RESUMO
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/ß-catenin, transforming growth factors-ß (TGF-ß), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/ß-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Hedgehog/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Células-Tronco Neoplásicas/metabolismo , Biologia MolecularRESUMO
Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-ß (TGF-ß) ligands. The endoglin/TGF-ß signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.
Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Suscetibilidade a Doenças , Endoglina/genética , Endoglina/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Endoglina/sangue , Endoglina/química , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/patologia , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Proteínas do Core Viral/metabolismoRESUMO
Chronic liver injury could lead the formation of liver fibrosis, eventually some would develop to hepatocellular carcinoma (HCC), one of the leading malignancies worldwide. The aim of the study is to dissect the role of extracellular signal-regulated kinase 2 (ERK2) signaling in liver fibrosis and inflammation. The choline-deficient, ethionine-supplemented (CDE) diet could lead to fatty livers and generate oval cells, activate hepatocyte stellate cell (HSC) and recruit immune cells as the liver fibrosis model mice. WT and ERK2 deficient (ERK2-/-) mice were compared in terms of liver weight/body weight, liver function, liver fibrosis markers and the differential gene expression in hepatotoxicity. ERK2-/- mice display the less degree of liver fibrosis when compared to WT mice. The protein level of alpha smooth muscle (α-SMA) was reduced and several hepatocellular carcinoma-related genes such as MMP9, FoxM1 were down-regulated. In addition, the cell proliferation and the percentages of activated T cells were reduced in ERK2-/- mice upon liver injury. Therefore, ERK2 plays an important role in regulating liver cirrhosis and inflammation.
Assuntos
Cirrose Hepática/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Actinas/metabolismo , Animais , Proliferação de Células , Proteína Forkhead Box M1/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/patologia , Ativação Linfocitária , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Mutação , Linfócitos T/imunologiaRESUMO
During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias/metabolismo , Microambiente Tumoral/genética , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/metabolismo , Proteínas Hedgehog/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Organogênese/genética , Organogênese/fisiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/genéticaRESUMO
Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Receptor Smoothened/antagonistas & inibidores , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor Smoothened/metabolismoRESUMO
Overexpression of Sonic Hedgehog signaling (Shh) pathway molecules is associated with invasiveness and recurrence in breast carcinoma. Therefore, inhibition of the Shh pathway downstream molecule Glioma-associated Oncogene Homolog (Gli) was investigated for its ability to reduce progression and invasiveness of patient-derived breast cancer cells and cell lines. Human primary breast cancer T2 cells with high expression of Shh signaling pathway molecules were compared with breast cancer line MDA-MB-231 cells. The therapeutic effects of Gli inhibitors were examined in terms of the cell proliferation, apoptosis, cancer stem cells, cell migration and gene expression. Blockade of the Shh signaling pathway could reduce cell proliferation and migration only in MDA-MB-231 cells. Hh pathway inhibitor-1 (HPI-1) increased the percentages of late apoptotic cells in MDA-MB-231 cells and early apoptotic cells in T2 cells. It reduced Bcl2 expression for cell proliferation and increased Bim expression for apoptosis. In addition, Gli inhibitor HPI-1 decreased significantly the percentages of cancer stem cells in T2 cells. HPI-1 worked more effectively than GANT-58 against breast carcinoma cells. In conclusion, HPI-1 could inhibit cell proliferation, reduce cell invasion and decrease cancer stem cell population in breast cancer cells. To target Gli-1 could be a potential strategy to suppress breast cancer stem cells.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas Hedgehog/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteína GLI1 em Dedos de Zinco/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piridinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Tiofenos/administração & dosagem , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidoresRESUMO
The torsion of vessels after liver transplantation rarely occurs. Likewise, calcification of a liver graft has seldom been reported. This report details a case which had torsion of the left hepatic vein on the seventh day after living-related donor liver transplantation. The torsion was reduced soon after re-exploration; however, congestion with partial necrosis of the graft occurred. On the follow-up imaging studies, some resolution of necrosis and graft regeneration were found, yet geographic calcification of the liver graft appeared.The patient died of pneumonia after 13 weeks, post-operation. The avoidance such torsion of vessels is necessary and important.
