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Micro RNAs (mi RNAs) are small, regulatory non-coding RNAs that have potent effects on gene expression. Several mi RNA are deregulated in cellular processes involved in human liver diseases and regulation of cellular processes. Recent studies have identified the involvement of mi R-29 in hepatic fibrosis and carcinogenesis. Although several targets of mi R-29 have been identified, there is limited information regarding the cell-type specific roles of mi R-29 in the liver, and we sought to evaluate the role of this mi RNA in hepatic pathobiology. We report the generation of a tissue-specific knockout mouse to evaluate the role of mi R-29 in hepatic fibrosis and carcinogenesis in response to injury. We hypothesized that mi R-29 contributes to the hepatocyte driven response to chronic cellular injury that results in fibrosis. In support of this hypothesis, fibrosis and mortality were enhanced in mi R29 knockout mice in response to carbon tetrachloride. Genome-wide gene expression analysis identified an over-representation of genes associated with fibrosis. The oncofetal RNA H19 was modulated in a mi R-29 dependent manner following exposure to carbon tetrachloride in vivo. The impact of a hepatocyte specific mi R-29 knockout on survival following chronic hepatic injury in vivo implicates this mi RNA as a potential target for intervention. These results provide evidence of the involvement of mi R-29 in chronic hepatic injury, and suggest a role for deregulated hepatocyte expression of mi R-29 in the response to hepatic injury, fibrosis and carcinogenesis. [ABSTRACT FROM AUTHOR]

Ptprj is a ubiquitously expressed murine gene encoding a receptor-type protein tyrosine phosphatase, which has recently been proposed as a candidate gene on the locus Scc1 for colon cancer susceptibility. It has been demonstrated that PTPRJ, the human homologue of Ptprj, is involved in the control of cell growth and adhesion, being furthermore altered in several types of cancer including mammary, thyroid, lung, colon, and pancreatic cancers. To investigate the biological functions of Ptprj, we have generated mice deficient in this receptor protein tyrosine phosphatase. Ptprj-deficient mice are viable, fertile, and show no gross anatomical alterations. Furthermore, neither changes in life span nor spontaneous tumor appearance were observed in Ptprj-null mice. Our results indicate that Ptprj is dispensable for normal growth and development in mice. [ABSTRACT FROM AUTHOR]

Metallothioneins (MT) are potent scavengers of free radicals that are silenced in primary hepatocellular carcinomas (HCC) of human and rodent origin. To examine whether loss of MT promotes hepatocarcinogenesis, male Mt-1 and Mt-2 double knockout (MTKO) and wild-type (WT) mice were exposed to diethylnitrosamine (DEN) and induction of HCC was monitored at 23 and 33 weeks. The size and number of liver tumors, the ratio between liver and body weight, and liver damage were markedly elevated in the MTKO mice at both time points compared with the WT mice. At 23 weeks, MTKO mice developed HCC whereas WT mice developed only preneoplastic nodules suggesting that loss of MT accelerates hepatocarcinogenesis. MTKO tumors also exhibited higher superoxide anion levels. Although NF-κB activity increased in the liver nuclear extracts of both genotypes after DEN exposure, the complex formed in MTKO mice was predominantly p50/65 heterodimer (transcriptional activator) as opposed to p50 homodimer (transcriptional repressor) in WT mice. Phosphorylation of p65 at Ser276 causing its activation was also significantly augmented in DEN-exposed MTKO livers. NF-κB targets that include early growth response genes and proinflammatory cytokines were significantly upregulated in MTKO mice. Concurrently, there was a remarkable increase (∼100-fold) in Pai-1 expression; significant increase in c-Jun, c-Fos, c-Myc, Ets2, and ATF3 expressions; and growth factor signaling that probably contributed to the increased tumor growth in MTKO mice. Taken together, these results demonstrate that MTs protect mice from hepatocarcinogen-induced liver damage and carcinogenesis, underscoring their potential therapeutic application against hepatocellular cancer., (©2010 AACR.)

We report here that miR-155 and miR-125b play a role in innate immune response. LPS stimulation of mouse Raw 264.7 macrophages resulted in the up-regulation of miR-155 and down-regulation of miR-125b levels. The same changes also occurred when C57BL/6 mice were i.p. injected with LPS. Furthermore, the levels of miR-155 and miR-125b in Raw 264.7 cells displayed oscillatory changes in response to TNF-alpha. These changes were impaired by pretreating the cells with the proteasome inhibitor MG-132, suggesting that these two microRNAs (miRNAs) may be at least transiently under the direct control of NF-kappaB transcriptional activity. We show that miR-155 most probably directly targets transcript coding for several proteins involved in LPS signaling such as the Fas-associated death domain protein (FADD), IkappaB kinase epsilon (IKKepsilon), and the receptor (TNFR superfamily)-interacting serine-threonine kinase 1 (Ripk1) while enhancing TNF-alpha translation. In contrast, miR-125b targets the 3'-untranslated region of TNF-alpha transcripts; therefore, its down-regulation in response to LPS may be required for proper TNF-alpha production. Finally, Emu-miR-155 transgenic mice produced higher levels of TNF-alpha when exposed to LPS and were hypersensitive to LPS/d-galactosamine-induced septic shock. Altogether, our data suggest that the LPS/TNF-alpha-dependent regulation of miR-155 and miR-125b may be implicated in the response to endotoxin shock, thus offering new targets for drug design.

Carcinoid tumours are enigmatic, slow growing malignancies, which occur most frequently (74%) in the gastrointestinal tract. Symptoms of the carcinoid syndrome (flushing and diarrhoea) are infrequent, occurring in approximately 10% of the patients with small bowel carcinoid. A 45-year-old patient with multiple liver metastases, diagnosed in 1994 with nonHodgkin's lymphoma after undergoing surgery for a distal ileal tumour, was referred to us by the Department of Haematology. At that moment the issue of a differential diagnosis with a carcinoid tumour arose, due to the long evolution and lack of evidence to support the initial diagnosis. The carcinoid syndrome was in fact present (the patient experiencing flush after small amounts of alcohol and emotions) and also we identified elevated values of 5HIAA. Reevaluation of the histologic sections of the ileal tumour as well as an ultrasound guided fine needle aspiration of an intrahepatic lesion confirmed the diagnosis of "carcinoid tumour". This conclusion lead to new therapeutic options for this patient. One of the main therapeutic options used in treating multiple liver metastases from a carcinoid tumour is chemoembolization and this case offered an excellent opportunity to present this therapy.