumor growth ability; inhibition of endogenous miR-422a, by contrast, promoted cell proliferation and tumor growth ability of CRC cells. MiR-422a directly targets 3'-UTR of the AKT1 and MAPK1, down-regulation of miR-422a led to the activation of Raf/MEK/ERK and PI3K/AKT signaling pathways to promote cell proliferation in CRC. In addition, miR-422a expression was negatively correlated with the expressions of AKT1 and MAPK1 in CRC tissues. CONCLUSION: miR-422a inhibits cell proliferation in colorectal cancer by targeting AKT1 and MAPK1.
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PURPOSE: No biomarker is available for pancreatic cancer early detection, but a small prospective European study involving 16 cases and 32 controls raised the possibility that anti-Ezrin autoantibodies may be associated with risk of pancreatic cancer. We aimed to validate this finding in a case-control study nested within a prospective study in the USA. METHODS: Levels of anti-Ezrin autoantibodies were examined using ELISA in pre-diagnostic plasma samples of 73 cases and 145 matched controls. Paired t test and paired signed rank tests were used to determine the difference between two groups, and conditional logistic regression was used to evaluate the association between anti-Ezrin autoantibody levels and risk of developing pancreatic cancer. RESULTS: No association was found between levels of anti-Ezrin plasma autoantibodies and subsequent risk of developing pancreatic cancer. CONCLUSION: Anti-Ezrin autoantibodies did not appear to be useful as a plasma biomarker for early detection of pancreatic cancer.
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Autoanticuerpos/inmunología , Proteínas del Citoesqueleto/inmunología , Neoplasias Pancreáticas/inmunología , Anciano , Estudios de Casos y Controles , Detección Precoz del Cáncer , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/epidemiología , Estudios Prospectivos , Riesgo , Estados Unidos/epidemiologíaRESUMEN
Colonoscopy remains the standard screening method for detecting colorectal cancer (CRC) at an early stage. However, many people avoid having a colonoscopy because of the fear for its potential complications. Our study aimed to identify plasma microRNAs for preliminarily screening CRC in general population, so that some unnecessary colonoscopies can be avoided. We investigated plasma microRNA expression in three independent cohorts including the discovery (n = 80), training (n = 112), and validation (n = 49) phases recruited at two medical centers. Microarrays were used for screening 723 microRNAs in 80 plasma samples to identify candidate microRNAs. Quantitative reverse-transcriptase PCR was performed on the 161 training and validation plasma samples to evaluate the candidate microRNAs discovered from microarrays. A logistic regression model was constructed based on the training cohort and then verified by using the validation dataset. Area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified a panel of miR-409-3p, miR-7, and miR-93 that yielded high diagnostic accuracy in discriminating CRC from healthy group (AUC: 0.866 and 0.897 for training and validation dataset, respectively). Moreover, the diagnostic performance of the microRNA panel persisted in nonmetastasis CRC stages (Dukes' A-B, AUC: 0.809 and 0.892 for training and validation dataset, respectively) and in metastasis CRC stages (Dukes' C-D, AUC: 0.917 and 0.865 for training and validation dataset, respectively). In conclusion, our study reveals a plasma microRNA panel that has potential clinical value in early CRC detection and would play a critical role on preliminarily screening CRC in general population.