Assuntos
Calcinose/etiologia , Veias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Doadores Vivos , Anormalidade Torcional/etiologia , Doenças Vasculares/etiologia , Aloenxertos , Calcinose/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Evolução Fatal , Veias Hepáticas/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Necrose , Flebografia/métodos , Reoperação , Fatores de Tempo , Anormalidade Torcional/diagnóstico por imagem , Anormalidade Torcional/cirurgia , Doenças Vasculares/diagnóstico por imagem , Doenças Vasculares/cirurgiaRESUMO
HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC.
RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) has a high recurrence rate after resection. Abnormal activation of the sonic hedgehog (SHH) signaling pathway contributing to the carcinogenesis of some organs had been reported. We hypothesize that activation of SHH pathway contributes to the recurrence of HCC after surgical resection. METHODS: In a prospective study, from January 2006 to June 2010, a total of 50 consecutive patients with HCC after curative resection were enrolled. The ratio of the expression of messenger RNA (mRNA) of SHH, patched homolog-1 (PTCH-1) and glioma-associated oncogene-1 (GLI-1) between HCC tissues and the paired noncancerous liver tissues were measured. Both the clinicopathologic characteristics and these ratios were compared between those with recurrence and those without recurrence. They were also compared between those with and without survival. RESULTS: There was a statistically significant correlation among the ratios of PTCH-1 mRNA and serum AFP level (p = 0.045), tumor size (p = 0.001), vascular permeation (p = 0.043) and tumor, node, metastasis staging system (TNM) stage (p = 0.003). A borderline significant correlation was found among ratios of GLI-1 mRNA and tumor size (p = 0.062) and TNM stage (p = 0.051). There was no such significant correlation between SHH mRNA and any parameter. Both the ratios of PTCH-1 mRNA and GLI-1 mRNA significantly adversely affected recurrence (p = 0.003 and 0.005, respectively) and survival (p < 0.001 and <0.001, respectively). CONCLUSIONS: Expression of PTCH-1 mRNA and GLI-1 mRNA in HCC tissues is a potential biomarker to predict postresection disease recurrence.
Assuntos
Carcinoma Hepatocelular/genética , Proteínas Hedgehog/genética , Neoplasias Hepáticas/genética , Recidiva Local de Neoplasia/genética , Complicações Pós-Operatórias , Receptores de Superfície Celular/genética , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Receptores Patched , Receptor Patched-1 , Prognóstico , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida , Proteína GLI1 em Dedos de ZincoRESUMO
Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Current therapies are effective for HCC patients with early disease, but many patients suffer recurrence after surgery and have a poor response to chemotherapy. Therefore, new therapeutic targets are needed. We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different. The analysis showed that AKR1C3 was upregulated in tumors, and high AKR1C3 expression was associated with a poorer prognosis in HCC patients. In vitro, assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines. Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo. To explore the mechanism, we performed pathway enrichment analysis, and the results linked the expression of AKR1C3 with prostaglandin F2 alpha (PGF2α) downstream target genes. Suppression of AKR1C3 activity reduced the production of PGF2α, and supplementation with PGF2α restored the growth of indomethacin-treated Huh7 cells. Knockdown of the PGF receptor (PTGFR) and treatment with a PTGFR inhibitor significantly reduced HCC growth. We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib. In summary, our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α, and suppression of PTGFR limited HCC growth. Therefore, targeting the AKR1C3-PGF2α-PTGFR axis may be a new strategy for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Aldo-Ceto Redutases/genética , Dinoprosta , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Linhagem Celular , Indometacina/farmacologia , Membro C3 da Família 1 de alfa-Ceto RedutaseRESUMO
