RESUMO
Lin-41 is a stem cell-specific E3 ligase and a known target of the tumour suppressor microRNA (miRNA) let-7. Lin-41 was recently reported to mediate ubiquitylation and degradation of the miRNA pathway protein Ago2. We demonstrate that Lin-41 is over-expressed in hepatocellular carcinoma (HCC). Lin-41 over-expression correlates with high α-fetoprotein level, high tumour grade and high tumour stage and predicts early tumour recurrence. Lin-41 is a strong predictor of poor long-term survival for patients with HCC. Lin-41 knock-down by RNA interference in HCC cell lines Huh7 and Hep3B suppressed proliferation in vitro and reduced in vivo tumour growth in NOD/SCID mice. On the other hand, over-expression of Lin-41 in the HCC cell line SK-Hep1 enhanced tumourigenicity. Over-expression and knock-down of Lin-41 led to inverse changes in the levels of Ago1 and Ago2 proteins. Over-expression of Ago1 and Ago2 reduced in vivo tumour growth. Lin-41 over-expression suppressed let-7 activity in HCC cell lines and expression of Lin-41 enhanced the expression of let-7-regulated oncogenes c-Myc, Lin-28B, HMGA2 and type 1 insulin-like growth factor receptor (IGF1R). Expression of Lin-28B and c-Myc enhanced the expression of Lin-41. Chromatin immunoprecipitation and reporter assays revealed direct association of c-Myc with the Lin-41 promoter, resulting in transcriptional transactivation. Our results indicate that Lin-41 plays an important role in the growth of HCC by regulating RISC complex proteins Ago1 and Ago2 to inhibit miRNA-mediated gene silencing and promote the expression of oncogenic proteins. Lin-41 is also a strong prognostic factor for patients with HCC.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/diagnóstico , Inativação Gênica/fisiologia , Neoplasias Hepáticas/diagnóstico , Proteínas de Membrana/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas Argonautas/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Fatores de Iniciação em Eucariotos/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Adulto JovemRESUMO
AIMS: Chromophobe renal cell carcinoma (ChRCC) is an uncommon malignant renal neoplasm with a generally indolent clinical behaviour. Previous studies revealed biallelic inactivation of the hepatocyte nuclear factor-1ß (HNF1ß) gene in several patients with ChRCC. The aims of this study were to determine HNF1ß expression in renal neoplasms and the potential of HNF1ß as a diagnostic marker for ChRCC. METHODS AND RESULTS: We performed immunohistochemical staining of 79 samples taken from patients with primary renal neoplasm [19 renal oncocytomas, 18 ChRCCs, 24 clear cell renal cell carcinomas (CCRCCs), and 18 papillary renal cell carcinomas]. HNF1ß was underexpressed in 16 of 18 cases of ChRCC (88.9%). By contrast, HNF1ß expression was preserved in the majority of renal oncocytoma (94.7%, 18/19) and CCRCC (95.8%, 23/24) cases. The combined use of HNF1ß and cytokeratin 7 (CK7) further increased the diagnostic sensitivity and specificity; the profile of HNF1ß positivity and CK7 negativity was not visible in any ChRCC sample, but was common in both renal oncocytoma (94.7%, 18/19) and CCRCC (91.7%, 22/24) samples. CONCLUSIONS: The results suggest that a lack of HNF1ß expression might play an important role in the pathogenesis of ChRCC, and may serve as a good diagnostic marker for this neoplasm.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Fator 1-beta Nuclear de Hepatócito/metabolismo , Neoplasias Renais/metabolismo , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Adenoma Oxífilo/metabolismo , Adenoma Oxífilo/patologia , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Sensibilidade e EspecificidadeRESUMO
Viral hepatitis-associated intrahepatic cholangiocarcinoma is thought to have common disease processes with hepatocellular carcinoma, but until now the histomorphological and genetic features of viral hepatitis-associated intrahepatic cholangiocarcinoma is still unknown. From 2000 to 2010, 170 patients with intrahepatic cholangiocarcinoma who received detailed pathological assessment and regular follow-up at the National Taiwan University Hospital were selected for this study. Of 170 patients, 69 (41%) were positive for hepatitis B and/or C virus. These patients were younger, were more frequently male, and had elevated serum α-fetoprotein levels as compared with seronegative intrahepatic cholangiocarcinoma patients. Grossly these tumors were mostly of the mass-forming type, and histologically, cholangiolar differentiation was more frequently seen. We identified N-cadherin as an immunohistochemical marker strongly associated with hepatitis virus infection. The prevalence of viral hepatitis in patients with N-cadherin-positive intrahepatic cholangiocarcinoma was 75%, and that in N-cadherin-negative patients was only 37%. N-cadherin-positive patients were younger, had elevated α-fetoprotein, and had no hepatolithiasis. All N-cadherin-positive intrahepatic cholangiocarcinomas were of the mass-forming type. N-cadherin positivity was strongly associated with cholangiolar morphology and lack of carcinoembryonic antigen and MUC2 expression, whereas K-RAS mutations were less frequent. Our results indicate that a subgroup of intrahepatic cholangiocarcinoma characterized by cholangiolar differentiation and N-cadherin expression is strongly associated with viral hepatitis.
