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Kinesin family member 20B (KIF20B) has been reported to have an oncogenic role in bladder and hepatocellular cancer cells, but its role in colorectal cancer (CRC) progression remains unclear. In this study, we assessed the mRNA and protein levels of KIF20B in CRC tissues using qRT-PCR and immunohistochemistry, respectively. KIF20B was overexpressed in CRC tissues and was associated with cancer invasion and metastasis. Mechanistically, KIF20B overexpression promoted the epithelial-mesenchymal transition (EMT) process mediated by glioma-associated oncogene 1 (Gli1) as well as CRC cell migration and invasion. Interestingly, KIF20B was localized in pseudopod protrusions of CRC cells and influenced the formation of cell protrusions, especially the EMT-related invadopodia. Moreover, intracellular actin dynamic participated in the modulation of the Gli1-mediated EMT and EMT-related cell pseudopod protrusion formation induced by KIF20B. We identified a role for KIF20B in CRC progression and revealed a correlation between KIF20B expression in CRC tissues and patient prognosis. The underlying mechanism was associated with the Gli1-mediated EMT and EMT-related cell protrusion formation modulated by intracellular actin dynamic. Thus, KIF20B may be a potential biomarker and promising treatment target for CRC.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Cinesinas/genética , Proteína GLI1 em Dedos de Zinco/genética , Actinas/genética , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , PrognósticoRESUMO
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.
Assuntos
Transformação Celular Neoplásica/patologia , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/patologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/patologia , Animais , Transformação Celular Neoplásica/metabolismo , Imunoprecipitação da Cromatina , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gerbillinae , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Técnicas Imunoenzimáticas , Masculino , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Células Tumorais CultivadasRESUMO
PURPOSE: Since observational data in the urban residents are required to better assess the risk factors of colorectal neoplasm occurrence and the effectiveness of colonoscopy screening and surveillance, we conducted a case-control study at multicenters in China to identify patient characteristics and neoplasm features of colorectal adenoma (CRA) and colorectal carcinoma (CRC). METHODS: A total of 4089 patients who had undergone a colonoscopy from 19 hospitals were enrolled, of which 1106 had CRA and 466 had CRC. They were compared with controls. The analysis provides features and risk factors of colorectal neoplasm using multivariate logistic regression. RESULTS: Increasing age, a family history of colorectal cancer or previous cases of colorectal adenoma or hypertension disease, gastrointestinal surgery, regular intake of pickled food (adjusted odds ratio [aOR] 1.42, 95 % confidence interval [CI], 1.048-1.924), consumption of alcohol, and a positive result of fecal occult blood testing (FOBT; aOR 2.509, 95 % CI 1.485-4.237) were associated with an increased risk of CRA. In the CRC group, increasing age, regular intake of pickled foods, and a positive FOBT result were risk factors. In addition, a positive abdominal computed tomography (CT) before a colonoscopy and physical signs of emaciation were also significantly associated with an increasing risk of colorectal carcinoma. Regular intake of vegetables decreased the risk of both CRA and CRC. CONCLUSIONS: Age, pickled foods, and a positive FOBT are risk factors for colorectal neoplasm. Vegetable intake was associated with a decreased risk of CRA and CRC.
Assuntos
Adenoma/epidemiologia , Adenoma/patologia , Carcinoma/epidemiologia , Carcinoma/patologia , Colonoscopia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Fatores Etários , Idoso , Estudos de Casos e Controles , China/epidemiologia , Estudos Transversais , Detecção Precoce de Câncer , Comportamento Alimentar , Humanos , Programas de Rastreamento , Pessoa de Meia-Idade , Sangue Oculto , Fatores de RiscoRESUMO
C9orf140 is a newly identified and characterized gene which is associated with cell proliferation and tumorigenicity. Expression of C9orf140 is upregulated in human gastric cancer and colorectal cancer (CRC); however, little is known about its role in CRC progression. We have investigated the clinical significance, biological effects and mechanisms of C9orf140 signaling. We found that the expression of C9orf140 is dramatically increased in a subset of CRC and correlates significantly with vascular invasion and lymph node metastasis. Our finding showed that knockdown of C9orf140 significantly reduced cell proliferation and invasion in vitro and dramatically increased overall survival and decreased lung metastasis in vivo. Conversely, overexpression of C9orf140 significantly increased lung metastasis and shortened overall survival when compared with control tumors. C9orf140-induced CRC cell invasion may depend on promoting the epithelial-mesenchymal transition progression. STAT5 may directly interact with the enhancer of zeste homolog 2 (EZH2) and ß-catenin to enhance C9orf140 gene transactivation. Furthermore, C9orf140 may participate in cell invasion which is induced by STAT5, EZH2 or ß-catenin activation. We describe the role of C9orf140 in CRC progression and find that C9orf140 overexpression may be regulated by STAT5, EZH2 and ß-catenin interaction.
