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1.
Gynecol Oncol ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32507651

RESUMO

OBJECTIVES: To determine the diagnostic performance and optimal protocol of frozen section examination (FSE) in SLNB for cervical cancer. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure were searched from inception to July 30, 2019, for studies concerning SLNB with FSE in cervical cancer. Sensitivity of FSE in detecting SLN metastasis was the primary diagnostic indicator for evaluation. RESULTS: The pooled sensitivity of FSE among 31 eligible studies (1887 patients) was 0.77 (95% CI 0.66-0.85) with high heterogeneity (I2 = 69.73%). Two representative sectioning protocols for FSE were identified from 26 studies, described as equatorial (E-protocol, SLN was bisected) and latitudinal (L-protocol, SLN was cut at intervals). Meta-regression showed that FSE protocol was the only source of heterogeneity (p < 0.001). The pooled sensitivity was 0.86 (95% CI 0.79-0.91, I2 = 0%) and 0.59 (0.46-0.72, I2 = 58.47%) for FSE using L- (13 studies, 650 patients) and E- (13 studies, 1047 patients) protocol, respectively. Among the available data, marcometastases (>2 mm) were missed in 4 and 20 patients; small-volume metastases (≤2 mm) were detected in 13 and 2 patients, respectively, under L- and E-protocol. The pooled sensitivity of FSE using L-protocol would reach 0.97 (95% CI 0.89-0.99) if only marcometastases were considered. These findings were robust to sensitivity analyses. CONCLUSION: The sectioning protocol determines the accuracy of FSE in SLNB. With L-protocol, FSE can provide precise intraoperative pathology for SLNB, which enables immediate decision-making for individualized managements.

3.
Cancer Causes Control ; 31(7): 683-689, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32394229

RESUMO

PURPOSE: To examine associations of KRAS mutation with tumor deposit status and overall survival in colorectal cancer (CRC) patients. METHODS: This retrospective cohort study included patients with incidental CRC diagnosed during 2010-2014 and recorded statuses of KRAS and tumor deposit in the National Cancer Database of the USA. Multivariable logistic regression and time-varying Cox regression analyses were used. RESULTS: We included 45,761 CRC patients with KRAS status (24,027 [52.5%] men, 24,240 [53.0%] < 65 years old, 17,338 [37.9%] with KRAS mutation). Adjusted for microsatellite instability, age, pathologic stage and tumor grade, KRAS mutation (versus wild type) was associated with tumor deposit presence (odds ratio = 1.11, 95% CI 1.02-1.20). KRAS mutation was also linked to worse overall survival of CRC patients regardless of tumor deposit status (adjusted Hazard ratio [HR] = 1.20, 95% CI 1.07-1.33 for CRC with tumor deposits, and adjusted HR = 1.24, 95% CI 1.14-1.35 or CRC without) or tumor stage (adjusted HR = 1.32, 95% CI 1.14-1.54 for early-stage and adjusted HR = 1.18, 95% CI 1.10-1.27 for late-stage). Microsatellite instability was associated with better overall survival in CRC without tumor deposit (adjusted HR = 0.89, 95% CI 0.79-0.99), but not in CRC with tumor deposit (adjusted HR = 1.12, 95% CI 0.97-1.30). CONCLUSION: KRAS mutation is independently associated with tumor deposit presence and a worse overall survival in CRC patients.

4.
Oncogene ; 39(23): 4538-4550, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32372060

RESUMO

Hepatocellular carcinoma (HCC) metastasis is largely responsible for HCC-associated recurrence and mortality. We aimed to identify metastasis-related long non-coding RNAs (lncRNAs) to understand the molecular mechanism of HCC metastasis. We first identified that miR-1258 was downregulated in HCC tissues both in The Cancer Genome Atlas (TCGA) and Sun Yat-sen University Cancer Center (SYSUCC) dataset. MiR-1258 expression negatively correlated with recurrence-free survival and overall survival of HCC patients. MiR-1258 overexpression inhibited migration and invasion of HCC cells both in vitro and in vivo, whereas miR-1258 downregulation promoted cell metastasis. Luciferase assays verified direct binding of miR-1258 to Smad2 and Smad3, thereby attenuating TGF-ß/Smad signaling. We further established that lncRNA LINC01278 was a negative regulator of miR-1258. In vivo and in vitro assays demonstrated that LINC01278-mediated HCC metastasis was dependent on miR-1258 expression. Furthermore, miR-1258 downregulation in turn increased LINC01278 expression. We also observed that TCF-4 could bind to the LINC01278 promoter site. In addition, LINC01278 downregulation decreased migration and invasion of HCC cells induced by ß-catenin and TGF-ß1 both in vitro and in vivo. We uncovered a novel mechanism for ß-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 feedback loop activation in HCC metastasis, and the study indicated that LINC01278 could serve as a therapeutic target for HCC metastasis.

