RESUMO
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant primary tumor in the liver, and the rates of incidence and mortality are rapidly increasing globally. Histone deacetylase 8 (HDAC8) is a transcriptional regulator and is associated with tumorigenesis of several tumor types. This study aimed to evaluate the correlation between HDAC8 expression and clinicopathological parameters in ICC patients. METHODS: ICC tissues and corresponding nonmalignant bile duct tissues were obtained from 60 patients. HDAC8 and Ki-67 expression were evaluated by immunohistochemistry staining. HDAC8 expression and the clinicopathological features and prognosis of the patients were analyzed. The mRNA level of HDAC8 in ICC was further analyzed using data from The Cancer Genome Atlas (TCGA). RESULTS: The expression of HDAC8 were lower in ICC tissues (39/60, 65%) than in the corresponding nonmalignant bile duct tissues (54/60, 90%) (Pâ¯=â¯0.001). Low HDAC8 expression in ICC was significantly associated with lymph node metastases (47.6% vs. 17.9%, Pâ¯=â¯0.015). In addition, the positive cells rate of HDAC8 was statistically and negatively correlated with the Ki-67 index in ICC lesions (r = -0.7660, P < 0.001). Importantly, the overall survival rate and recurrence-free survival rate in ICC patients with low HDAC8 expression were lower than those with high HDAC8 expression (Pâ¯=â¯0.008 and Pâ¯=â¯0.011, respectively). CONCLUSIONS: Decreased HDAC8 expression in ICC is related to poor prognosis, and HDAC8 may be an independent prognostic indicator of ICC patients after curative resection.
Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Colangiocarcinoma/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/genética , Colangiocarcinoma/secundário , Intervalo Livre de Doença , Feminino , Humanos , Antígeno Ki-67/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Taxa de SobrevidaRESUMO
Histone deacetylase 3 (HDAC3) plays pivotal roles in cell cycle regulation and is often aberrantly expressed in various cancers including hepatocellular carcinoma (HCC), but little is known about its role in liver regeneration and liver cancer cells proliferation. Using an inducible hepatocyte-selective HDAC3 knockout mouse, we find that lack of HDAC3 dramatically impaired liver regeneration and blocked hepatocyte proliferation in the G1 phase entry. HDAC3 inactivation robustly disrupted the signal transducer and activator of transcription 3 (STAT3) cascade. HDAC3 silencing impaired the ac-STAT3-to-p-STAT3 transition in the cytoplasm, leading to the subsequent breakdown of STAT3 signaling. Furthermore, overexpressed HDAC3 was further associated with increased tumor growth and a poor prognosis in HCC patients. Inhibition of HDAC3 expression reduced liver cancer cells growth and inhibited xenograft tumor growth. Our results suggest that HDAC3 is an important regulator of STAT3-dependent cell proliferation in liver regeneration and cancer. These findings provide novel insights into the HDAC3-STAT3 pathway in liver pathophysiological processes.
Assuntos
Histona Desacetilases/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Fator de Transcrição STAT3/metabolismo , Animais , Proliferação de Células , Hepatócitos/citologia , Hepatócitos/metabolismo , Histona Desacetilases/genética , Humanos , Neoplasias Hepáticas/genética , Regeneração Hepática , Masculino , Camundongos , Camundongos Knockout , Fator de Transcrição STAT3/genética , Transdução de SinaisRESUMO
BACKGROUND: The stimulatory G protein a subunit (Gsα) plays important roles in diverse cell processes including tumorigenesis. Activating mutations in Gsα gene (GNAS) have been reported to be associated with poor prognosis in various human carcinomas. Furthermore, Gsα signaling is crucial in promoting liver regeneration by interacting with growth factor signaling, indicating that Gsα might play a promoting role in cancer development. However, little is known about the correlation between Gsα levels and clinicopathological parameters in intrahepatic cholangiocarcinoma (ICC). METHODS: We performed immunoblotting to examine the expression levels of Gsα and Ki67 proteins in tumor tissues and the corresponding adjacent tissues. A total of 74 pair of specimens resected from 74 ICC patients were examined. The association between Gsα levels and clinicopathological findings and prognosis of the patients was evaluated. RESULTS: Western blotting demonstrated that the expression of Gsα was significantly higher in ICC tissues compared with that in their corresponding adjacent tissues. Gsα protein was highly expressed in about half of ICC tissues (48.6%, 36/74) while only 28.4% (21/74) of tumor adjacent tissues showed Gsα high expression (P=0.011). High Gsα expression in ICC was significantly associated with the numbers of tumor nodules (P=0.037) and lymph node metastases (P=0.010). Moreover, the level of Gsα was significantly and positively correlated with Ki67 expression (P<0.001). In addition, the recurrence-free survival rate and overall survival rate in the Gsα high group were significantly lower than those in the Gsα low group (P=0.004 and P=0.005, respectively). CONCLUSIONS: High Gsα expression is correlated with poor prognosis in ICC patients. Gsα might serve as a potential prognostic indicator of ICC.
