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Background: Reports on Lenvatinib-based therapies show promising treatment outcomes for patients with unresectable hepatocellular carcinoma (uHCC). However, the effect and safety of Lenvatinib-based therapies still need to be further studies. Methods: This was a retrospective, single-center study on the safety and treatment efficacy of Lenvatinib-based combination therapies for uHCC Patients. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR). Results: Of 91 patients, there were 16 females and 75 males with uHCC who received systemic therapies based on Lenvatinib in our center. Forty-six patients (50.5%) received Lenvatinib combined with PD-1 antibody treatment. All these patients also received local therapy with the exception of 2 patients. The remaining 36 patinets received Lenvatinib combined with transcatheter arterial chemoembolization (TACE), 1 patient treated Lenvatinib combined with radiotherapy, 8 patients received Lenvatinib alone. At a median treatment time of 8 months, the objective response rate (ORR) of the entire cohort was 58.2% (53 patients), including 7 patients with CR and 46 patients with PR. 21 patients (23.1%) had SD. The disease control rate (DCR) of all patients was 81.3% (74 patients). However, 17 patients (18.7%) developed PD. The 1- and 2-year cumulative OS rates for the entire cohort were 66.8% and 39.3%, while the corresponding PFS rates were 38.0% and 17.1%, respectively. Univariate and multivariate Cox regression analysis revealed multiple tumor sites to be an independent OS risk factor for uHCC patients (HR=2.204, 95% CI=1.104-4.399, P=0.025). The most frequently reported adverse events in all patients were AST elevation (51.6%), followed by hypertension (33.0%), ALT elevation (26.4%), and decreased appetite (25.3%). After a combination treatment of Lenvatinib-based therapies, 15 patients met the criteria for salvage liver resection and underwent down-staging hepatectomy with a curative intent. The combination of PD-1 treatment was not very effective in improving the prognosis of uHCC patients treated with Lenvatinib combined with TACE. Conclusion: Our study demonstrated that a proportive of patients benefited from Lenvatinib-based combination therapies with manageable safety profiles, allowing these patients to undergo downstaging surgery with curative intent.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Femenino , Masculino , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Estudios Retrospectivos , Receptor de Muerte Celular Programada 1 , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Background: The differences in short- and long-term outcome between laparoscopic liver resection (LLR) and open liver resection (OLR) for BCLC stage A large hepatocellular carcinoma (HCC) in difficult segments (I, IVa, VII, VIII) remain unclear. This PSM two-centre study aimed to compare perioperative and long-term survival outcomes of LLR with OLR for this HCC. Methods: HCC patients with BCLC stage A who underwent OLR or LLR in two medical centres were enrolled in the study. PSM analysis was performed to match patients between the LLR cohort and OLR cohort. Survival was analysed based on the Kaplan-Meier method. Independent risk factors were identified by Cox regression. Results: After PSM, 35 patients remained in the LLR cohort, and 84 remained in the OLR cohort. Patients in the LLR cohort had more intraoperative blood loss (p=0.036) and shorter hospital stays after surgery (p<0.001). The LLR cohort and OLR cohort had no difference in intraoperative blood transfusion, surgical margin or postoperative short-term outcomes. The OS and RFS were not significantly different between the two cohorts. The OS and RFS of these two cohorts were not different in the subgroup analysis. Surgical margin was identified as an independent risk factor for tumour recurrence. Conclusion: For BCLC stage A large HCC patients with lesions in difficult segments, LLR was feasible and had shorter hospital stay than OLR. In addition, a surgical margin ≥1 cm could significantly decrease the recurrence probability for large HCC located in different segments without compromising short-term outcomes.