5.
Mol Cancer ; 19(1): 60, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188489

RESUMO

BACKGROUND: Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet. METHODS: A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis. RESULTS: A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness. CONCLUSIONS: Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.

6.
Cancer Lett ; 476: 48-56, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32061952

RESUMO

Solid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which lead to a poor prognosis in patients with hepatocellular carcinoma (HCC). Through an in vitro liver T-IC enrichment approach, we identified nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a transcription regulator that is significantly activated in enriched liver T-IC populations. In human HCCs, NRF2 was found to be overexpressed, which was associated with poor patient survival. Through a lentiviral based knockdown approach, NRF2 was found to be critical for regulating liver T-IC properties, including self-renewal, tumorigenicity, drug resistance and expression of liver T-IC markers. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance in HCC cells. Mechanistically, NRF2 was found to physically bind to the promoter of sonic hedgehog homolog (SHH), which triggers activation of the sonic hedgehog pathway. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated T-IC function via upregulation of SHH expression. Our study suggests a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through the NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes.

7.
Cancer Res ; 80(10): 1957-1969, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060148

RESUMO

Nasopharyngeal carcinoma is an Epstein-Barr virus (EBV)-related malignancy. Recently, we found that the EBV-encoded miRNA BART2-5p was increased in the serum of patients with preclinical nasopharyngeal carcinoma and that the copy number positively correlated with disease progression. In this study, we established its role in nasopharyngeal carcinoma progression and explored underlying mechanisms and clinical significance. BART2-5p was an independent unfavorable prognostic factor for progression-free survival and its circulating abundance positively associated with distant metastasis. Ectopic expression of BART2-5p promoted migration and invasion of EBV-negative nasopharyngeal carcinoma cells, whereas genetic downregulation of BART2-5p in EBV-positive nasopharyngeal carcinoma cells decreased aggressiveness. Mechanistically, BART2-5p targeted RND3, a negative regulator of Rho signaling. Downregulation of RND3 phenocopied the effect of BART2-5p and reconstitution of RND3 rescued the phenotype. By suppressing RND3, BART2-5p activated Rho signaling to enhance cell motility. These findings suggest a novel role for EBV miRNA BART2-5p in promoting nasopharyngeal carcinoma metastasis and its potential value as a prognostic indicator or therapeutic target. SIGNIFICANCE: This study shows that EBV-encoded BART2-5p miRNA suppresses expression of the RND3 Rho family GTPase, consequently promoting ROCK signaling, cell motility, and metastatic behavior of NPC cells.

8.
Mol Oncol ; 14(2): 373-386, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31670863

RESUMO

Hepatocellular carcinoma (HCC), with its ineffective therapeutic options and poor prognosis, represents a global threat. In the present study, we show that RAD52 motif 1 (RDM1), a key regulator of DNA double-strand break repair and recombination, is downregulated in HCC tissues and suppresses tumor growth. In clinical HCC samples, low expression of RDM1 correlates with larger tumor size, poor tumor differentiation, and unfavorable survival. In vitro and in vivo data demonstrate that knockdown of RDM1 increases HCC cell proliferation, colony formation, and cell population at G2/M phase, whereas RDM1 overexpression results in the opposite phenotypes. Mechanistically, RDM1 binds to the tumor suppressor p53 and enhances its protein stability. In the presence of p53, RDM1 suppresses the phosphorylation of Raf and ERK. Overexpression of p53 or treatment with ERK inhibitor significantly abolishes cell proliferation induced by the depletion of RDM1. In addition, overexpression of methyltransferase-like 3 markedly induces N6-methyladenosine modification of RDM1 mRNA and represses its expression. Taken together, our study indicates that RDM1 functions as a tumor suppressor and may be a potential prognostic and therapeutic factor for HCC.

10.
Int J Cancer ; 146(1): 272-280, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162842

RESUMO

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.