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is hypervascular. Pigment epithelial derived factor (PEDF), a potent angiogenic inhibitor, usually coexists with the stimulator, vascular endothelial growth factor (VEGF). To assess the treatment effect of PEDF on growing HCCs we conducted this study. METHODOLOGY: Pathogen-free male LEW/SsN rats (n=150 in 5 groups), group A as control, groups B, C, D and E were given diethyl nitrosamine (DEN) to induce HCC. Group C received intraperitoneal injection (i.p.) of PEDF (0.3mg/kg/day) since induction. Group D received i.p. of PEDF (0.3mg/kg/day) since 18th week (wk). Group E received i.p. of normal saline. We examined VEGF mRNA and PEDF mRNA of livers of group A and 3 different areas (advancing edge, inner edge and central area) of HCC of other 4 groups at 24th wk. RESULTS: Tumor weight and metastasis score of group C were significantly lower (p=0.026). Comparing among 5 groups, the ratio of VEGF/PEDF mRNA of inner edge of HCC of group C and D were significantly lower (p=0.002 and p=0.011). By multivariate analysis, the difference of group C remains significant (p=0.030). CONCLUSIONS: PEDF significantly suppresses rat hepatocarcinogenesis if given simultaneously since cancer induction. The significant decrease of VEGF/PEDF mRNA is at the inner edge of HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas do Olho/metabolismo , Proteínas do Olho/farmacologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/farmacologia , Serpinas/metabolismo , Serpinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Dietilnitrosamina , Proteínas do Olho/uso terapêutico , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Masculino , Análise Multivariada , Metástase Neoplásica , Fatores de Crescimento Neural/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Serpinas/uso terapêutico , Estatísticas não ParamétricasRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) can occasionally develop with other non-HCC cell types, either in a combined type or collision type. A collision tumor is defined as two histopathologically distinct tumors of the same organ lacking a clear transition zone. Hepatic collision tumors are rare. Among them, "hepatocellular carcinoma-hepatic neuroendocrine carcinoma" (HCC-NEC) collision tumors are especially rare and information about them is rarely published. CASE SUMMARY: A 48-year-old man with typical findings of HCC underwent consecutive therapies, including radiofrequency ablation and embolization prior to resection. Diagnosis of the HCC-NEC collision tumor in the right liver and another HCC in the left liver was established following surgical resection. The patient displayed NEC metastasis following resection and succumbed to septicemia after 2 more rounds of chemotherapy. To our knowledge, this is the 25th reported case of mixed HCC-NEC tumor. The rarity of HCC-NEC collision tumors and the absence of diagnostic criteria make it difficult to differentiate this condition from simple liver tumors, especially in patients with chronic liver disease. CONCLUSION: Our case highlights the difficulty in accurately diagnosing HCC-NEC in the absence of histological evidence. The prognosis is poor for this condition, although ultrasound-guided liver biopsy can be helpful to establish a prompt diagnosis. Further accumulation of such cases could help establish an accurate diagnosis earlier. Early discovery of NEC may allow for better treatment strategies and better prognoses.
RESUMO
The extended scope of upper gastrointestinal cancer can include esophageal cancer, gastric cancer and pancreatic cancer. A higher incidence rate of gastric cancer and esophageal cancer in patients with liver cirrhosis has been reported. It is attributable to four possible causes which exist in cirrhotic patients, including a higher prevalence of gastric ulcers and congestive gastropathy, zinc deficiency, alcohol drinking and tobacco use and coexisting gut microbiota. Helicobacter pylori infection enhances the development of gastric cancer. In addition, Helicobacter pylori, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans also contribute to the development of pancreatic cancer in cirrhotic patients. Cirrhotic patients (especially those with alcoholic liver cirrhosis) who undergo liver transplantation have a higher overall risk of developing de novo malignancies. Most de novo malignancies are upper gastrointestinal malignancies. The prognosis is usually poor. Considering the surgical risk of upper gastrointestinal cancer among those with liver cirrhosis, a radical gastrectomy with D1 or D2 lymph node dissection can be undertaken in Child class A patients. D1 lymph node dissection can be performed in Child class B patients. Endoscopic submucosal dissection for gastric cancer or esophageal cancer can be undertaken safely in selected cirrhotic patients. In Child class C patients, a radical gastrectomy is potentially fatal. Pancreatic radical surgery should be avoided in those with liver cirrhosis with Child class B or a MELD score over 15. The current review focuses on the recent reports on some factors in liver cirrhosis that contribute to the development of upper gastrointestinal cancer. Quitting alcohol drinking and tobacco use is important. How to decrease the risk of the development of gastrointestinal cancer in those with liver cirrhosis remains a challenging problem.