Assuntos
Proteínas de Ciclo Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Fator de Transcrição STAT5/metabolismo , beta Catenina/metabolismo , Adulto , Idoso , Animais , Sequência de Bases , Sítios de Ligação , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Nucleares , Ligação Proteica , Transdução de SinaisRESUMO
The development of gastric cancer (GC) is a complex multistep process, including numerous genetic and epigenetic changes. CD24 is associated with enhanced invasiveness of GC and a poor prognosis. However, the mechanism by which CD24 induces GC progression remains poorly characterized. Here, we found that the expression of CD24 gradually increased in samples of normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis (CAG), CAG with intestinal metaplasia, dysplasia and GC. Moreover, the knockdown of CD24 induced significant levels of apoptosis in GC cells via the mitochondrial apoptotic pathway. CD24 may also promote cellular invasion and regulate the expression of E-cadherin, fibronectin and vitamin D receptor in GC cells. The activation of signal transducer and activator of transcription 3 (STAT3) may mediate CD24-induced GC survival and invasion in vitro. Furthermore, CD24-induced GC progression and STAT3 activation could also be detected in vivo and in clinical GC tissues samples. Taken together, our results indicate that CD24 mediates gastric carcinogenesis and may promote GC progression by suppressing apoptosis and promoting invasion, with the activation of STAT3 playing a critical role.
Assuntos
Antígeno CD24/metabolismo , Carcinogênese/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Animais , Apoptose , Antígeno CD24/genética , Carcinogênese/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Doença Crônica , Progressão da Doença , Feminino , Gastrite/metabolismo , Xenoenxertos , Humanos , Mucosa Intestinal/metabolismo , Masculino , Metaplasia , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Transplante de Neoplasias , Neoplasias Gástricas/patologiaRESUMO
The polycomb group protein enhancer of zeste homologue 2 (EZH2), which has histone methyltransferase (HMT) activity, is overexpressed in malignant tumours. However, the role of EZH2 in colorectal cancer (CRC) invasion is little known. Here we investigated the clinical significance, biological effects, and mechanisms of EZH2 signalling. Knockdown of EZH2 significantly reduced cell invasion and secretion of matrix metalloproteinases 2/9 (MMP2/9) in in vitro studies. Knockdown of EZH2 dramatically increased overall survival and decreased metastasis of lung in in vivo studies. Conversely, overexpression of EZH2 significantly increased lung metastasis and shortened overall survival when compared with control tumours. EZH2-induced CRC cell invasion may depend on down-regulation of vitamin D receptor (VDR), which is considered to be a marker of CRC invasion. EZH2 regulates the histone trimethylation of lysine 27 (H3K27me3) in the VDR promoter. Moreover, we found that STAT3 directly binds to the EZH2 promoter and regulates VDR down-regulation in CRC cells. Significant inverse correlations were observed between the expression of EZH2 and pSTAT3 and that of VDR in CRC tissues compared with normal tissue in patients. We show the role of EZH2 in CRC metastasis and identify VDR as a target gene of EZH2. EZH2 expression may be directly regulated by STAT3, and STAT3 may play an important role in EZH2-mediated VDR down-regulation in CRC. This pathway may provide potential targets in aggressive CRC.