Assuntos
DNA Viral/sangue , Herpesvirus Humano 4/isolamento & purificação , Neoplasias Gástricas/virologia , Carga Viral , Idoso , Feminino , Herpesvirus Humano 4/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
12.
Cancer Manag Res ; 11: 9715-9723, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31814766

RESUMO

Purpose: The aim of the study is to construct an intraoperative nomogram for the prediction of non-sentinel lymph node (NSLN) metastasis based on the one-step nucleic acid amplification assay in breast cancer patients. Methods: A total of 552 patients were enrolled in the training study and 1090 patients were enrolled in the validation study. The nomogram was constructed based on the molecular assay with logistic multivariate regression analysis in the training study and was validated in the validation study. Results: A novel nomogram model was constructed with the total tumor load, the clinical primary tumor size, the number of positive and negative sentinel lymph nodes. The area under the receiver operating characteristic curve (AUC) of the model was 0.842. The AUC of the model which was sensitive to discern the patients with the stage of pN1 and ≥pN2 was 0.861. Conclusion: The nomogram model will help to guide the axillary management intraoperatively and precisely confirm the target region of radiotherapy postoperatively.

13.
J Immunother Cancer ; 7(1): 298, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722750

RESUMO

BACKGROUND: Immunotherapy, especially immune checkpoint inhibition, has provided powerful tools against cancer. We aimed to detect the expression of common immune checkpoints and evaluate their prognostic values in nasopharyngeal carcinoma (NPC). METHODS: The expression of 9 immune checkpoints consistent with 13 features was detected in the training cohort (n = 208) by immunohistochemistry and quantified by computational pathology. Then, the LASSO cox regression model was used to construct an immune checkpoint-based signature (ICS), which was validated in a validation cohort containing 125 patients. RESULTS: High positive expression of PD-L1 and B7-H4 was observed in tumour cells (TCs), whereas PD-L1, B7-H3, B7-H4, IDO-1, VISTA, ICOS and OX40 were highly expressed in tumour-associated immune cells (TAICs). Eight of the 13 immune features were associated with patient overall survival, and an ICS classifier consisting of 5 features (B7-H3TAIC, IDO-1TAIC, VISTATAIC, ICOSTAIC, and LAG3TAIC) was established. Patients with high-risk scores in the training cohort had shorter overall (P < 0.001), disease-free (P = 0.002), and distant metastasis-free survival (P = 0.004), which were confirmed in the validation cohort. Multivariate analysis revealed that the ICS classifier was an independent prognostic factor. A combination of the ICS classifier and TNM stage had better prognostic value than the TNM stage alone. In addition, the ICS classifier was significantly associated with survivals in patients with high EBV-DNA load. CONCLUSIONS: We determined the expression status of nine immune checkpoints consistent with 13 features in NPC and further constructed an ICS prognostic model, which might add prognostic value to the TNM staging system.

14.
Nat Commun ; 10(1): 4695, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619685

RESUMO

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.


Assuntos
Adenosina/análogos & derivados , Carcinoma/secundário , Neoplasias Colorretais/patologia , Proteína HMGA2/genética , Neoplasias Hepáticas/secundário , Metiltransferases/genética , RNA Circular/genética , Adenosina/metabolismo , Animais , Carcinoma/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Células HCT116 , Células HEK293 , Humanos , Neoplasias Hepáticas/genética , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo
15.
Cancer Res ; 79(23): 5930-5943, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484669

RESUMO

The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (TRAF3, CYLD, and NFKBIA) were significantly mutated in both pNPC and rNPC. Notably, mutations in TRAF3, CYLD, and NFKBIA were all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity in vitro and in vivo. In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival. SIGNIFICANCE: This study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications.See related commentary by Sehgal and Barbie, p. 5915.


Assuntos
Carcinoma , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Mutação , NF-kappa B/genética , Recidiva Local de Neoplasia
16.
Theranostics ; 9(7): 1965-1979, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037150