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BACKGROUND: At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs. METHODS: In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation. RESULTS: We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor. CONCLUSIONS: In summary, we found a key molecule-TSP1-that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Gemcitabina , Desoxicitidina , Colangiocarcinoma/patología , Cisplatino , Biomarcadores , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/patología , Trombospondinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Tripartite motif containing 59 (TRIM59) is a crucial gene that is involved in the process of various types of cancerï¼including breast cancer, lung cancer, colorectal cancer,and so on. Its abnormal expression can affect tumor cell proliferation, metastasis, or apoptosis. In liver cancer, the incidence of intrahepatic cholangiocarcinoma (ICC) is increasing. However, However, it has not been clearly reported on TRIM59 affects the progress of intrahepatic cholangiocarcinoma cells.Firstly, we review the expression of TRIM59 in different cancers and the corresponding normal tissuesï¼and the results preliminarily showed that TRIM59 may be abnormally expressed in many cancers. The author focuses on whether TRIM59 plays a crucial biological role in intrahepatic cholangiocarcinoma. Therefore, we have confirmed through online websites that TRIM59 is highly expressed in intrahepatic cholangiocarcinoma tissues. Furthermore we further found that TRIM59 can be used as an effective prognostic marker for the prognostic guidance of patient survival time. Next, we explore whether the expression level of TRIM59 in intrahepatic cholangiocarcinoma is related to proliferation through the CCK-8 and EDU assay in two ICC cell lines. To further explore how TRIM59 affected the molecular mechanism involved in intrahepatic cholangiocarcinoma cell growth, we found that STAT3 promotes TRIM59 transcription and TRIM59 can affect tumor progression by regulating the PI3K/AKT signaling pathway through luciferase reporter assay and Western blot experiments. In summary, we first found that TRIM59 has great research value in ICC through bioinformatic analysis, then its expression level is closely related to the prognosis through the analysis of clinicopathological indicators of patients with ICC, and the biological mechanism of TRIM59 in ICC provides precise research or therapeutic targets for future cancer treatment. The findings improve our understanding of the potential of TRIM59 in biological functions in ICC and may hold promise as markers for the diagnosis,treatment, and prognosis of ICC. DATA AVAILABILITY: The raw data of this study are derived from the TCGA database, which are publicly available databases.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Línea Celular Tumoral , Proliferación Celular/genética , Colangiocarcinoma/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Proteínas de Motivos Tripartitos/genéticaRESUMEN
BACKGROUND: The impact of antiviral therapy on long-term survival outcomes in patients with small HBV-related hepatocellular carcinoma (HBV-related HCC) after liver resection is still controversial, as the impact can be overshadowed by tumor-related factors. This study investigated this impact on recurrence and survival in patients with HCC of less than 3â¯cm. OBJECTIVE: This study was designed to further determine the impact of antiviral treatment on prognosis of patients with HCC after liver resection, to verify whether patients with cirrhosis still benefited from antiviral treatment, to study the impact of antiviral treatment on post-operative HCC recurrence, and to determine whether patients with a low preoperative HBV-DNA viral load should receive antiviral therapy. METHODS: The clinical data on patients who underwent curative liver resection for histopathologically confirmed small HCC (≤3â¯cm in diameter) were analyzed to determine factors which were related with HCC recurrence and survival. The disease-free and overall survival outcomes were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify the risk factors of long-term survival. RESULTS: Of the 795 patients in this study, patients with high preoperative HBV-DNA levels had significantly worse DFS and OS outcomes at 1-, 3- and 5- year after liver resection when compared with those with low HBV-DNA levels (86.1%, 60.8%, 46.6% vs 90.5%, 71.3%, 51.4%; and 98.5%, 89.3%, 75.2% vs 98.8%, 91.5%, 84%, respectively). Patients who received antiviral therapy had significantly better DFS and OS outcomes at 1-, 3- and 5- year after liver resection when compared with those without (91.6%, 69.5%, 55% vs 80.2%, 56%, 44.2%; and 99.6%, 93.5%, 87% vs 96.1%, 80.5%, 61.3%, respectively). Antiviral therapy significantly improved the OS but not DFS outcomes in patients with low HBV-DNA levels. The corresponding 1-, 3- and 5- year DFS and OS outcomes were 92.6%, 73%, 59.1% vs 87.1%, 68.5%, 57.9%; and 99.5%, 95.1%, 91.1% vs 97.6%, 85.5%, 72.4%, respectively. Antiviral treatment significantly prolonged DFS and OS in patients with cirrhosis. The corresponding 1-, 3- and 5- year DFS and OS were 90.2%, 66%, 49% vs 73.9%, 46.6%, 32.8%; and 100%, 93.6%, 85% vs 93.8%, 73.3%, 52.6%, respectively. CONCLUSION: Antiviral therapy improved the prognosis of small HBV-related HCC of less than 3â¯cm. The survival benefit was also detected in patients with cirrhosis. Antiviral therapy should be considered a routine post-operative therapy for patients with HBV-related HCC.