Assuntos
Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Caderinas/metabolismo , Colangiocarcinoma/patologia , Hepatite Viral Humana/patologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/virologia , Ductos Biliares Intra-Hepáticos/metabolismo , Biomarcadores Tumorais/metabolismo , Transdiferenciação Celular , Transformação Celular Neoplásica , Transformação Celular Viral , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/virologia , Feminino , Genes ras , Hepatite B/complicações , Hepatite B/patologia , Hepatite C/complicações , Hepatite C/patologia , Hepatite Viral Humana/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , alfa-Fetoproteínas/análiseRESUMO
BACKGROUND: Taking advantage of isomeric form of vitamin E in the supplement, adherence to supplement could be evaluated by changes in circulating α- and γ-tocopherol concentrations. Accordingly, effects of supplementation on postoperative nutrition and bone metabolism were studied in terms of adherence. METHODS: Thirty-eight SG patients were all prescribed a postoperative nutritional supplement containing a low dose of vitamin D (600 IU) and calcium (200 mg). Blood samples were collected prior to (M0) and 6 months after (M6) surgery and concentrations of nutrients and C-terminal telopeptide of type I collage (CTX), a marker of bone resorption, were measured. Adherence and non-adherence were stratified according to change (â³, M6-M0) in serum α-tocopherol concentrations (> 0 vs. ≤ 0, respectively). RESULTS: When M0 and M6 were compared, there were significant increases in serum concentrations of 25(OH)D, α-tocopherol and selenium, whereas there were reductions in parathyroid hormone, ferritin, and γ-tocopherol. At M6, the prevalence of vitamin D insufficiency (25(OH)D < 30 ng/mL) and high CTX were 72 and 26%, respectively. When comparison was made between adherence and non-adherence, only â³25(OH)D concentrations, but no other nutrients nor postoperative CTX differed. Multiple linear regression demonstrated that postoperative vitamin D status was independently associated with its preoperative concentrations (ß = 0.85, p < 0.001) and adherence (ß = 0.52, p < 0.05). CONCLUSION: SG patients' adherence to supplementation, even with a low dose of vitamin D and calcium, determined vitamin D status but not bone resorption marker concentrations, at least within 6 months after surgery.
Assuntos
Reabsorção Óssea , Obesidade Mórbida , Deficiência de Vitamina D , Suplementos Nutricionais , Gastrectomia , Humanos , Obesidade Mórbida/cirurgia , Hormônio Paratireóideo , Vitamina DRESUMO
MicroRNAs (miRNAs) play critical roles in embryonic development and are frequently deregulated in human cancers. The let-7 family members are tumor-suppressing miRNAs and are frequently downregulated in cancer cells. Lin-28 and Lin-28B are RNA-binding proteins highly expressed in embryonic tissues. Lin-28 proteins block let-7 precursors from being processed to mature miRNAs by inducing terminal uridylation and degradation of let-7 precursors. Here, we report that Lin-28B, but not Lin-28, is highly expressed in hepatocellular carcinoma (HCC). Lin-28B expression was more frequently noted in high-grade HCCs with high alpha-fetoprotein levels. Knockdown of Lin-28B by RNA interference in the HCC cell line HCC36 suppressed proliferation in vitro and reduced in vivo tumor growth in NOD/SCID mice. In contrast, overexpression of Lin-28B in the HCC cell line HA22T enhanced tumorigenicity. Overexpression of Lin-28B also induced epithelial-mesenchymal transition in HA22T cells and hence, invasion capacity. Large-scale real-time PCR array analysis revealed that, among 380 miRNAs, only let-7/mir-98 family members were regulated by Lin-28B. Lin-28B overexpression enhanced the expression of the known let-7 targets c-myc and HMGA2. It was also found that Lin-28B enhanced the expression of type 1 insulin-like growth factor receptor in a let-7-dependent manner. These results indicate that Lin-28B regulates tumor formation and invasion in HCC through coordinated repression of the let-7/mir-98 family and induction of multiple oncogenic pathways.