The hallmark of scleroderma is fibrosis by excessive extracellular matrix (ECM) deposition in the skin, lung, and other organs. Increasing evidence suggests that overexpression of transforming growth factor-beta (TGF-beta) and its receptors play a key pathogenic role in the development of tissue fibrosis in scleroderma. TGF-beta is known to induce the expression of ECM proteins in the pathogenesis of fibrosis in systemic sclerosis. Investigations into TGF-beta pathways will suggest new treatment strategies for fibrotic diseases.
Animals ; Extracellular Matrix ; metabolism ; pathology ; Extracellular Matrix Proteins ; metabolism ; Fibroblasts ; metabolism ; Fibrosis ; Humans ; Receptors, Transforming Growth Factor beta ; metabolism ; Scleroderma, Systemic ; etiology ; metabolism ; Transforming Growth Factor beta ; metabolism

OBJECTIVETo explore the role of transforming growth factor beta (TGF beta) and their receptors (TGF beta-R) in the pathogenesis of hypertrophic scar.

METHODSSpecimens of normal skin and hypertrophic scar were harvested and the distribution and the expression of the TGF beta and TGF beta-R were determined by immunohistochemistry and in situ hybridization method.

RESULTSThe expressions of TGF beta and TGF beta-RII in normal skin were higher than the expression of TGF beta 1, TGF beta 2 and TGF-RI. But in hypertrophic scar the results were on the contrary. The mRNA expressions of TGF beta 1, TGF beta 2 and TGFRI were evidently increased with decreased mRNA expression of TGF-beta 3 and TGFR II in the hypertrophic scar when compared with those in the normal skin.

CONCLUSIONThe expression of TGF-beta (beta 1, beta 2, beta 3) and their receptors in different levels during the process of wound healing might be related to the formation of hypertrophic scars.

Cicatrix, Hypertrophic ; genetics ; metabolism ; Humans ; Immunohistochemistry ; In Situ Hybridization ; RNA, Messenger ; genetics ; metabolism ; Receptors, Transforming Growth Factor beta ; genetics ; metabolism ; Skin ; metabolism ; pathology ; Transforming Growth Factor beta ; genetics ; metabolism

BACKGROUND: TGF - beta is known as a cell growth inhibitory factor to suppress almost all cells, including the epithelial cell. Unlike normal cells, cancer cells are not affected by TGF- beta growth inhibitory action and the lack of TGF- beta receptor expression or mutation is being reported as its mechanism, which is rarely studied in Korea. Therefore, we investigated this study to clarify the role of TGF - beta I and TGF - beta II receptors in gastric cancer. METHODS: 23 cases that underwent operations for gastric cancer provided RNA collected from their carcinoma tissues and adjacent normal tissues. We investigated the level of TGF - beta 1 and T beta R-II mRNA expression with semi- quantitatively reverse transcription PCR and analyzed the correlation with prognostic factors, such as tumor size, depth of invasion, tumor differentiation and lymph-node metastasis. RESULTS: (1) TGF- beta I and T beta R-II mRNA were expressed in all carcinoma tissues and adjacent normal tissues of the 23 cases without statistical difference in the level of the expression. (2) The level of TGF - beta 1 mRNA expression was higher in patients with gastric cancer invaded only at the mucosa and submucosa than in patients with gastric cancer invaded over muscular propria, and also higher in the patients without lymph-node metastasis or perineural invasion than in the patients with lymph-node metastasis or perineural invasion. There was no significant correlation between the level of T beta R-II mRNA expression and several parameters, such as age, gender, tumor size, location, differentiation, Lauren's classification and vascular invasion. (3) There was a significant correlation between the level of TGF - beta 1 and T beta R-II mRNA expression in carcinoma tissues. CONCLUSION: It indicated that TGF - beta 1 mRNA expression in gastric cancer might concern the early stage of gastric carcinogenesis and, unlike the earlier reports, it was higher in patients with early gastric cancer, negative lymph-nodes or negative perineural invasion. Further studies are required to clarify the role of TGF - beta 1 in gastric carcinogenesis with more patients.
Female ; Human ; Male ; Middle Age ; Prognosis ; RNA, Messenger/genetics/metabolism ; Receptors, Transforming Growth Factor beta/*genetics ; Stomach Neoplasms/*genetics/metabolism ; Transforming Growth Factor beta/metabolism

OBJECTIVETo investigate the antitumor effect of natural killer (NK) cells on human colorectal cancer cells HT-29 in vitro by blocking transforming growth factor-β (TGF-β) signaling in NK cells transfected with vector containing dominant negative TGF-β type 2 receptor (DNTβR2).

