Stanniocalcin-1 Reduces Tumor Size in Human Hepatocellular Carcinoma

Growing evidence has revealed high expression levels of stanniocalcin-1 (STC1) in different types of human cancers. Numerous experimental studies using cancer cell lines demonstrated the involvement of STC1 in inflammatory and apoptotic processes; however the role of STC1 in carcinogenesis remains elusive. Hepatocellular carcinoma (HCC) an exemplified model of inflammation-related cancer, represents a paradigm of studying the association between STC1 and tumor development. Therefore, we conducted a statistical analysis on the expression levels of STC1 using clinicopathological data from 216 HCC patients. We found that STC1 was upregulated in the tumor tissues and its expression levels was positively correlated with the levels of interleukin (IL)-6 and IL-8. Intriguingly tumors with greater expression levels of STC1 (tumor/normal >= 2) were significantly smaller than the lower level (tumor/normal<2) samples (p = 0.008). A pharmacological approach was implemented to reveal the functional correlation between STC1 and the ILs in the HCC cell-lines. IL-6 and IL-8 treatment of Hep3B cells induced STC1 expression. Lentiviral-based STC1 over-expression in Hep3B and MHCC-97L cells however showed inhibitory action on the pro-migratory effects of IL-6 and IL-8 and reduced size of tumor spheroids. The inhibitory effect of STC1 on tumor growth was confirmed in vivo using the stable STC1-overexpressing 97L cells on a mouse xenograft model. Genetic analysis of the xenografts derived from the STC1-overexpressing 97L cells, showed upregulation of the pro-apoptotic genes interleukin-12 and NOD-like receptor family, pyrin domain-containing 3. Collectively, the anti-inflammatory and pro-apoptotic functions of STC1 were suggested to relate its inhibitory effect on the growth of HCC cells. This study supports the notion that STC1 may be a potential therapeutic target for inflammatory tumors in HCC patients.published_or_final_versio

Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma

Cadherin is an important cell adhesion molecule that plays paramount roles in organ development and the maintenance of tissue integrity. Dysregulation of cadherin expression is often associated with disease pathology including tissue dysplasia, tumor formation, and metastasis. Cadherin-17 (CDH17), belonging to a subclass of 7D-cadherin superfamily, is present in fetal liver and gastrointestinal tract during embryogenesis, but the gene becomes silenced in healthy adult liver and stomach tissues. It functions as a peptide transporter and a cell adhesion molecule to maintain tissue integrity in epithelia. However, recent findings from our group and others have reported aberrant expression of CDH17 in major gastrointestinal malignancies including hepatocellular carcinoma (HCC), stomach and colorectal cancers, and its clinical association with tumor metastasis and advanced tumor stages. Furthermore, alternative splice isoforms and genetic polymorphisms of CDH17 gene have been identified in HCC and linked to an increased risk of HCC. CDH17 is an attractive target for HCC therapy. Targeting CDH17 in HCC can inhibit tumor growth and inactivate Wnt signaling pathway in concomitance with activation of tumor suppressor genes. Further investigation on CDH17-mediated oncogenic signaling and cognate molecular mechanisms would shed light on new targeting therapy on HCC and potentially other gastrointestinal malignancies. © 2010 Elsevier B.V.link_to_subscribed_fulltex

Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma

Using comparative proteomic and genomic approaches, the authors identified eukaryotic translation initiation factor 5A (eIF5A) as an oncofetal molecule highly abundant in mouse embryonic livers and human hepatocellular carcinoma (HCC) cell lines. To evaluate the oncogenic role and prognostic significance of eIF5A in HCC, we investigate the expression patterns of the two isoforms (eIF5A1 and eIF5A2) in a cohort of 258 HCC cases by cDNA microarray. Both eIF5A isoforms were expressed in the tumors, and clinically correlated eIF5A1 with more numbers of tumor nodules and eIF5A2 with tumor venous infiltration in HCC. In a separate cohort of 50 HCCs, high level of eIF5A2, but not eIF5A1, was associated with elevated levels of deoxyhypusine synthase and deoxyhypusine hydroxylase that catalyze post-translational hypusination of eIF5A protein. Interestingly, N1-guanyl-1,7-diaminoheptane (GC7), which is an inhibitor for the first step of eIF5A hypusination, was shown to significantly impair the cell proliferation and invasion of primary HCC cells (HepG2 and Hep3B). To further demonstrate the tumorigenic role associated with eIF5A, a drastic reduction of cell proliferation was associated with suppression of eIF5A2 by transfecting Hep3B, H2-P and H2-M HCC cells expressing high level of this isoform using small interfering RNA (siRNA) against eIF5A2. For these assays, a milder response was usually observed in normal hepatocyte cell line. Therefore, these findings suggest that eIF5A plays an important role in HCC tumorigenesis and metastasis, and targeting eIF5A hypusination by GC7 inhibitor or eIF5A2 by RNA interference (RNAi) may offer new therapeutic alternatives to HCC patients. © 2009 UICC.link_to_subscribed_fulltex

DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival

Hepatocellular carcinoma (HCC) is a heterogeneous and highly aggressive malignancy, for which there are no effective cures. Identification of a malignant stemlike subtype of HCC may offer patients with a dismal prognosis a potential targeted therapy using c-MET and Wnt pathway inhibitors. MicroRNAs (miRNAs) show promise as diagnostic and prognostic tools for cancer detection and stratification. Using a TRE-c-Met-driven transgenic HCC mouse model, we identified a cluster of 23 miRNAs that is encoded within the Dlk1-Gtl2 imprinted region on chromosome 12qF1 overexpressed in all of the isolated liver tumors. Interestingly, this region is conserved among mammalian species and maps to the human DLK1-DIO3 region on chromosome 14q32.2. We thus examined the expression of the DLK1-DIO3 miRNA cluster in a cohort of 97 hepatitis B virus-associated HCC patients and identified a subgroup (n = 18) of patients showing strong coordinate overexpression of miRNAs in this cluster but not in other cancer types (breast, lung, kidney, stomach, and colon) that were tested. Expression levels of imprinted gene transcripts from neighboring loci in this 14q32.2 region and from a subset of other imprinted sites were concomitantly elevated in human HCC. Interestingly, overexpression of the DLK1-DIO3 miRNA cluster was positively correlated with HCC stem cell markers (CD133, CD90, EpCAM, Nestin) and associated with a high level of serum α-fetoprotein, a conventional biomarker for liver cancer, and poor survival rate in HCC patients. In conclusion, our findings suggest that coordinate up-regulation of the DLK1-DIO3 miRNA cluster at 14q32.2 may define a novel molecular (stem cell-like) subtype of HCC associated with poor prognosis. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.link_to_OA_fulltex

Regeneração pós-traumática do nervo facial em coelhos Posttraumatic facial nerve regeneration in rabbits

A paralisia facial periférica traumática constitui-se em afecção freqüente. OBJETIVO: estudo da regeneração pós-traumática do nervo facial em coelhos, por avaliação funcional histológica dos nervos traumatizados comparados aos normais contralaterais. METODOLOGIA: Vinte coelhos foram submetidos à compressão do tronco do nervo facial esquerdo e sacrificados após duas (grupo AL), quatro (BL) e seis (CL) semanas da lesão. A comparação entre os grupos foi feita pelas densidades total e parcial de axônios mielinizados. ESTUDO ESTATÍSTICO: método de Tukey (p < 0,05). RESULTADOS: Houve recuperação funcional parcial após duas, e completa após cinco semanas. Na análise qualitativa, verificou-se em AL um padrão degenerativo, com maior processo inflamatório tecidual. Em BL, sinais de regeneração neural, praticamente completa em CL. Os nervos normais (N) apresentaram DT média de 15705,59 e DP média de 21800,75. O grupo BL revelou DT média de 10818,55 e DP média de 15340,56 e o CL, DT média de 13920,36 e DP média de 16589,15. BL obteve 68,88%, e o grupo CL, 88,63% da DT de N. N mostrou DP maior que os lesados; porém, esta não evidenciou diferença estatística entre BL e CL. A DT dos nervos revelou-se um método analítico mais fidedigno do que a DP estudada.<br>Posttraumatic facial paralysis is a frequent disease. This work studies posttraumatic regeneration of the facial nerve in rabbits. Functional and histological analysis compared injured and normal nerves on opposite sides. The left facial nerve trunk of twenty rabbits were subjectedto compression lesion, and sacrificed after two (subgroup AL), four (BL) and six (CL) weeks. Comparison between groups was made by analysing total and partial densities of myelinated axons. STATISTICAL ANALYSIS: Tukey Method (p<0.05). RESULTS:There was partial functional recovery after two weeks, and complete recovery after five weeks. Qualitative analysis demonstrated a degenerative pattern in the AL group, with an increased tissue inflammatory process. Evident regeneration signs were observed in the BL group, and almost complete regeneration was seen in the CL group. Normal nerves (N) had an average TD of 15705.59 and average PD of 21800.75. The BL group had an average TD of 10818.55 and an average PD of 15340.56. The CL group had an average TD of 13920.36 and an average PD of 16589.15. The BL group had an average TD of N equal to 68.88%, and the CL group had an average TD of N equal to 88,63% (statistically significant). N showed a significant higher PD than injured nerves. However, this was not statistically different between BL and CL subgroups. Nerve DT was a more reliable method than PD in this study

Role of sympathetic nervous system and neuropeptides in obesity hypertension

Obesity is the most common cause of human essential hypertension in most industrialized countries. Although the precise mechanisms of obesity hypertension are not fully understood, considerable evidence suggests that excess renal sodium reabsorption and a hypertensive shift of pressure natriuresis play a major role. Sympathetic activation appears to mediate at least part of the obesity-induced sodium retention and hypertension since adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with neuropeptides in the hypothalamus may link excess weight gain with increased sympathetic activity. Leptin is produced mainly in adipocytes and is believed to regulate energy balance by acting on the hypothalamus to reduce food intake and to increase energy expenditure via sympathetic activation. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term leptin infusion at rates that mimic plasma concentrations found in obesity raises arterial pressure and heart rate via adrenergic activation in non-obese rodents. Transgenic mice overexpressing leptin also develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including the melanocortin-4 receptor (MC4-R). However, the role of this pathway in mediating the long-term effects of leptin on blood pressure is unclear. Also, it is uncertain whether there is resistance to the chronic renal sympathetic and blood pressure effects of leptin in obese subjects. In addition, leptin also has other cardiovascular and renal actions, such as stimulation of nitric oxide formation and improvement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the role of these mechanisms in human obesity has not been elucidated, this remains a fruitful area for further investigation, especially in view of the current "epidemic" of obesity in most industrialized countries