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1.
Gut ; 68(12): 2195-2205, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31358576

RESUMEN

OBJECTIVE: The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC. DESIGN: Applying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection. RESULTS: The 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history). CONCLUSION: We have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.


Asunto(s)
5-Metilcitosina/análogos & derivados , Carcinoma Hepatocelular/genética , Ácidos Nucleicos Libres de Células/sangre , ADN de Neoplasias/análisis , Detección Precoz del Cáncer/métodos , Estudio de Asociación del Genoma Completo/métodos , Neoplasias Hepáticas/genética , 5-Metilcitosina/sangre , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/diagnóstico , Femenino , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC
2.
J Cell Mol Med ; 23(5): 3369-3374, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30784182

RESUMEN

Hepatocellular carcinoma (HCC) is closely associated with abnormal DNA methylation. In this study, we analyzed 450K methylation chip data from 377 HCC samples and 50 adjacent normal samples in the TCGA database. We screened 47,099 differentially methylated sites using Cox regression as well as SVM-RFE and FW-SVM algorithms, and constructed a model using three risk categories to predict the overall survival based on 134 methylation sites. The model showed a 10-fold cross-validation score of 0.95 and satisfactory predictive power, and correctly classified 26 of 33 samples in testing set obtained by stratified sampling from high, intermediate and low risk groups.


Asunto(s)
Carcinoma Hepatocelular/genética , Metilación de ADN/genética , Neoplasias Hepáticas/genética , Aprendizaje Automático , Carcinoma Hepatocelular/cirugía , Humanos , Neoplasias Hepáticas/cirugía , Modelos Biológicos , Reproducibilidad de los Resultados , Análisis de Supervivencia
3.
Cancer Sci ; 110(7): 2133-2144, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31066149

RESUMEN

Lymphoid-specific helicase (LSH) is overexpressed in tumor tissues and its overexpression is associated with poor prognosis in several cancers. However, the role and molecular mechanism of LSH in hepatocellular carcinoma (HCC) remains largely unknown. Herein, we report that LSH was overexpressed in tumor tissues of HCC, and overexpression of LSH was associated with poor prognosis from a public HCC database, and validated by clinical samples from our department. Ectopic LSH expression promoted the growth of HCC cells in vivo and in vitro. Mechanistically, LSH overexpression promoted tumor growth by activating transcription of centromere protein F (CENPF). Clinically, overexpression of LSH and/or CENPF correlated with shorter overall survival and higher cumulative recurrence rates of HCC. In conclusion, LSH promotes tumor growth of HCC through transcriptional regulation of CENPF expression. Therefore, LSH may be a novel predictor for prognosis and a potential therapeutic target for HCC.


Asunto(s)
Carcinoma Hepatocelular/patología , Proteínas Cromosómicas no Histona/genética , ADN Helicasas/metabolismo , Neoplasias Hepáticas/patología , Proteínas de Microfilamentos/genética , Regulación hacia Arriba , Anciano , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Invasividad Neoplásica , Trasplante de Neoplasias , Pronóstico , Análisis de Secuencia de ARN , Análisis de Supervivencia , Análisis de Matrices Tisulares , Activación Transcripcional
4.
Cancer Lett ; 564: 216186, 2023 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-37105392

RESUMEN

Evading immune destruction is an emerging hallmark of cancer and a potential key step in tumorigenesis. Immune checkpoint blocker (ICB)-based combination therapies revolutionize the landscape of systemic therapy for HCC. However, the molecular underpinnings governing immune evasion and responses remain unclear. Our study aims to find new regulatory molecules that drive HCC immune escape and tumorigenesis and find new promising immunotherapeutic approaches for HCC. In our study, laser capture microdissection (LCM) and miRNA sequencing combined with in vitro and in vivo experiments identified miR-93-5p as a crucial initiating oncogene during liver progenitor cell (LPC) malignant transformation and immune escape. Mechanistically, miR-93-5p could directly target canonical tumour suppressors such as APC to promote LPC malignant transformation and hepatocarcinogenesis. More importantly, miR-93-5p could induce deviant GAL-9 augmentation to inactivate infiltrated CD8(+) T cells and induce immune evasion by targeting several epigenetic regulators, such as AEBP2, and then regulating H3K4me3/H3K27me3 bivalency. Experiments in C57BL/6 mice demonstrated that blockade of Gal-9 abrogated miR-93-5p-induced HCC progression and improved their prognosis. Clinically, we identified a unique subtype of HCC closely associated with high GAL-9 expression and anti-PD1 treatment resistance. Our study highlights the pivotal role of the miR-93-5p/Gal-9 axis in driving HCC immune escape and tumorigenesis. Blocking GAL-9 is an effective and promising immunotherapeutic approach for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Animales , Ratones , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , Linfocitos T CD8-positivos/metabolismo , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Inmunoterapia , Carcinogénesis/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral
5.
Clin Transl Med ; 11(3): e313, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33783990

