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Objective: To investigate possible associations between disease-specific survival (DSS) of oral cancer and single nucleotide polymorphisms (SNPs) in transforming growth factor beta receptor 1 (TGFBR1).Methods: Using iPLEX Sequenom MassARRAY platform, three SNPs in TGFBR1 gene were genotyped in 356 newly diagnosed patients with histologically confirmed primary oral cancer. Demographic and clinical information of all cases were obtained from face-to-face interviews and electronic medical records, and telephone interviews were carried out every 6 months to timely gain follow-up data. Univariate and multivariate Cox proportional hazards model were used to assess the association between the polymorphisms of tagging loci and DSS of oral cancer.Results: TGFBR1 rs33438 polymorphism was protective against death of oral cancer in codominant (AG vs AA: HR = 0.55, 95% CI = 0.35-0.88) and dominant (GG + AG vs AA: HR = 0.57, 95% CI = 0.38-0.87) models. Moreover, better DSS was particularly significant in radiotherapy patients who carrying GG + AG genotype. There also existed a positive multiplicative interaction on DSS between the polymorphism of TGFBR1 rs334348 and radiotherapy (P = .001). Not any associations between TGFBR1 rs334354 or rs3739798 polymorphism and DSS were observed.Conclusions: This preliminary prospective study suggests that polymorphism of TGFBR1 rs334348 may act as a potentially independent factor and novel genetic biomarker to predict oral cancer DSS especially for patients with radiotherapy. A much more extensive investigation will need to confirm our findings. [ABSTRACT FROM AUTHOR]