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Antivirales/uso terapéutico , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/terapia , Hepatitis B Crónica/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/terapia , Pérdida de Sangre Quirúrgica , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Estudios de Cohortes , ADN Viral/análisis , Supervivencia sin Enfermedad , Femenino , Hepatectomía , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/patogenicidad , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/terapia , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carga ViralRESUMEN
BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. METHODS: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (nâ¯=â¯284). Two independent HBV-related HCC cohorts, a validation cohort (nâ¯=â¯171) and a serum cohort (nâ¯=â¯168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. RESULTS: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. CONCLUSION: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. LAY SUMMARY: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.
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Carcinoma Hepatocelular/genética , Janus Quinasa 1/fisiología , Neoplasias Hepáticas/genética , Factores de Transcripción STAT/fisiología , Transactivadores/genética , Proteínas Reguladoras y Accesorias Virales/genética , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Línea Celular Tumoral , Genotipo , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Estadificación de Neoplasias , Pronóstico , Transducción de Señal/fisiología , Transactivadores/sangre , Transactivadores/clasificación , Proteínas Reguladoras y Accesorias Virales/sangre , Proteínas Reguladoras y Accesorias Virales/clasificaciónRESUMEN
Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3' untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24-AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets.
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Empalme Alternativo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Paxillin/metabolismo , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismo , Regiones no Traducidas 3' , Animales , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Sitios de Unión , Carcinoma Hepatocelular/genética , Proteínas Portadoras/metabolismo , Proliferación Celular , Exones , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Proteína Homeótica Nanog/genética , Proteína Homeótica Nanog/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Paxillin/genética , Unión Proteica , Interferencia de ARN , ARN Largo no Codificante/genética , Proteínas de Unión al ARN/genética , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Tiempo , Transfección , Carga Tumoral , Regulación hacia ArribaRESUMEN
Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV integration between tumour and non-tumour tissues. HBV insertional sites are significantly enriched in the proximity of telomeres in tumours. Recurrent HBV target genes are identified with few that overlap. The overall HBV integration frequency is much higher in tumour genomes of males than in females, with a significant enrichment of integration into chromosome 17. Furthermore, a cirrhosis-dependent HBV integration pattern is observed, affecting distinct targeted genes. Our data suggest that HBV integration has a high potential to drive oncogenic transformation.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Virus de la Hepatitis B/fisiología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Transformación Celular Neoplásica , Islas de CpG , ADN Viral/genética , Femenino , Genoma Humano , Genoma Viral , Hepatitis B Crónica/genética , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/genética , Cirrosis Hepática/virología , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Integración ViralRESUMEN
Paraoxonase 3 (PON3) exerts prominent anti-inflammation and anti-oxidation properties mainly at the cellular level, and is primarily expressed in the liver. However, its role in HCC remains unexplored. Here, we investigated the expression pattern, clinical significance, and function of PON3 in HCC. PON3 mRNA and protein levels were respectively determined in two large cohorts using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) of tissue microarray. We found that PON3 was downregulated in most HCCs. Kaplan-Meier and log-rank test showed that PON3 downregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in all HCC patients, especially early-stage HCC patients. Cox regression analysis revealed that the PON3 downregulation was an independent risk factor for RFS and OS. Gain- and loss-of-function experiments revealed that PON3 suppressed cell proliferation in vivo and in vitro, which was attributed to its cell-cycle arrest effect. In addition, microarray analysis showed that some pro-proliferative genes were elevated when PON3 was knockdown, and these genes possibly involved in the underlying mechanisms. In conclusion, our studies reveal the cell proliferation inhibitory function of PON3 and offer a potential prognostic predictor and therapeutic target for HCC.
