Integrated TCGA and GEO analysis showed that SMAD7 is an independent prognostic factor for lung adenocarcinoma.

The lack of effective markers leads to missed optimal treatment times, resulting in poorer prognosis in most cancers. Drosophila mothers against decapentaplegic protein (SMAD) family members are important cytokines in the transforming growth factor-beta family. They jointly regulate the processes of cell growth, differentiation, and apoptosis. However, the expression of SMAD family genes in pan-cancers and their impact on prognosis have not been elucidated. Perl software and R software were used to perform expression analysis and survival curve analysis on the data collected by TCGA, GTEx, and GEO, and the potential regulatory pathways were determined through gene ontology enrichment and kyoto encyclopedia of genes and genomes enrichment analysis. It was found that SMAD7 and SMAD9 expression decreased in lung adenocarcinoma (LUAD), and their expression was positively correlated with survival time. Additionally, SMAD7 could be used as an independent prognostic factor for LUAD. In general, SMAD7 and SMAD9 can be used as prognostic markers of LUAD. Further, SMAD7 is expected to become a therapeutic target for LUAD.

Anti-fibrotic impact of Carvedilol in a CCl-4 model of liver fibrosis via serum microRNA-200a/SMAD7 enhancement to bridle TGF-ß1/EMT track.

Circulating microRNAs (miRNAs) play a role in modulating the prevalence of fibrosis and have been a target of the cardiac anti-fibrotic effect of Carvedilol. However, the impact of miRNAs on the hepatoprotective effect of this non-selective ß-blocker has not been yet elucidated. Hence, the current goal is to evaluate the potential role of circulating miR-200a in the hepatic anti-fibrotic pathway of Carvedilol. Male Wistar rats were randomized into normal, CCl4 (2 ml/kg, i.p, twice weekly for 8 weeks), and CCl4 + Carvedilol (10 mg/kg, p.o, daily). Carvedilol over-expressed the circulating miR-200a to modulate epithelial mesenchymal transition (EMT) markers (vimentin, E-Cadherin). In turn, Carvedilol increased SMAD7 gene expression and protein content to attenuate the pro-fibrogenic marker transforming growth factor ß1 (TGF-ß1) and the inflammatory markers (p-38 MAPK and p-S536-NF-κB p65). The anti-fibrotic potential was reflected on the decreased expression of the mesenchymal product and EMT marker α-SMA, besides the improved histopathological examination, and the fibrosis scores/collagen quantification to enhance liver functions (AST, ALT, ALP, and AST/platelet ratio index; APRI). In conclusion, circulating miR-200a/SMAD7/TGF-ß1/EMT/MAPK axis is crucial in the hepatic anti-fibrotic mechanism of Carvedilol.

MicroRNA-181a and its target Smad 7 as potential biomarkers for tracking child acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic tumor. MiR-181a was expected to have a role in the development of hematological malignancies; it might act as tumor suppressor or oncogene. Smad7 was selected as miR-181a target pair. It is a negative regulator for the TGF-ß1 signaling pathway. In this study, relative expression levels of miR-181a by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), both Smad 7 and TGF-ß1 proteins levels by enzyme linked immunosorbent assay (ELISA) were all measured in serum of 60 child, 30 with ALL and 30 age and sex matched healthy child as control group. MiR-181a expression showed highly significant decrease; plus a significant increase and decrease of Smad7 and TGF-ß1 protein levels respectively, in serum samples of ALL as compared to control group. MiR-181a expression achieved a highly significant positive and a significant negative correlation with TGF-ß1 and Smad7 respectively. Furthermore, the levels of Smad7 and TGF-ß1 were negatively correlated with each other (p<0.05). Although, positivity rate of both Smad7 and TGF-ß1 in ALL group increased with presence of hepatosplenomegaly, still there was no statistical significance. In conclusion, miR-181a could act as a tumor suppressor in pediatric ALL with over expression of its target pair, Smad7. Smad7 regulates TGF-ß1 signaling via a negative feedback loop and mediates the interaction between TGF-ß1 and other signaling pathways; suggesting that Smad7 over expression may have therapeutic potential in ALL.

[Effect of lamivudine and silymarin on liver fibrosis-relevant factors in HBV transgenic mice with alcohol drinking].