RESUMO

Rationale: The incidence of hepatocellular carcinoma is rising worldwide. It is predicted that nearly half of the early-stage hepatocellular carcinoma (E-HCC) patients will develop recurrence. Dysregulated pH, a hallmark of E-HCC, is correlated with poor prognosis. The acidic microenvironment has been shown to promote the release of exosomes, the membrane vesicles recognized as intercellular communicators associated with tumor progression, recurrence, and metastasis. We, therefore, aimed to identify exosomes induced by acidic microenvironment that may regulate E-HCC progression and to explore their mechanisms and clinical significance in E-HCCs. Methods: miRNA microarray analysis and LASSO logistic statistic model were used to identify the main functional exosomal miRNAs. Invasion and scratch assays were performed to examine the migration and invasion of HCC cells. Immunoblotting and immunofluorescence were employed to detect the epithelial-to-mesenchymal transition (EMT) in HCC cells. Chromatin immunoprecipitation (ChIP) was used to analyze the binding of HIF-1α and HIF-2α to promoter regions of miR-21 and miR-10b. Results: The acidic microenvironment in HCC was correlated with poor prognosis of patients. Exosomes from HCC cells cultured in the acidic medium could promote cell proliferation, migration, and invasion of recipient HCC cells. We identified miR-21 and miR-10b as the most important functional miRNAs in acidic HCC-derived exosomes. Also, the acidic microenvironment triggered the activation of HIF-1α and HIF-2α and stimulated exosomal miR-21 and miR-10b expression substantially promoting HCC cell proliferation, migration, and invasion both in vivo and in vitro. In E-HCC patients, serum exosomal miR-21 and miR-10b levels were associated with advanced tumor stage and HIF-1α and HIF-2α expression and were independent prognostic factors for disease-free survival of E-HCC patients. Most importantly, we developed a nano-drug to target exosomal miR-21 and/or miR-10b and examined its therapeutic effects against HCC in vivo. Conclusion: Our findings suggested that the exosomal miR-21 and miR-10b induced by acidic microenvironment in HCC promote cancer cell proliferation and metastasis and may serve as prognostic molecular markers and therapeutic targets for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Proliferação de Células/genética , Exossomos/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Metástase Neoplásica/genética , Microambiente Tumoral/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Transdução de Sinais/genética , Ativação Transcricional/genética , Regulação para Cima/genética
17.
Hepatology ; 69(1): 179-195, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30028541

RESUMO

Deregulation of alternative splicing contributes to the malignant progression of cancer. Little is known about the significant alternative splicing events in hepatocellular carcinoma (HCC). High-throughput sequencing revealed that coiled-coil domain containing 50 (CCDC50) pre-mRNA is aberrantly spliced in 50% of our HCC cases. A BaseScope assay was performed to examine the expression of CCDC50S (a truncated oncogenic splice variant) in HCC tissues. Compared with benign liver tumors and several other types of solid tumors, CCDC50S mRNA was up-regulated in HCC, with a diagnostic potential (sensitivity, 0.711; specificity, 0.793). High expression of CCDC50S mRNA in HCC was significantly correlated with poor tumor differentiation, advanced tumor node metastasis (TNM) stage, and unfavorable prognosis. Overexpression of CCDC50S exerted tumorigenic activities that promoted HCC growth and metastasis by activation of Ras/forkhead box protein O4 (Foxo4) signaling. Either suppression of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation or overexpression of Foxo4 markedly attenuated CCDC50S-mediated phenotypes. Furthermore, serine- and arginine-rich splicing factor 3 (SRSF3) directly bound to CCDC50S mRNA to maintain its stability in the cytoplasm. The cytosolic retention of SRSF3 was mediated by the interaction of hepatitis B virus-encoded X protein (HBx) and 14-3-3ß. Ectopic HBx expression induced expression of cytosolic SRSF3 and CCDC50S. Conclusion: Our study provided compelling evidence that up-regulation of CCDC50S was modulated by HBx/SRSF3/14-3-3ß complex and enhanced oncogenic progression of HCC through the Ras/Foxo4 signaling pathway. These data suggest that CCDC50S may serve as a diagnostic and prognostic biomarker and probably a promising therapeutic target in HCC.


Assuntos
Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/etiologia , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Fatores de Processamento de Serina-Arginina/fisiologia , Transdução de Sinais/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C
18.
Cancer Res ; 79(3): 534-545, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30584071

RESUMO

Hepatocellular carcinogenesis is attributed to the reprogramming of cellular metabolism as a consequence of the alteration in metabolite-related gene regulation. Identifying the mechanism of aberrant metabolism is of great potential to provide novel targets for the treatment of hepatocellular carcinoma (HCC). Here, we demonstrated that glycogen synthase 2 (GYS2) restricted tumor growth in hepatitis B virus-related HCC via a negative feedback loop with p53. Expression of GYS2 was significantly downregulated in HCC and correlated with decreased glycogen content and unfavorable patient outcomes. GYS2 overexpression suppressed, whereas GYS2 knockdown facilitated cell proliferation in vitro and tumor growth in vivo via modulating p53 expression. GYS2 competitively bound to MDM2 to prevent p53 from MDM2-mediated ubiquitination and degradation. Furthermore, GYS2 enhanced the p300-induced acetylation of p53 at K373/382, which in turn inhibited the transcription of GYS2 in the support of HBx/HDAC1 complex. In summary, our findings suggest that GYS2 serves as a prognostic factor and functions as a tumor suppressor in HCC. The newly identified HBx/GYS2/p53 axis is responsible for the deregulation of glycogen metabolism and represents a promising therapeutic target for the clinical management of HCC. SIGNIFICANCE: We elucidated the clinical significance, biological function, and regulation of the HBx/GYS2/p53 axis, which supplement the understanding of tumor glycogen metabolism and provide potential prognostic and therapeutic targets for HCC treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/3/534/F1.large.jpg.