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Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Complexo Repressor Polycomb 2/metabolismo , Receptores de Calcitriol/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste , Histona Metiltransferases , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Dados de Sequência Molecular , Invasividade Neoplásica , Complexo Repressor Polycomb 2/genética , Interferência de RNA , Receptores de Calcitriol/genética , Proteínas Recombinantes de Fusão , Fator de Transcrição STAT3/genética , Transdução de SinaisRESUMO
This study investigated fluorescence photobleaching and the recovery of fluorescein sodium (FS)-loaded carbomer films. To mitigate errors caused by the self-quenching effect, the experiments were conducted at FS concentrations of 0.1, 0.5, and 1 wt%. The results revealed a nonlinear relationship between fluorescence intensity and FS concentration (0.1-1 wt%). Moreover, the degree and rate of photobleaching increased with FS concentration. The recovery level and recovery rate exhibited contrasting relationships with FS concentration. Higher FS concentrations were associated with a longer recovery time, which can be attributed to the prolonged irradiation, resulting in a bleached region that was larger than the initially irradiated area.
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Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
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Fusobacterium nucleatum can bind to host cells and potentiate intestinal tumorigenesis. Here we used a genome-wide screen to identify an adhesin, RadD, which facilitates the attachment of F. nucleatum to colorectal cancer (CRC) cells in vitro. RadD directly binds to CD147, a receptor overexpressed on CRC cell surfaces, which initiated a PI3K-AKT-NF-κB-MMP9 cascade, subsequently enhancing tumorigenesis in mice. Clinical specimen analysis showed that elevated radD gene levels in CRC tissues correlated positively with activated oncogenic signalling and poor patient outcomes. Finally, blockade of the interaction between RadD and CD147 in mice effectively impaired F. nucleatum attachment and attenuated F. nucleatum-induced oncogenic response. Together, our study provides insights into an oncogenic mechanism driven by F. nucleatum RadD and suggests that the RadD-CD147 interaction could be a potential therapeutic target for CRC.
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Immune checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-ß pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.
Assuntos
Neoplasias Colorretais , Infecções por Fusobacterium , Animais , Camundongos , Fusobacterium nucleatum , Neoplasias Colorretais/tratamento farmacológico , Ácido Succínico , Infecções por Fusobacterium/microbiologia , Imunoterapia , Microambiente TumoralRESUMO
OBJECTIVE: To clarify the endoscopic, clinicopathological, and growth characteristics of minute gastric cancer (MGC) and to improve its detection rate. METHODS: Patients with early gastric cancer who underwent endoscopic submucosal dissection from July 2012 to September 2021 were retrospectively reviewed. MGC was defined as gastric cancer of 5 mm or less in size. Preoperative and postoperative endoscopic and pathological data were collected and analyzed. Follow-up information was collected until 9 April 2022. RESULTS: Eighty patients were enrolled, with 82 lesions observed under endoscopy and 87 diagnosed histopathologically. All patients received en bloc and curative resection. Compared with the time point when the last endoscopic examiniation prior to lesion deteciton was performed (t0), 64.29% of patients with MGC had disease progression at lesion detection (t1). However, 21.43% showed normal or only atrophic changes under white-light endoscopy, and their lesions were diagnosed accidentally by random biopsy. The majority of MGC lesions presented as type IIc and reddish, and 95.00% of cases had well-differentiated tubular adenocarcinoma. The mean growth rate of MGC was 0.0071 mm/day, and it took an average of 3.42 years to grow to 5 mm. There was no significant difference in the depth of invasion between the low cellular atypia group and the high cellular atypia group. CONCLUSIONS: Type IIc and reddish appearance are main endoscopic features of MGC. For cases with no obvious endoscopic changes, multipoint biopsy is helpful. MGC is mostly well differentiated and grows relatively slowly; therefore, MGC can still have a chance to be identified and resected curatively if it is missed diagnosed.