RESUMEN

Lysine acetylation (Kac) as an important posttranslational modification of histones is essential for the regulation of gene expression in hepatocellular carcinoma (HCC). However, the atlas of whole acetylated proteins in HCC tissues and the difference in protein acetylation between normal human tissues and HCC tissues are unknown. In this report, we characterized the proteome and acetyl proteome (acetylome) profile of normal, paracancerous, and HCC liver tissues in human clinical samples by quantitative proteomics techniques. We identified 6781 acetylation sites of 2582 proteins and quantified 2492 acetylation sites of 1190 proteins in normal, paracancerous, and HCC liver tissues. Among them, 15 proteins were multiacetylated with more than 10 lysine residues. The histone acetyltransferases p300 and CBP were found to be hyperacetylated in hepatitis B virus pathway. Moreover, we found that 250 Kac sites of 214 proteins were upregulated and 662 Kac sites of 451 proteins were downregulated in HCC compared with normal liver tissues. Additionally, the acetylation levels of lysine 120 in histone H2B (H2BK120ac), lysine 18 in histone H3.3 (H3.3K18ac), and lysine 77 in histone H4 (H4K77ac) were increased in HCC. Interestingly, the higher levels of H2BK120ac, H3.3K18ac, and H4K77ac were significantly associated with worse prognosis, such as poorer survival and higher recurrence in an independent clinical cohort of HCC patients. Overall, this study lays a foundation for understanding the functions of acetylation in HCC and provides potential prognostic factors for the diagnosis and therapy of HCC.


Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Hepatitis B/complicaciones , Histonas/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/metabolismo , Proteómica/métodos , Acetilación , Humanos , Hígado/metabolismo , Pronóstico , Proteoma/metabolismo , Tasa de Supervivencia
6.
Am J Cancer Res ; 9(5): 1079-1090, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31218114

RESUMEN

eIF3a is the largest subunit of eIF3 complex and is a key player in translational control. Recently eIF3a is recognized as a proto-oncogene, which is overexpressed and connected to tumorigenesis of many cancers. However, the mechanistic roles of eIF3a during the tumorigenesis remain largely elusive. Here, we report that depletion of eIF3a significantly reduced HIF1α protein level and cellular glycolysis ability. Mechanistically, we found that eIF3a regulates HIF1α protein synthesis through internal ribosomal entry site (IRES)-dependent translation. Importantly, through analyses of our own sample collection, we found that eIF3a is overexpressed in hepatocellular carcinoma (HCC) tissues, and a high level of eIF3a predicts poor prognosis of HCC patients. TCGA analyses further confirmed that eIF3a is coincident with an elevated activity of HIF1α pathway genes. Collectively, we identify eIF3a as a regulator for glycolysis through HIF1α IRES-dependent translational regulation, which may be a potential therapeutic target for HCC.

7.
J Cancer ; 10(25): 6199-6206, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31772652

RESUMEN

Background: Our previous studies showed that tetraspanin CD151 was implicated in the progression of hepatocellular carcinoma (HCC), mainly depending on the formation of functional complexes with molecular partners, including Mortalin. In this study, we investigate the role of mortalin in CD151-depedent progression of HCCs. Methods: Immunofluorescent staining, western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to investigate the expression and location of CD151 and Mortalin in four HCC cell lines with different metastatic ability. The relationship between Mortalin and CD151 was investigated in HCCLM3 cells using co-immunoprecipitation. CD151 or Mortalin expression in HCC cells were modified by transfection technology. Wound-healing assay and Transwell assay were used to assay the role of CD151 and Mortalin in cell migration and invasion. The expression and prognostic implication of CD151 and Mortalin in 187 cases of HCCs were analyzed. Results: Expression of Mortalin in HCC cells was positive related to their metastatic ability and its tendency was in line with the expression of CD151. Immunofluorescent staining showed that Mortalin was located in cytoplasm, while positive staining for CD151 was observed in cytoplasm and membrane of HCC cells. co-IP revealed that Mortalin formed a complex with CD151. Down-regulation of Mortalin induced a moderate decreased CD151 protein, but not CD151 mRNA, while inhibition of CD151 did not influence the expression of Mortalin at the level of both protein and mRNA. Interference of Mortalin significantly inhibited the invasion and migration of HCC cells with high CD151 expression and partially restored the invasion and migration of HCC cells induced by CD151 over-expression. Clinically, high Mortalin expression correlated with malignant phenotype of HCC, such as microvascular invasion (p=0.017) and tumor diameter (p=0.001). HCC patients expressing high Mortalin were tend to have higher expression of CD151. HCC patients expressing high level of CD151 showed the poorer prognosis in a Mortalin-dependent manner. Conclusions: Mortalin maybe stabilize of the structure of CD151-dependent tetraspanin-enriched microdomains and implicate in the progression of HCC.