Transforming growth factor‐β (TGF‐β) is a multifunctional cytokine that is known to modulate various aspects of endothelial cell (EC) biology. Retinal pigment epithelium (RPE) is important for regulating angiogenesis of choriocapillaris and one of the main cell sources of TGF‐β secretion, particularly TGF‐β2. However, it is largely unclear whether and how TGF‐β2 affects angiogenic responses of ECs. In the current study, we demonstrated that TGF‐β2 reduces vascular endothelial growth factor receptor‐2 (VEGFR‐2) expression in ECs and thereby inhibits vascular endothelial growth factor (VEGF) signaling and VEGF‐induced angiogenic responses such as EC migration and tube formation. We also demonstrated that the reduction of VEGFR‐2 expression by TGF‐β2 is due to the suppression of JNK signaling. In coculture of RPE cells and ECs, RPE cells decreased VEGFR‐2 levels in ECs and EC migration. In addition, we showed that TGF‐β2 derived from RPE cells is involved in the reduction of VEGFR‐2 expression and inhibition of EC migration. These results suggest that TGF‐β2 plays an important role in inhibiting the angiogenic responses of ECs during the interaction between RPE cells and ECs and that angiogenic responses of ECs may be amplified by a decrease in TGF‐β2 expression in RPE cells under pathologic conditions. We demonstrated that transforming growth factor‐β2 (TGF‐β2) reduces vascular endothelial growth factor receptor‐2 (VEGFR‐2) expression in endothelial cells (ECs) and thereby inhibits vascular endothelial growth factor signaling. In coculture of retinal pigment epithelium (RPE) cells and ECs, RPE cells decreased VEGFR‐2 levels in ECs and EC migration. We showed that TGF‐β2 derived from RPE cells is involved in the reduction of VEGFR‐2 expression and inhibition of EC migration. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we aimed at investigating effects of lncRNA ADAMTS9‐AS2 on lung cancer progression through regulating miR‐223‐3p and TGFBR3 expressions. Expressions of ADAMTS9‐AS2 in lung cancer tissues and cell lines were determined by reverse transcriptase polymerase chain reaction (qRT‐PCR). TargetScan and miRcode were used to predict the targeting relationships, respectively. The luciferase reporter system was used to verify that the relationship among ADAMTS9‐AS2, TGFBR3 and miR‐223‐3p. Western blot assay tested the protein level changes in TGFBR3. Cell proliferation was determined by CCK‐8 assay. Cell cycle and cell apoptosis were detected by flow cytometry assay, and migration and invasion were determined by transwell assay. Tumor xenograft model was developed to study the influence of ADAMTS9‐AS2 on tumor growth in vivo. qRT‐PCR results demonstrated that lncADAMTS9‐AS2 was lowly expressed in lung cancer tissues. High expression of ADAMTS9‐AS2 in lung cancer cells significantly reduced proliferation ability and inhibited migration, as well as elevating their apoptosis rate. In vivo assay found that ADAMTS9‐AS2 suppressed the lung tumor growth. Bioinformatics predicted that miR‐223‐3p bound directly to the ADAMTS9‐AS2 and TGFBR3, which was later confirmed by luciferase reporter system. ADAMTS9‐AS2 transfection increased TGFBR3 mRNA and protein expressions in lung cancer cells, but miR‐223‐3p transfection significantly decreased them. Besides, our results showed that miR‐223‐3p induced cellular apoptosis while TGFBR3 group showed the complete opposite effect. It was proved that ADAMTS9‐AS2 and TGFBR3 were the direct genes of miR‐223‐3p. MiR‐223‐3p promotes proliferation, migration and invasion of lung cancer cells by targeting TGFBR3. Therefore, ADAMTS9‐AS2, miR‐223‐3p and TGFBR3 may provide potential targets for the treatment of lung cancer patients. © 2018 IUBMB Life, 70(6):536–546, 2018 [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM). However, the exact mechanism is not clearly understood. In this study, our results showed that 24 h urinary protein, kidney index, and glomerular area were decreased, while creatinine clearance ratio was increased in DN rats when the rats were treated with NAR 50 mg/d for 6 weeks. Mesangial cell (MMCs) proliferation was inhibited in the NAR group by 3,(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and the cell cycle analysis showed that cells stayed in G2 phase in NAR group. And NAR treatment attenuated the deposition of ECM in DN rats and MMCs. Moreover, our data showed that let-7a was downexpressed in both DN rats and MMCs under high glucose condition. Surprisingly, NAR affected the expressions of Col4 and FN through upregulating let-7a in MMCs. In addition, we found that let-7a negatively regulated the expression of transforming growth factor-β1 receptor 1 (TGFBR1), and TGFBR1 was required for the let-7a-mediated downregulation of TGF-β1/smad signaling. Interestingly, NAR inhibited TGF-β1/smads signaling activation by upregulating let-7a. Therefore, our findings indicated that NAR ameliorated kidney injury by regulating let-7a/TGFBR1 signaling. [ABSTRACT FROM AUTHOR]

The structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix ( ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three-dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down-regulates TGF-β type II receptor (Tβ RII) and thus impairs TGF-β/Smad signaling pathway. Both Tβ RII mRNA and protein were decreased, resulting in 90% loss of TGF-β binding to fibroblasts. Down-regulation of Tβ RII was associated with significantly decreased phosphorylation, DNA-binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3-regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor ( CTGF/ CCN2). Restoration of Tβ RII significantly increased TGF-β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of Tβ RII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of Tβ RII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging. [ABSTRACT FROM AUTHOR]

We present a 37-year-old woman who underwent extensive facial surgery for removal of multiple eruptive squamous cell carcinoma ( SCC)-like lesions resembling invasive SCC histologically. The patient's mother had undergone numerous surgical procedures and radiotherapy for facial SCC. A review of the histology and immunohistochemistry for DNA mismatch repair proteins excluded Muir- Torre syndrome. A diagnosis of Ferguson- Smith disease (or multiple self-healing squamous epitheliomata) was suspected. Blood was sent for DNA analysis. Twelve months later, mutations of the TGFBR1 gene were demonstrated in 18 families (67 individuals) with Ferguson- Smith disease; among whom our patient and her mother were family 11. [ABSTRACT FROM AUTHOR]