Assuntos
Carcinoma Hepatocelular/metabolismo , Glicogênio Sintase/metabolismo , Hepatite B Crônica/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Retroalimentação Fisiológica , Células Hep G2 , Vírus da Hepatite B , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Análise Serial de Tecidos
19.
Cancer Manag Res ; 10: 6275-6284, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538573

RESUMO

Objective: Hepatocellular carcinoma (HCC) is a rapidly proliferating malignancy that requires large amounts of fatty acids to synthesize cellular membranes and provide energy. Epidermal fatty acid-binding protein (EFABP) is uniquely expressed in epidermal cells, but its role and expression in HCC are not clear. Subjects and methods: A total of 804 HCC specimens were collected to construct a tissue microarray (TMA) and for immunohistochemistry (IHC) analysis. The relationship between EFABP expression and clinical features of patients with HCC was analyzed. Results: The EFABP IHC score for HCC tissue was 0.76±0.69, being significantly higher than that for matched nontumorous tissue (0.48±0.55; P<0.001). Using the median IHC score (ie, 0.8) in the tumorous tissue, a high level of EFABP expression was found in 57.3% (461/804) of the cases. Patients with HCC displaying high EFABP expression had poorer tumor differentiation (P=0.029), more vascular invasion (P=0.006), and a higher proportion of late TNM stage disease (P=0.042). Kaplan-Meier analysis revealed that the patients with high EFABP expression had significantly worse outcomes in terms of overall survival (P=0.003), worse disease-free survival (P=0.021), and a higher probability of recurrence (P=0.014). Multivariate analysis indicated that EFABP expression was an independent prognostic variable for overall survival (P=0.021) and disease-free survival (P=0.044). For HCC recurrence, only vascular invasion (P=0.020) and EFABP expression (P=0.026) were independent risk factors. Conclusion: Our data revealed that EFABP expression was increased in HCC samples. High EFABP expression was correlated with shorter survival times in patients with HCC and served as an independent factor for worse outcomes. Our study therefore provides a promising bio-marker for the prognostic prediction of HCC and a potential therapeutic target for the disease.

20.
Cancer Manag Res ; 10: 3707-3715, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30288102

RESUMO

Objective: Hepatocellular carcinoma (HCC) recurrence is a clinical challenge. An accurate prediction system for patients with HCC is needed, since the choice of HCC treatment strategies is very important. Patients and methods: A total of 804 patients with HCC who underwent curative resection at Sun Yat-sen University Cancer Center were included in this study. Demographics, clinicopathological data, and follow-up information were collected. Results: A logistic regression analysis was conducted to investigate the relationships between clinical features and HCC recurrence. Tumor size (OR=1.454, 95% CI: 1.047-2.020, P=0.026) and TNM stage (OR=1.360, 95% CI: 1.021-1.813, P=0.036) were independent predictors of HCC recurrence after curative resection. Therefore, the following equation was established to predict HCC recurrence: 0.308×TNM+0.374×tumor size-0.639. The equation score was 0.53±0.23 in patients who experienced HCC recurrence compared with 0.47±0.24 in other patients. A similar trend was observed in patients who survived after the last follow-up, compared with those who did not, with scores of 0.37±0.26 vs 0.52±0.22, respectively (P<0.001). The Kaplan-Meier analysis showed that patients with HCC with equation values >0.5 had significantly worse outcomes than those with equation values ≤0.5 (P<0.001) for overall survival (OS) and recurrence (P=0.043). Multivariate Cox analyses showed that tumor multiplicity (P=0.039), involucrum (P=0.029), vascular invasion (P<0.001), and equation value (P<0.001) were independent prognostic variables for OS, whereas tumor multiplicity (P=0.01), tumor differentiation (P=0.007), vascular invasion (P<0.001), involucrum (P=0.01), and equation value (P<0.001) were independent prognostic variables for HCC recurrence. Conclusion: We established a novel and effective equation for predicting the probability of recurrence and OS after curative resection. Patients with a high recurrence score, based on this equation, should undergo additional high-end imaging examinations.

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