8.
Theranostics ; 9(16): 4678-4687, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31367249

RESUMEN

Rationale: PD1/PD-L1 immune checkpoint inhibitors have shown promising results for several malignancies. However, PD1/PD-L1 signaling and its therapeutic significance remains largely unknown in intrahepatic cholangiocarcinoma (ICC) cases with complex etiology. Methods: We investigated the expression and clinical significance of CD3 and PD1/PD-L1 in 320 ICC patients with different risk factors. In addition, we retrospectively analyzed 7 advanced ICC patients who were treated with PD1 inhibitor. Results: The cohort comprised 233 patients with HBV infection, 18 patients with hepatolithiasis, and 76 patients with undetermined risk factors. PD-L1 was mainly expressed in tumor cells, while CD3 and PD1 were expressed in infiltrating lymphocytes of tumor tissues. PD1/PD-L1 signals were activated in tumor tissues, and expression was positively correlated with HBV infection and lymph node invasion. More PD1+ T cells and higher PD-L1 expression were observed in tumor tissues of ICC patients with HBV infection compared to patients with hepatolithiasis or undetermined risk factors. More PD1+ T cells and/or high PD-L1 expression negatively impacted the prognosis of patients with HBV infection but not those with hepatolithiasis. Multivariate analysis showed PD1/PD-L1 expression was an independent indicator of ICC patient prognosis. Advanced ICC patients with HBV infection and less PD1+ T cells tended to have good response to anti-PD1 therapy. Conclusion: Hyperactivated PD1/PD-L1 signals in tumor tissues are a negative prognostic marker for ICCs after resection. HBV infection- and hepatolithiasis-related ICCs have distinct PD1/PD-L1 profiles. Further, PD1+ T cells could be used as a biomarker to predict prognosis and assay the efficiency of anti-PD1 immunotherapy in ICC patients with HBV infection.


Asunto(s)
Colangiocarcinoma/genética , Neoplasias Hepáticas/genética , Receptor de Muerte Celular Programada 1/genética , Adulto , Anciano , Colangiocarcinoma/metabolismo , Colangiocarcinoma/virología , Femenino , Virus de la Hepatitis B/fisiología , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Estudios Retrospectivos , Factores de Riesgo
9.
Am J Cancer Res ; 8(6): 1040-1049, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30034941

RESUMEN

Decreased selenium-binding protein 1 (SBP1) is associated with increased invasion and poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains unknown. To unravel this mechanism, HCC cells expressing SBP1 were constructed and the impact on migration, invasion, and epithelial-mesenchymal transition (EMT) was evaluated. SBP1 expression reduced HCC cell migration and invasion by inhibiting EMT. Gene expression profiles of control and SBP1 expressing HCC cells revealed 186 differentially expressed genes, of which fibroblast growth factor 5, vascular endothelial growth factor receptor 1, and C-X-C motif chemokine receptor 4 (CXCR4) showed the greatest differences. CXCR4 expression was inhibited by SBP1 and restored the migration and invasion ability of HCC cells through activation of AKT signaling. Tumor samples from 200 HCC patients supported our in vitro findings and revealed an inverse correlation between SBP1 and CXCR4 expression. Patients with low SBP1 and high CXCR4 expression had the poorest prognosis and survival rate. Our results suggest that downregulation of SBP1 induces increased CXCR4 expression and results in EMT of HCC cells. Together, SBP1 and CXCR4 are promising potential biomarkers and therapeutic targets for HCC patients.

10.
J Clin Pathol ; 70(8): 677-683, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28096273

RESUMEN

AIMS: The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) remains poor in terms of overall survival (OS) and recurrence rate. Mortalin, a stress chaperone, has been reported to be involved in carcinogenesis and metastasis. However, its role in ICC has not been defined. METHODS: Mortalin expression in tumour samples from patients with ICC was examined by Western blot and immunohistochemistry, and correlation between its expression and clinicopathological features was assessed. In addition, invasion, migration proliferation and apoptosis, and the expression of epithelial-mesenchymal transition (EMT)-related markers in ICC cells were assessed after mortalin depletion. Finally, the prognostic significance of mortalin in patients with ICC was further evaluated by Kaplan-Meier and Cox regression analysis. RESULTS: We provide evidence that expression of mortalin in human ICC tissues is higher than that in matched peritumoural tissues. The interference of mortalin expression inhibited the proliferation and invasion of ICC cells in vitro. Mechanistically, inhibition of mortalin expression in ICC cells upregulated E-cadherin expression and decreased vimentin and snail expression. Clinically, a high level of mortalin in ICC samples was associated with loss of E-cadherin, and increased expression of vimentin and snail. Patients with ICC and high mortalin expression had a shorter OS and a higher recurrence rate. Multivariate analysis revealed that mortalin overexpression was an independent prognostic indicator for patients with ICC. CONCLUSIONS: Mortalin may promote cell proliferation and invasion via induction of EMT of ICC cells. A high level of mortalin may be used as a prognostic biomarker and therapeutic target for patients with ICC.


Asunto(s)
Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Transición Epitelial-Mesenquimal/fisiología , Proteínas HSP70 de Choque Térmico/fisiología , Apoptosis/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , Transformación Celular Neoplásica/patología , Regulación hacia Abajo/fisiología , Técnicas de Silenciamiento del Gen , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Recurrencia Local de Neoplasia/patología , Pronóstico , ARN Interferente Pequeño/farmacología , Regulación hacia Arriba/fisiología
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