METHODSTGF-β1 was added at the final concentration of 10 ng/ml for HT-29 cells. Primary NK cells were transfected with recombinant plasmid pIRES2-AcGFP-DNTβR2 and control plasmid pIRES2-AcGFP using Amaxa Nucleofector technology respectively. The cytotoxicity of these two types of NK cells to HT-29 cells was detected and analyzed by cell counting kit-8.

RESULTSThe transfection efficiency of primary NK cells was 18.85% for the plasmid pIRES2-AcGFP-DNTβR2 and 35.28% for the control plasmid pIRES2-AcGFP. The expression of DNTβR2 in NK cells was confirmed by Western blotting and RT-PCR. Primary NK cells displayed significantly lower cytotoxicity against HT-29 cells incubated with TGF-β1 than that without TGF-β1 (effect-target cell ratio 10:1,14.40%∓ 2.00% vs. 26.14% ∓ 2.50%, P > 0.05; effect-target cell ratio 20:1, 19.18% ∓ 2.49% vs. 40.81% ∓ 3.50%, P > 0.05). The cytotoxicity of NK cells transfected with DNTβR2 vector was significantly higher than that with control vector against HT-29 cells cultured with 10 ng/ml TGF-β1 (effect-target cell ratio 10:1, 21.17% ∓ 2.49% vs. 11.48% ∓ 1.11% ,P > 0.05; and effect-target cell ratio 20:1, 35.30% ∓ 3.78% vs. 17.19% ∓ 2.29%, P > 0.05).

CONCLUSIONNK cells transfected with DNTβR2 vector show better antitumor effect, which may provide new method for NK-based adoptive immunotherapy for cancer.

HT29 Cells ; Humans ; Killer Cells, Natural ; immunology ; metabolism ; Plasmids ; genetics ; Receptors, Transforming Growth Factor beta ; genetics ; Transfection ; Transforming Growth Factor beta ; metabolism ; pharmacology

Transforming growth factor-β (TGF-β) members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II (TβR II) and type I (TβRI) and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes (DUBs). In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regulatory roles of these DUBs as a driving force for cancer progression as well as their underlying working mechanisms are also discussed.
Animals ; Humans ; Molecular Targeted Therapy ; Receptors, Transforming Growth Factor beta ; metabolism ; Signal Transduction ; Smad Proteins ; physiology ; Transforming Growth Factor beta ; physiology ; Ubiquitin Thiolesterase ; metabolism ; Ubiquitin-Specific Proteases ; Ubiquitination

OBJECTIVETo probe into periostin's role in the pathological mechanism of hyperplasic scars, by examining the expression of periostin in hyperplasic scar tissues. To investigate the correlations between periostin and TGF-beta1, TGF-beta R I, TGF-beta R II.

METHODSRT-PCR was used to assess the mRNA expression levels of TGF-beta1, TGF-beta R I, TGF-beta R II in three kinds of tissues, which are keloid (K), hypertrophic scar (HS) and normal skin (SK). The protein expression of periostin was measured with Western blotting.

RESULTSThe mRNA level of periostin in K was higher than that in SK. The mRNA expression of TGF-beta1 in K was higher than that in HS and SK. The mRNA level of TGF-beta R I in K was higher than that in HS and SK. The significances above all was at P < 0.01. The protein expression level of periostin in HS increased, compared with that in SK (P < 0.05). Periostin was related to TGF-beta1 positively (P <0.01).