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Arildialquilfosfatasa/fisiología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Adulto , Anciano , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/mortalidad , Puntos de Control del Ciclo Celular , Proliferación Celular , Femenino , Hepatectomía , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Matrices TisularesRESUMEN
UNLABELLED: Tumor cells with stemness (stem-cell) features contribute to initiation and progression of hepatocellular carcinoma (HCC), but involvement of long noncoding RNAs (lncRNAs) remains largely unclear. Genome-wide analyses were applied to identify tumor-associated lncRNA-DANCR. DANCR expression level and prognostic values of DANCR were assayed in two HCC cohorts (China and Korea, n = 135 and 223). Artificial modulation of DANCR (down- and overexpression) was done to explore the role of DANCR in tumorigenesis and colonization, and tumor-bearing mice were used to determine therapeutic effects. We found that lncRNA-DANCR is overexpressed in stem-like HCC cells, and this can serve as a prognostic biomarker for HCC patients. Experiments showed that DANCR markedly increased stemness features of HCC cells to promote tumorigenesis and intra-/extrahepatic tumor colonization. Conversely, DANCR knockdown attenuated the stem-cell properties and in vivo interference with DANCR action led to decreased tumor cell vitality, tumor shrinkage, and improved mouse survival. Additionally, we found that the role of DANCR relied largely on an association with, and regulation of, CTNNB1. Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)-214, miR-320a, and miR-199a on CTNNB1. This observation was confirmed in vivo, suggesting a novel mechanism of tumorigenesis involving lncRNAs, messenger RNAs, and microRNAs. CONCLUSIONS: These studies reveal a significance and mechanism of DANCR action in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HCC.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/patología , ARN Largo no Codificante/fisiología , beta Catenina/fisiología , Animales , Carcinogénesis , Masculino , Ratones , Ratones DesnudosRESUMEN
BACKGROUND: Downregulation of Aldolase B (ALDOB) has been reported in hepatocellular carcinoma. However, its clinical significance and its role in pathogenesis of HCC remain largely unknown. METHODS: We analyzed the expression of ALDOB and its clinical features in a large cohort of 313 HCC patients using tissue microarray and immunohistochemistry. Moreover, the function of stably overexpressed ALDOB in HCC cells was explored in vitro and in vivo. Gene expression microarray analysis was performed on ALDOB-overexpressing SMMC7721 cells to elucidate its mechanism of action. RESULTS: ALDOB downregulation in HCC was significantly correlated with aggressive characteristics including absence of encapsulation, increased tumor size (>5 cm) and early recurrence. ALDOB downregulation was indicative of a shorter recurrence-free survival (RFS) and overall survival (OS) for all HCC patients and early-stage HCC patients (BCLC 0-A and TNM I stage patients). Multiple analyses revealed that ALDOB downregulation was an independent risk factor of RFS and OS. Stable expression of ALDOB in HCC cell lines reduced cell migration in vitro and inhibited lung metastasis, intrahepatic metastasis, and reduced circulating tumor cells in vivo. Mechanistically, we found that cells stably expressing ALDOB show elevated Ten-Eleven Translocation 1 (TET1) expression. Moreover, ALDOB expressing cells have higher levels of methylglyoxal than do control cells, which can upregulate TET1 expression. CONCLUSION: The downregulation of ALDOB could indicate a poor prognosis for HCC patients, and therefore, ALDOB might be considered a prognostic biomarker for HCC, especially at the early stage. In addition, ALDOB inhibits the invasive features of cell lines partly through TET1 expression.