RESUMO
BACKGROUND/AIMS: Telomerase activation contributes to hepatocarcinogenesis. We designed an animal study to investigate the effect and possible mechanisms of treatment with telomerase inhibitor on HCC in a rat model. METHODOLOGY: Adult male LEW/SsN rats were divided into 3 groups (n=60). Group A as the control. Groups B and C were given diethylnitrosamine (DEN), 5mg/kg/day. In addition, Group C rats received an intraperitoneal injection of 3'-azido2,3'dideoxythymidine azidothymidine (AZT), 0.3mg/kg/day for 14 days starting on week 18. Ten animals in each group were sacrificed at 18, 20, 22 and 24 weeks to evaluate the liver tumor. We compared telomerase mRNA, telomerase activity and Bcl-2 mRNA among the liver tissue of group A rats and tumor tissue of HCC from group B and C rats. RESULTS: No HCC developed in group A, but tumors were present in group B and C rats by the 18th week. Group B's telomerase mRNA was significantly higher than group A's (p=0.009), but group C's was significantly higher than group A's (p=0.017) and lower than group B's (p=0.014). The same intergroup B vs. A and C vs. A relationship was also true for telomerase activity (p=0.009 and 0.009), but with no significant differences between group B and C (p=0.175). CONCLUSIONS: AZT, the telomerase blocker, effectively inhibits the growth of liver tumor weight and decreases the metastasis score of HCC induced by DEN in rats in vivo.
Assuntos
Neoplasias Hepáticas Experimentais/tratamento farmacológico , Telomerase/antagonistas & inibidores , Zidovudina/uso terapêutico , Animais , Genes bcl-2 , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/enzimologia , Masculino , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos Lew , Telomerase/genética , Telomerase/fisiologiaRESUMO
BACKGROUND/AIMS: Isolated resection of the caudate lobe harboring hepatocellular carcinoma (HCC) in the paracaval portion is a challenge. To obtain a bloodless surgical field and to minimize the intraoperative blood loss, various vascular procedures of the outflow occlusion have been introduced. However, in those with liver cirrhosis and portal hypertension total outflow occlusion, may increase the hemodynamic instability and postoperative morbidity. METHODOLOGY: Of 21 patients receiving curative resection of HCC in caudate lobe, 3 had tumors in the paracaval portion (a largest diameter of 2.5cm, 9.5cm and 7.3cm, respectively). A Satinsky vascular clamp was applied obliquely on one side of inferior vena cava (IVC) to preserve the hepatic outflow. Pringle's maneuver was used for inflow control. RESULTS: Using such measures, curative resection was performed smoothly in these 3 patients. Repair of an IVC defect by simple continuous suture with prolene 4-0 was undertaken in the second one. All patients had an uneventful postoperative course. CONCLUSION: During resection of HCC in the paracaval portion of caudate lobe, using side clamp ing of IVC without complete interruption of hepatic outflow is safe and feasible. We suggest it as an alternative approach. It would reduce the hemodynamic instability and perioperative morbidity in a cirrhotic liver.
Assuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/cirurgia , Veia Cava Inferior/cirurgia , Idoso , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Fígado/irrigação sanguínea , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIMS: Laminin-5 has been reported as a prognostic indicator of some malignancies. This prospective study aimed to elucidate the correlation between the ratio of the expression of different laminin-5 subchain mRNAs in HCC tissue and the clinical relevance or prognosis of patients. METHODOLOGY: Using RT-PCR, a3, ß3 and ?2 mRNA levels were determined prospectively from 29 patients with HCC undergoing curative resection. The ratio of the value of each subchain mRNA in HCC tissue to non-cancerous liver tissue was measured. RESULTS: The mRNA of a3, ß3 and ß2 was detected in both HCC tissue and the liver remnants in 29 (100%), 29 (100%) and 28 (96.5%) patients, respectively. The ratio of ?2 mRNA correlated with the absence of complete encapsulation (p=0.033) and with the presence of hepatitis, with borderline significance (p=0.081). The ratio of a3 mRNA correlated with tumor hemorrhage and tumor necrosis with borderline significance (p=0.082 and p=0.082, respectively). The ratios of a3, ß3 and ?2 mRNA did not correlate significantly with postresection recurrence, recurrence and patient survival. CONCLUSIONS: Expression of a3, ß3 and ?2 cannot predict the prognosis. However, high expression of ?2 mRNA in HCC/non-cancerous liver correlated significantly with the absence of complete encapsulation, which is an important tumor invasiveness factor.
Assuntos
Carcinoma Hepatocelular/genética , Moléculas de Adesão Celular/genética , Neoplasias Hepáticas/genética , RNA Mensageiro/genética , Adulto , Idoso , Análise de Variância , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Prognóstico , Estudos Prospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , CalininaRESUMO
Obesity is closely linked to metabolic diseases, particularly non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), ultimately leading to hepatocellular carcinoma (HCC). However, the molecular mechanisms of NASH-associated HCC (NAHCC) remain elusive. To explore the impact of Max dimerization protein 3 (MXD3), a transcription factor that regulates several cellular functions in disorders associated with metabolic diseases, we conditionally expressed Mxd3 proteins using Tet-on mxd3 transgenic zebrafish (MXs) with doxycycline (MXs + Dox) or without doxycycline (MXs - Dox) treatment. Overexpression of global MXD3 (gMX) or hepatic Mxd3 (hMX) was associated with obesity-related NAFLD pathophysiology in gMX + Dox, and liver fibrosis and HCC in hMX + Dox. Oil Red O (ORO)-stained signals were seen in intravascular blood vessels and liver buds of larval gMX + Dox, indicating that Mxd3 functionally promotes lipogenesis. The gMX + Dox-treated young adults exhibited an increase in body weight and visceral fat accumulation. The hMX + Dox-treated young adults showed normal body characteristics but exhibited liver steatosis and NASH-like phenotypes. Subsequently, steatohepatitis, liver fibrosis, and NAHCC were found in 6-month-old gMX + Dox adults compared with gMX - Dox adults at the same stage. Overexpression of Mxd3 also enhanced AR expression accompanied by the increase of AR-signaling pathways resulting in hepatocarcinogenesis in males. Our results demonstrate that global actions of Mxd3 are central to the initiation of obesity in the gMX zebrafish through their effects on adipogenesis and that MXD3 could serve as a therapeutic target for obesity-associated liver diseases.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Obesidade/genética , Receptores Androgênicos/genética , Proteínas Repressoras/genética , Adipogenia/genética , Animais , Animais Geneticamente Modificados/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Doxiciclina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Transdução de Sinais/genética , Peixe-Zebra/genéticaRESUMO