Assuntos
Adenocarcinoma , Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Humanos , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Endoscopia Gastrointestinal , Adenocarcinoma/patologia , Mucosa Gástrica/patologiaRESUMO
Interleukin (IL)-16 was one of the cytokines with the function of T helper cell recruitment, whose expression in the thyrocyte and orbital fibroblast of Graves' disease (GD) patients was increased. Recently association of IL-16 gene polymorphisms with autoimmune diseases had been reported. However, there was little known about the impact of IL-16 gene polymorphisms on GD. In this study, we performed a case-control association study of three tagSNPs (rs4778889-rs1131445-rs4778641) within the IL-16 gene on 258 patients with GD and 208 healthy subjects in the Chinese population. Our data showed that common IL-16 variants were associated with GD (P=0.013-0.0186) and Graves' disease associated ophthalmopathy (GO) (P=0.0033-0.041). A novel protective haplotype containing the three tagSNPs (C-T-C) was observed in association with GO (P=0.013). In conclusion, IL-16 gene was significantly associated with susceptibility to Graves' disease and Graves' disease associated ophthalmopathy in the Chinese population.
Assuntos
Predisposição Genética para Doença , Doença de Graves/genética , Interleucina-16/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Alelos , Criança , China , Feminino , Genótipo , Doença de Graves/imunologia , Humanos , Interleucina-16/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/metabolismo , Proteínas Musculares/metabolismo , Fosfoproteínas/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenoma/genética , Adenoma/patologia , Animais , Sequência de Bases , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Fosfoproteínas/metabolismo , Ligação Proteica , Transdução de Sinais , Fatores de Transcrição de Domínio TEA , Ativação Transcricional/genética , Proteínas de Sinalização YAPRESUMO
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 Colorretais/genética , Neoplasias Colorretais/patologia , MicroRNAs/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Metástase NeoplásicaRESUMO
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 Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Animais , Antígenos CD/biossíntese , Células CACO-2 , Caderinas/biossíntese , Linhagem Celular Tumoral , Movimento Celular/genética , Células HCT116 , Células HT29 , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Invasividade Neoplásica/genética , Transplante de Neoplasias , Complexo Repressor Polycomb 1/biossíntese , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Fatores de Transcrição/biossíntese , Transplante Heterólogo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/biossínteseRESUMO
Previous studies have found that G-protein-coupled receptor 116 (GPR116) is a regulator of breast cancer metastasis. However, the role of GPR116 in colorectal carcinoma (CRC) carcinogenesis and progression is unknown. In this study, We found GPR116 expression was significantly up-regulated in CRC specimens compared with corresponding non-cancerous tissues. Increased GPR116 expression in CRC was correlated with histological differentiation and distant metastasis. In addition, high expression of GPR116 was significantly associated with poor overall survival of CRC patients, which was also confirmed by GSE14333, GSE17536 and GSE33113 datasets from the Gene Expression Omnibus (GEO). Furthermore, we demonstrated that the ability of proliferation and invasion of CRC cell lines HCT116 and LOVO was markedly reduced after transfected with siRNA-GPR116. Meanwhile, GPR116 may drive EMT in CRC cells through AKT/EKR signaling pathway, resulting in metastasis. Thus, GPR116 may be a novel reliable prognostic indicator and a risk factor in CRC progression.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Regulação Neoplásica da Expressão Gênica , Receptores Acoplados a Proteínas G/genética , Idoso , Proliferação de Células , Neoplasias Colorretais/patologia , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , MAP Quinases Reguladas por Sinal Extracelular , Feminino , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
NADPH oxidase 4 (NOX4), a major source of reactive oxygen species (ROS) production, has been increasingly reported to be involved in tumorigenesis and/or tumor progression, but limited data are available regarding the role of NOX4 in colorectal carcinoma (CRC). We retrieved six independent investigations from Oncomine database and found that NOX4 is highly expressed in CRC tissues compared with corresponding normal controls. Similar results were also found in clinical specimens at both mRNA and protein levels. Immunohistochemical analysis indicated that NOX4 overexpression was highly correlated with T classification, N classification, distant metastasis, and poor prognosis of CRC patients, which was also confirmed by GSE14333 and GSE17536 datasets from the Gene Expression Omnibus. Furthermore, we demonstrated that when NOX4 expression was knocked down by siRNAs, cell proliferation, cell-cycle and apoptosis, migration and invasion were significantly altered in CRC cell lines HCT116 and LOVO. Meanwhile, NOX4 promoted cancer cell proliferation and apoptosis, migration and invasion by regulating the expression of relevant genes. By these approaches we aim to elucidate NOX4 may be a reliable prognostic factor or therapeutic target in CRC.