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Biomarcadores de Tumor/biosíntesis , Carcinoma Hepatocelular/genética , Proteínas de Unión al ADN/biosíntesis , Fructosa-Bifosfato Aldolasa/biosíntesis , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogénicas/biosíntesis , Anciano , Animales , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/patología , Movimiento Celular/genética , Proliferación Celular/genética , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Femenino , Fructosa-Bifosfato Aldolasa/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Oxigenasas de Función Mixta , Metástasis de la Neoplasia , Pronóstico , Proteínas Proto-Oncogénicas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pioglitazone (PGZ), a synthetic PPARγ ligand, is known to have anti-tumor activity. However, it is unclear how it acts against hepatocellular carcinoma (HCC). We hypothesized that the pathological receptor for advanced glycation end products (RAGE) is involved in the PGZ anti-tumor process. To test this notion, human primary HCC tissues and corresponding adjacent non-cancerous tissues (ANCT) from 75 consecutive cases were analyzed. The expression and clinical significance of RAGE was assessed by immunohistochemical assay through tissue microarray. After HCC cells were pretreated with different concentrations of PGZ, cell proliferation, apoptosis, cell invasion, and cell cycle distribution were evaluated by multiple assays. The results showed that, the positive expression of RAGE was significantly higher in HCC tissues than in ANCT (66.7% vs. 36.0%, P < 0.001), and was closely associated with pathological staging (P = 0.014) and lymph-vascular space invasion (P = 0.003). Moreover, PGZ inhibited proliferative activity and invasive potential, and induced apoptosis and cell cycle arrest in HCC cells resulting in increased expression of PPARγ and decreased expression of RAGE, NF-κB, HMGB1, p38MAPK, Ki-67, MMP-2, and CyclinD1. Furthermore, knockdown of RAGE or NF-κB by siRNA effectively suppressed cell proliferation and invasion, and mediated the inhibitory effects of PGZ in HCC cells. Taken together, our findings suggest that, RAGE is overexpressed in human HCC tissues, and is closely associated with the pathological staging and tumor invasion of HCC. In addition, PGZ as a PPARγ agonist may inhibit growth and invasion of HCC cells via blockade of the RAGE signaling.
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Carcinoma Hepatocelular/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Invasividad Neoplásica/prevención & control , PPAR gamma/agonistas , Receptor para Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Tiazolidinedionas/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Pioglitazona , Transducción de Señal/efectos de los fármacosRESUMEN
The role of TGF-ß-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of lncRNAs in TGF-ß signaling is still unknown. In this study, we observed that the lncRNA-activated by TGF-ß (lncRNA-ATB) was upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis. lncRNA-ATB upregulated ZEB1 and ZEB2 by competitively binding the miR-200 family and then induced EMT and invasion. In addition, lncRNA-ATB promoted organ colonization of disseminated tumor cells by binding IL-11 mRNA, autocrine induction of IL-11, and triggering STAT3 signaling. Globally, lncRNA-ATB promotes the invasion-metastasis cascade. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-ß signaling, could predispose HCC patients to metastases and may serve as a potential target for antimetastatic therapies.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , ARN Largo no Codificante/genética , Factor de Crecimiento Transformador beta/metabolismo , Animales , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/metabolismo , Humanos , Interleucina-11/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Trasplante de Neoplasias , Pronóstico , ARN Mensajero/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/metabolismo , Trasplante Heterólogo , Células Tumorales Cultivadas , Regulación hacia Arriba , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