OBJECTIVE: MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and it plays an important role in regulating liver metabolism and tumor formation. Previous studies also reveal an anti-inflammatory function of miR-122; however, relatively little is known about the mechanisms by which miR-122 suppresses inflammation. This study aims to search the effect of miR-122 on proinflammatory chemokines/cytokines production in mice. METHODS: Quantitative real-time PCR, Western blot analysis, and ELISA were performed to examine gene expression. TargetScan, miRanda, and microT v3.0 were used to search for possible miR-122 target sites in the 3'-untranslated regions (3'-UTR) of candidate genes. Luciferase reporter assay and site-directed mutagenesis were applied to verify miR-122 target sequences. LPS was applied to peritoneal macrophages and mice to evaluate inflammatory response. RESULTS: The expression of proinflammatory chemokines, including Ccl2, Ccl4, Ccl20, Cxcl2, and Cxcl10, and Relb in the livers of miR-122 knockout (KO) mice was increased. We identified Relb as a direct miR-122 target. Overexpressing RelB in the mouse liver increased the expression of Ccl2, Ccl4, Ccl20, Cxcl2, and Cxcl10. Peritoneal macrophages from miR-122 KO mice had a higher level of RelB, and they showed a stronger NF-κB activation and more TNF-α and IL-6 secretion after LPS stimulation. Overexpression of RelB in a macrophage cell line augmented LPS-induced TNF-α and IL-6 production. miR-122 KO mice showed a greatly increased mortality rate and generated a stronger and lasting inflammatory response to LPS. CONCLUSIONS: Deletion of miR-122 caused an upregulation of proinflammatory chemokines and RelB in the liver. Increased RelB may contribute to increases in these chemokine in the liver. Intriguingly, deletion of miR-122 also enhanced the sensitivity of macrophages and mice to LPS. Our results reveal that reducing RelB expression is a new mechanism by which miR-122 regulates inflammation.
Assuntos
Fígado/fisiologia , Macrófagos/fisiologia , MicroRNAs/genética , Fator de Transcrição RelB/metabolismo , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Fator de Transcrição RelB/genética , Regulação para CimaRESUMO
Unresectable hepatocellular carcinoma (HCC) has a poor therapeutic outcome. We report here on a 40-year-old male HCC patient who had undergone partial hepatectomy and was refractory to therapeutic embolization. In addition, the tumour expressed phosphorylated extracellular signal-regulated kinase and CD34. Sorafenib was administered as salvage treatment and resulted in a rapid decline in alpha-fetoprotein (AFP) levels. However, this was accompanied by a grade 3 skin reaction, which improved as sorafenib dosage was gradually reduced. Unfortunately, reducing the dose of sorafenib also resulted in a rebound in AFP levels and portal vein thrombosis was noted thereafter. Sorafenib 800 mg/day was resumed, but the tumour failed to respond. Intensity-modulated radiation therapy (IMRT) combined with sorafenib was administered, resulting in marked tumour shrinkage and causing recurrence of the systemic skin reaction and development of photosensitivity. The patient survived for 20 months after the start of sorafenib treatment. This case suggests that the combination of sorafenib and IMRT might provide clinical benefits in patients with HCC who express potential targets but fail to respond to sorafenib; however, skin reactions should be monitored.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Piridinas/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Humanos , Masculino , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Radioterapia de Intensidade Modulada/instrumentação , Radioterapia de Intensidade Modulada/métodos , Terapia de Salvação , Sorafenibe , Resultado do TratamentoRESUMO
Spontaneous rupture of hepatocellular carcinoma (HCC), defined as T4 in TNM stage by the American Joint Committee on Cancer (eighth edition), is a serious life-threatening complication. Effective treatment remains challenging because of a high 1-month mortality, a short median survival, and the potential of peritoneal metastasis. We reported on a case that received a living related donor liver transplantation (LDLT) after successful consecutive downstaging therapies. A 63-year-old man with alcohol-related liver cirrhosis and multiple HCC developed spontaneous rupture and hemoperitoneum. He received 3 sessions of transcatheter hepatic arterial chemoembolization and target therapy with sorafenib. Computed tomography scans and magnetic resonance imaging after 11 months of treatment showed that the patient's HCCs fulfilled the Milan criteria and the University of California San Francisco criteria prior to LDLT. The perioperative course was rather smooth. After discharge, interval follow-up computed tomography studies of chest and liver and a whole-body bone scan showed no tumor recurrence or metastasis up to 20 months post-operation. Successful downstaging therapies of ruptured HCC to fulfill Milan criteria to receive liver transplantation is advisable in highly selected patients.