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Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Expressão Gênica , NADPH Oxidase 4/genética , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Neoplasias Colorretais/patologia , Biologia Computacional/métodos , Bases de Dados de Ácidos Nucleicos , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Curva ROCRESUMO
FAM83B (family with sequence similarity 83, member B) seems to emerge as a new class of players involved in the development of a variety of malignant tumors. Yet the molecular mechanisms are not well understood. The present study is intended to investigate the expression and function of FAM83B in pancreatic ductal adenocarcinoma (PDAC). In this study, we found that the expression of FAM83B was significantly increased both in PDAC cell lines and PDAC tumor tissues. FAM83B expression was positively related with advanced clinical stage and poor vital status. Higher FAM83B expression predicted shorter overall survival in PDAC patients, regardless of lymphatic metastasis status and histological differentiation. Actually, FAM83B may act as an independent prognostic indicator as well. What's more, down-regulation of FAM83B in PDAC cells contributed to G0/G1 phase arrest and inhibition of cell proliferation. Finally, a subcutaneous xenograft model indicated that knockdown of FAM83B significantly reduced the tumor volume in vivo. Our findings have provided supporting evidence for the potential molecular biomarker role of FAM83B in PDAC. It's of great interest and broad significance to target FAM83B in PDAC, which may conduce to develop a meaningful and effective strategy in the diagnosis and treatment of PDAC.
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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been implicated in cancer biogenesis and prognosis. By repurposing microarray probes, we herein analysed the lncRNA expression profiles in two public PDAC microarray datasets and identified 34 dysregulated lncRNAs in PDAC. In addition, the expression of 6 selected lncRNAs was confirmed in Ren Ji cohort and pancreatic cell lines, and their association with 80 PDAC patients' clinicopathological features and prognosis was investigated. Results indicated that AFAP1-AS1, UCA1 and ENSG00000218510 might be involved in PDAC progression and significantly associated with overall survival of PDAC. UCA1 and ENSG00000218510 expression status may serve as independent prognostic biomarkers for overall survival of PDAC. Gene set enrichment analysis (GSEA) analysis suggested that high AFAP1-AS1, UCA1 and low ENSG00000218510 expression were correlated with several tumorigenesis related pathways. Functional experiments demonstrated that AFAP1-AS1 and UCA1 were required for efficient invasion and/or proliferation promotion in PDAC cell lines, while ENSG00000218510 acted the opposite. Our findings provide novel information on lncRNAs expression profiles which might be beneficial to the precise diagnosis, subcategorization and ultimately, the individualized therapy of PDAC.
Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Adenocarcinoma/patologia , Idoso , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , RNA Longo não Codificante/metabolismo , Reprodutibilidade dos Testes , Neoplasias PancreáticasRESUMO
Members of the inositol phosphate metabolism pathway regulate cell proliferation, migration and phosphatidylinositol-3-kinase (PI3K)/Akt signaling, and are frequently dysregulated in cancer. Whether germline genetic variants in inositol phosphate metabolism pathway are associated with cancer risk remains to be clarified. We examined the association between inositol phosphate metabolism pathway genes and risk of eight types of cancer using data from genome-wide association studies. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-based associations were tested using the permutation-based adaptive rank-truncated product method. The overall inositol phosphate metabolism pathway was significantly associated with risk of lung cancer (P = 2.00 × 10(-4)), esophageal squamous cell carcinoma (P = 5.70 × 10(-3)), gastric cancer (P = 3.03 × 10(-2)) and renal cell carcinoma (P = 1.26 × 10(-2)), but not with pancreatic cancer (P = 1.40 × 10(-1)), breast cancer (P = 3.03 × 10(-1)), prostate cancer (P = 4.51 × 10(-1)), and bladder cancer (P = 6.30 × 10(-1)). Our results provide a link between inherited variation in the overall inositol phosphate metabolism pathway and several individual genes and cancer. Further studies will be needed to validate these positive findings, and to explore its mechanisms.