About 61-72% of transcribed regions possess long noncoding RNAs in antisense orientation (Antisense long noncoding RNAs, aslncRNAs). However, the function of aslncRNAs in HCC remains unclear. We found numerous aslncRNAs were deregulated and might be involved in regulatory gene-net of HCC. The PCNA-AS1, antisense to PCNA, is significantly up-regulated in HCC and could promote tumor growth in vitro and in vivo. The effects of PCNA-AS1 rely on regulation of PCNA via forming RNA hybridization to increase PCNA mRNA stability. We concluded that aslncRNAs might act as upstream regulators in HCC and PCNA-AS1 could serve as a novel therapeutic target.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Antígeno Nuclear de Célula en Proliferación/genética , ARN sin Sentido/genética , ARN Largo no Codificante/genética , Animales , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , ARN Mensajero/genética , Regulación hacia ArribaRESUMEN
PURPOSE: To investigate the expression and clinical significance of CADM2 in hepatocellular carcinomas (HCC). METHODS: The level of expression of CADM2 mRNA was assessed in frozen tumor specimens and adjacent noncancerous tissues from 30 HCC patients by real-time PCR. The protein level was determined by immunohistochemistry on a tissue microarray containing tumor and adjacent noncancerous tissues from 234 HCC patients. Clinicopathological characteristics associated analysis was performed through SPSS18 . RESULTS: CADM2 was strikingly down regulated in HCC. CADM2 expression was associated with differentiation (P = 0.000), serum alpha-fetoprotein (P = 0.003), vascular invasion (P = 0.001), and hepatitis B surface antigen (HBsAg, P = 0.038). Furthermore, patients with low CADM2 expression had significantly poorer recurrence-free survival (RFS) (40.8 and 34.2 % vs. 56.3 and 50.1 % in 3- and 5-year RFS, respectively, P = 0.005). Subgroup analysis revealed that the difference in RFS between groups with low- and high-CADM2 expression still existed among patients belonging to stage 0 or A of BCLC staging system (P = 0.008), patients with tumor ≤5 cm in size (P = 0.013), and alpha-fetoprotein-negative patients (P = 0.003). Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.007). Further multivariate Cox regression analysis indicated that CADM2 expression level, tumor size, tumor number, vascular invasion, HBsAg were independent risk factors for HCC recurrence. CONCLUSION: CADM2 serves as a novel predictor of RFS in HCC patients after curative resection.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Moléculas de Adhesión Celular/biosíntesis , Neoplasias Hepáticas/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Moléculas de Adhesión Celular/genética , Regulación hacia Abajo , Femenino , Hepatectomía , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Matrices TisularesRESUMEN
UNLABELLED: Survival of patients with hepatocellular carcinoma (HCC) remains poor, which is largely attributed to active angiogenesis. However, the mechanisms underlying angiogenesis in HCC remain to be discovered. In this study, we found that long noncoding RNA associated with microvascular invasion in HCC (lncRNA MVIH) (lncRNA associated with microvascular invasion in HCC) was generally overexpressed in HCC. In a cohort of 215 HCC patients, the overexpression of MVIH was associated with frequent microvascular invasion (P = 0.016) and a higher tumor node metastasis stage (P = 0.009) as well as decreased recurrence-free survival (RFS) (P < 0.001) and overall survival (P = 0.007). Moreover, the up-regulation of MVIH served as an independent risk factor to predict poor RFS. We also found that MVIH could promote tumor growth and intrahepatic metastasis by activating angiogenesis in mouse models. Subsequent investigations indicated that MVIH could activate tumor-inducing angiogenesis by inhibiting the secretion of phosphoglycerate kinase 1 (PGK1). Additionally, in 65 HCC samples, MVIH expression was inversely correlated with the serum level of PGK1 and positively correlated with the microvessel density. CONCLUSION: Deregulation of lncRNA MVIH is a predictor for poor RFS of HCC patients after hepatectomy and could be utilized as a potential target for new adjuvant therapies against active angiogenesis.