The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism.

Hepatocellular carcinoma expressing hepatobiliary progenitor markers, is considered of poor prognosis. By using a hepatocarcinogenesis model, laser capture microdissection, and RNA-Sequencing analysis, we identified an expression profile in GGT/KRT19-positive experimental tumors; 438 differentially expressed genes were found in early and late nodules along with increased collagen deposition. Dysregulated genes were involved in Fatty Acid Metabolism, RXR function, and Hepatic Stellate Cells Activation. Downregulation of Slc27a5, Acsl1, and Cyp2e1, demonstrated that Retinoid X Receptor α (RXRα) function is compromised in GGT/KRT19-positive nodules. Since RXRα controls NRF2 pathway activation, we determined the expression of NRF2 targeted genes; Akr1b8, Akr7a3, Gstp1, Abcc3, Ptgr1, and Txnrd1 were upregulated, indicating NRF2 pathway activation. A comparative analysis in human HCC showed that SLC27A5, ACSL1, CYP2E1, and RXRα gene expression is mutually exclusive with KRT19 gene expression. Our results indicate that the downregulation of Slc27a5, Acsl1, Rxrα, and Cyp2e1 genes is an early event within GGT/KRT19-positive HCC.

Enrichment of progenitor cells by 2-acetylaminofluorene accelerates liver carcinogenesis induced by diethylnitrosamine in vivo.

The potential role of hepatocytes versus hepatic progenitor cells (HPC) on the onset and pathogenesis of hepatocellular carcinoma (HCC) has not been fully clarified. Because the administration of 2-acetylaminofluorene (2AAF) followed by a partial hepatectomy, selectively induces the HPC proliferation, we investigated the effects of chronic 2AAF administration on the HCC development caused by the chronic administration of the carcinogen diethylnitrosamine (DEN) for 16 weeks in the rat. DEN + 2AAF protocol impeded weight gain of animals but promoted prominent hepatomegaly and exacerbated liver alterations compared to DEN protocol alone. The tumor areas detected by γ-glutamyl transferase, prostaglandin reductase-1, and glutathione S-transferase Pi-1 liver cancer markers increased up to 80% as early as 12 weeks of treatment, meaning 6 weeks earlier than DEN alone. This protocol also increased the number of Ki67-positive cells and those of CD90 and CK19, two well-known progenitor cell markers. Interestingly, microarray analysis revealed that DEN + 2AAF protocol differentially modified the global gene expression signature and induced the differential expression of 30 genes identified as HPC markers as early as 6 weeks of treatment. In conclusion, 2AAF induces the early appearance of HPC markers and as a result, accelerates the hepatocarcinogenesis induced by DEN in the rat. Thus, since 2AAF simultaneously administrated with DEN enriches HPC during hepatocarcinogenesis, we propose that DEN + 2AAF protocol might be a useful tool to investigate the cellular origin of HCC with progenitor features.

Differential Expression of Ion Channels and Transporters During Hepatocellular Carcinoma Development.

BACKGROUND: Ion channels and transporters are potential markers and therapeutic targets for several cancers. However, their expression during hepatocellular carcinoma (HCC) development remains unclear. AIM: To investigate the mRNA expression of Na(+), K(+) and Ca(2+) channels and ABC transporters during rat HCC development, as well as Abcc3 protein in human liver biopsies. METHODS: Wistar rats were treated with diethylnitrosamine (DEN) and developed both cirrhosis (12 weeks of treatment) and either pre-neoplastic lesions (16 weeks of treatment) or multinodular HCC (16 weeks of treatment plus 2 weeks DEN-free). The mRNA expression of 12 ion channels and two ABC transporters was studied using real-time RT-PCR. Tumor-containing or tumor-free liver sections were isolated by laser-capture microdissection. Abcc3 protein expression was studied by immunohistochemistry in healthy, cirrhotic and HCC human biopsies. RESULTS: We observed expression changes in seven genes. Kcna3, Kcnn4, Kcnrg and Kcnj11 potassium channel mRNA expression reached peak values at the end of DEN treatment, while Scn2a1 sodium channel, Trpc6 calcium channel and Abcc3 transporter mRNA expression reached their highest levels in the presence of HCC (18 weeks). Whereas Kcnn4 and Scn2a1 channel expression was similar in non-tumor and tumor tissue, the Abcc3 transporter and Kcna3 potassium channels were preferentially overexpressed in the tumor sections. We observed differential Abcc3 protein subcellular localization and expression in human samples. CONCLUSIONS: The ion channel/transporter expression profile observed suggests that these genes are potential early markers or therapeutic targets of HCC. The differential localization of Abcc3 may be useful in the diagnosis of cirrhosis and HCC.

Linfomas tipo MALT de la conjuntiva. Estudio clinicopatológico de 12 casos del Hospital General de México / MALT type lymphomas of the conjunctiva. A study of 12 cases from the Mexico General Hospital

Introducción. Las neoplasias linfoides de los anexos oculares ocupan del 7 al 8% de todos los linfomas extranodales. De éstos, el más frecuente es el linfoma B de la zona marginal extranodal de tejido linfoide asociado a mucosas (MALT), seguido del linfoma B difuso de células grandes. Algunos agentes infecciosos se han asociado de forma inconstante en la etiología de los linfomas MALT. También se han encontrado translocaciones características, que en su mayoría causan la activación del factor nuclear unido al promotor de cadenas ligeras kappa de los linfocitos B activados (NF-κB). Los linfomas MALT son el tipo de linfoma predominante en la conjuntiva y en los anexos oculares. El promedio de edad es de 61 años, siendo muy raros antes de los 25 años y predominando en el sexo femenino. Material y método. Se revisó el archivo de la Unidad de Patología Quirúrgica del Hospital General de México (2003-2010). Resultados. Se encontraron 12 casos de tipo MALT. El espectro de edad fluctuó entre los 23 y los 74 años, con promedio de 50,7 años; 7 (58,3%) fueron del sexo femenino y 5 (41,6%) pacientes del sexo masculino. Presentaron morfología de linfoma de linfocitos pequeños tipo MALT y se realizó inmunohistoquímica para confirmar el diagnóstico(AU)

Introduction. Lymphoid ocular adnexa neoplasms comprise 7-8% of all extranodal lymphomas, the most common being the extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), followed by diffuse large B-cell lymphoma. Some infectious organisms may play an aetiological role in the development of MALT lymphomas, although this is not a consistent finding. Specific translocations have also been identified which cause activation of nuclear factor bound to the promoter kappa light chains of activated B-lymphocites (NF-kB). MALT lymphomas are the predominant type of lymphoma in the conjunctiva and other occular adnexa. They occur more frequently in females and the average age of patients is 61; they are extremely rare before the age of 25. Material and methods. Clinical and morphological data from biopsies diagnosed as MALT lymphoma, from the General Hospital of Mexico during the years 2003 to 2010, were reviewed. Results. Of the 12 cases found, the age range was 23 to 74, with an average age of 50.7; 7 (58.3%) were female and 5 (41.6%) were male. The morphology of the present cases was that of small lymphocytic lymphoma (MALT lymphoma) and the diagnosis was confirmed by immunohistochemistry(AU)