OBJECTIVE: To observe the role of lamividine and silymarin preventing and curing liver fibrosis-relevant factors induced by alcohol drinking in hepatitis B virus (HBV) transgenic mice (Tg mice).
 Methods: Forty HBV-Tg BALB/C mice with 1.3 copy were randomly divided into 4 groups: a control group, a model group, a lamivudine group and a silymarin group. Tg mice in control group were treated with normal saline via intragastric administration; Tg-mice in the model group were treated with 50% alcohol (5 mL/kg) once a day via intragastric administration; while Tg-mice in lamivudine group and silymarin group were treated with alcohol (5 mL/kg) plus laminvudine (100 mg/kg) and silymarin (200 mg/kg) once a day via intragastric administration respectively. All groups were raised for 10 weeks. The levels of HBV-DNA copy number, ALT, AST in serum, the degree of inflammation, the degree of fibrosis, the mRNA expression levels of TGF-ß1, Smad3, Smad7 and connective tissue growth factor (CTGF), and the protein expression levels of TGF-ß1, CTGF and α-SMA in liver tissue were detected. All the images were scanned with electronic computer and the data were analyzed with SPSS13.0 software.
 Results: Compared with the control group, liver injury were significantly aggravated, while HBV-DNA copies, mRNA levels of TGF-ß1, Smad3, Smad7 and CTGF as well as the protein levels of TGF-ß1, CTGF and α-SMA were significantly increased (P<0.05). Compared with the model group, liver injury were significantly attenuated in silymarine group and lamivudine group, while mRNA levels of TGF-ß1, Smad3 and CTGF as well as the protein levels of TGF-ß1, CTGF and α-SMA were significantly decreased; mRNA level of Smad7 was further increased (P<0.05); the levels of ALT and AST in serum were decreased in the silymarine group (P<0.05).
 Conclusion: Lamivudine and silymarin relieve the histological damage in the liver of alcohol-fed Tg mice. The mechanisms for the beneficial effects of lamivudine or silymarin might be related to inhibiting the expression of TGF-ß1, Smad3 and CTGF, modulating the expression of Smads and suppressing the activation of HSC.

miR-195 plays a role in steroid resistance of ulcerative colitis by targeting Smad7.

An imbalance in pro- and anti-inflammation is an important mechanism of steroid resistance in UC (ulcerative colitis), and miRNAs may participate in this process. The present study aimed to explore whether miRNAs play a role in the steroid resistance of UC by regulating gene expression of the inflammation signal pathway. SS (steroid-sensitive) patients, SR (steroid-resistant) patients and healthy individuals were recruited. In vivo miRNA profiles of serum samples showed that miR-195 was decreased significantly in the SR group compared with the SS group (P<0.05). This result was confirmed by qPCR (quantitative real-time PCR) and miRNA ISH (in situ hybridization) in serum and colon tissue samples. Online software was used to identify Smad7 mRNA as a potential target of miR-195. The direct interaction of miR-195 and Smad7 mRNA was investigated using a biotinylated miR-195 pull-down assay. Overexpression of a miR-195 precursor lowered cellular levels of Smad7 protein; conversely, antagonism of miR-195 enhanced Smad7 translation without disturbing Smad7 mRNA levels. A luciferase reporter assay revealed a repressive effect of miR-195 via a single Smad7 3'-UTR target site, and point mutation of this site prevented miR-195-induced repression of Smad7 translation. Furthermore, increased levels of miR-195 led to a decrease in c-Jun and p65 expression. In contrast, transfection with anti-miR-195 led to increased levels of c-Jun and p65 protein. The decrease in miR-195 led to an increase in Smad7 expression and corresponding up-regulation of p65 and the AP-1 (activator protein 1) pathway, which might explain the mechanism of steroid resistance in UC patients.

TGF-ß signaling is altered in the peripheral blood of subjects with multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system inflammatory disorder with evidence of peripheral immune dysregulation. Abnormalities of the immune suppressive cytokine TGF-ß have been reported, but not fully defined, in MS. Through a pathway-focused expression profiling of the peripheral blood, we found abnormalities of TGF-ßRII, SMAD4 and SMAD7 expression in subjects with MS, and reduction in the levels of TGF-ß regulated genes, indicating an overall reduction in TGF-ß signaling in MS. The response to exogenous TGF-ß was intact, however, indicating an extrinsic defect of TGF-ß signaling in MS. These results indicate that TGF-ß control is diminished in MS.