CONCLUSIONSThe periostin's expression is increased in keloids. Periostin is a cicatrix specific gene. Periostin appears to play an important role in the formation of keloids, which is related to TGF-beta1 closely.

Adult ; Cell Adhesion Molecules ; metabolism ; Cicatrix, Hypertrophic ; metabolism ; pathology ; Female ; Humans ; Keloid ; metabolism ; pathology ; Male ; Receptors, Transforming Growth Factor beta ; metabolism ; Transforming Growth Factor beta1 ; metabolism

Cytokines ; metabolism ; Humans ; Interleukins ; metabolism ; Lung ; metabolism ; pathology ; Pneumoconiosis ; etiology ; metabolism ; Receptors, Platelet-Derived Growth Factor ; metabolism ; Transforming Growth Factor beta ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo observe the influence of Niupo Zhibao pellet (NZP) on transforming growth factor-beta1 (TGF-beta1) and its receptor's expression.

METHODSEndotoxic shock model was established by intravenous injection of lipopolysaccharide (LPS) 1.5 mg/kg and intraperitoneal injection of D-galactosamine 100 mg/kg, and intervened by NZP, TGF-beta1 and its receptor's expression in lung tissue were detected by immunohistochemical method.

RESULTSNZP could enhance the TGF-beta1 and its receptor's expression in endotoxic shock lung tissue, and reduce the injury of lung.

CONCLUSIONThe mechanism of NZP in reducing endotoxic shock lung injury is possibly related with its effect in enhancing the TGF-beta1 and its receptor's expression in lung tissue.

Animals ; Drugs, Chinese Herbal ; pharmacology ; Female ; Galactosamine ; Lipopolysaccharides ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Transforming Growth Factor beta ; biosynthesis ; Respiratory Distress Syndrome, Adult ; etiology ; metabolism ; Shock, Septic ; chemically induced ; complications ; metabolism ; Transforming Growth Factor beta ; biosynthesis ; Transforming Growth Factor beta1

OBJECTIVETo study the relationship between the morphologic mechanism of human embryonic epidermic cells and mesenchymal-epithelial transformation (MET) and its modulation factor.

METHODSMorphological occurrence of epidermis was detected with histologic methods in earlier period [estimated gestational age (EGA) 6-14 weeks] human embryonic skin samples. At the same time, the characteristic expression and their distribution markers of mesenchymal cells [vimentin and alpha-smooth muscle actin (alpha-SMA)], embryonic specific epidermic protein CK8&18, specific protein of epidermic stem cell CK19, transforming growth factor-beta1) (TGF-beta1) and its receptor (TGFbetaRI) in embryonic epidermis were examined with immunohistochemistry and indirect-immunofluorescent doble-labelling method.

RESULTSDuring EAG 6-8 weeks, ectodermal cells containing Vim+/alpha-SMA(-) were found to transform into epidermal stem cells with CK8&18+/CK19+. In ectodermal cells, protein expression density of TGFbetaRI was moderate (+ +), while positive signal of TGFbeta1 was weak (+/-). After EGA10 weeks, epidermal cells showed typical morphological characteristics.

CONCLUSIONSAt EGA 6-8 weeks, human embryonic skin epidermal cells began to form through MET, in which the signal pathway mediated by TGFbetaRI might play important roles, but the role of TGFbeta1 need to be further studied.

Cell Differentiation ; physiology ; Epidermis ; cytology ; embryology ; Epithelial Cells ; cytology ; Humans ; In Vitro Techniques ; Mesoderm ; cytology ; Receptors, Transforming Growth Factor beta ; metabolism ; Transforming Growth Factor beta1 ; metabolism

DNA-Binding Proteins ; chemistry ; genetics ; physiology ; Humans ; Liver Cirrhosis ; pathology ; physiopathology ; Receptors, Transforming Growth Factor beta ; physiology ; Signal Transduction ; physiology ; Smad7 Protein ; Trans-Activators ; chemistry ; genetics ; metabolism ; physiology ; Transcription, Genetic ; physiology ; Transforming Growth Factor beta ; physiology ; Transforming Growth Factor beta1