scholarly journals The Dual Role of STAT1 in Ovarian Cancer: Insight Into Molecular Mechanisms and Application Potentials

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin Li ◽  
Fanchen Wang ◽  
Xiaolin Xu ◽  
Jinguo Zhang ◽  
Guoxiong Xu
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Transforming Growth Factor Β ◽  
Janus Kinase ◽  
Atypical Symptoms ◽  
Stat1 Signaling

The signal transducer and activator of transcription 1 (STAT1) is a transducer protein and acts as a transcription factor but its role in ovarian cancer (OC) is not completely understood. Practically, there are two-faced effects of STAT1 on tumorigenesis in different kinds of cancers. Existing evidence reveals that STAT1 has both tumor-suppressing and tumor-promoting functions involved in angiogenesis, cell proliferation, migration, invasion, apoptosis, drug resistance, stemness, and immune responses mainly through interacting and regulating target genes at multiple levels. The canonical STAT1 signaling pathway shows that STAT1 is phosphorylated and activated by the receptor-activated kinases such as Janus kinase in response to interferon stimulation. The STAT1 signaling can also be crosstalk with other signaling such as transforming growth factor-β signaling involved in cancer cell behavior. OC is often diagnosed at an advanced stage due to symptomless or atypical symptoms and the lack of effective detection at an early stage. Furthermore, patients with OC often develop chemoresistance and recurrence. This review focuses on the multi-faced role of STAT1 and highlights the molecular mechanisms and biological functions of STAT1 in OC.

scholarly journals The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

2021 ◽  
pp. 1-8
Author(s):  
Mahmood Tavakkoli ◽  
Saeed Aali ◽  
Borzoo Khaledifar ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Angiotensin Receptor Blockers ◽  
Surgical Techniques ◽  
Treatment Strategies ◽  
Transforming Growth Factor Β

<b><i>Background:</i></b> Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. <b><i>Summary:</i></b> Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. <b><i>Key Message:</i></b> The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

scholarly journals Transforming Growth Factor β-Mediated Transcriptional Repression of c-myc Is Dependent on Direct Binding of Smad3 to a Novel Repressive Smad Binding Element

2004 ◽  
Vol 24 (6) ◽  
pp. 2546-2559 ◽  
Author(s):  
Joshua P. Frederick ◽  
Nicole T. Liberati ◽  
David S. Waddell ◽  
Yigong Shi ◽  
Xiao-Fan Wang
Keyword(s):  
Growth Factor ◽  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Specific Cell ◽  
Smad Proteins ◽  
Smad Binding Element

ABSTRACT Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor β (TGF-β) signal. The ability of the Smads to act as transcriptional activators via TGF-β-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-β target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-β-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-β, and this repression is required for the manifestation of the TGF-β cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-β-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-β inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

pVHL-mediated SMAD3 degradation suppresses TGF-β signaling

2021 ◽  
Vol 221 (1) ◽  
Author(s):  
Jun Zhou ◽  
Yasamin Dabiri ◽  
Rodrigo A. Gama-Brambila ◽  
Shahrouz Ghafoory ◽  
Mukaddes Altinbay ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Wing Development ◽  
Dynamic Regulation ◽  
Drosophila Wing ◽  
Wing Growth ◽  
Expression And Activity

Transforming growth factor β (TGF-β) signaling plays a fundamental role in metazoan development and tissue homeostasis. However, the molecular mechanisms concerning the ubiquitin-related dynamic regulation of TGF-β signaling are not thoroughly understood. Using a combination of proteomics and an siRNA screen, we identify pVHL as an E3 ligase for SMAD3 ubiquitination. We show that pVHL directly interacts with conserved lysine and proline residues in the MH2 domain of SMAD3, triggering degradation. As a result, the level of pVHL expression negatively correlates with the expression and activity of SMAD3 in cells, Drosophila wing, and patient tissues. In Drosophila, loss of pVHL leads to the up-regulation of TGF-β targets visible in a downward wing blade phenotype, which is rescued by inhibition of SMAD activity. Drosophila pVHL expression exhibited ectopic veinlets and reduced wing growth in a similar manner as upon loss of TGF-β/SMAD signaling. Thus, our study demonstrates a conserved role of pVHL in the regulation of TGF-β/SMAD3 signaling in human cells and Drosophila wing development.

scholarly journals The Role of MicroRNAs in Ovarian Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yasuto Kinose ◽  
Kenjiro Sawada ◽  
Koji Nakamura ◽  
Tadashi Kimura
Keyword(s):  
Ovarian Cancer ◽  
Tumor Suppressor Genes ◽  
Target Genes ◽  
Early Stage ◽  
Noncoding Rnas ◽  
Circulating Micrornas ◽  
Gynecological Tumors ◽  
Prevention And Treatment ◽  
Prognostic And Predictive Markers

Ovarian cancer is the most lethal of malignant gynecological tumors. Its lethality may be due to difficulties in detecting it at an early stage and lack of effective treatments for patients with an advanced or recurrent status. Therefore, there is a strong need for prognostic and predictive markers to diagnose it early and to help optimize and personalize treatment. MicroRNAs are noncoding RNAs that regulate target genes posttranscriptionally. They are involved in carcinogenesis, cell cycle, apoptosis, proliferation, invasion, metastasis, and chemoresistance. The dysregulation of microRNAs is involved in the initiation and progression of human cancers including ovarian cancer, and strong evidence that microRNAs can act as oncogenes or tumor suppressor genes has emerged. Several microRNA signatures that are unique to ovarian cancer have been proposed, and serum-circulating microRNAs have the potential to be useful diagnostic and prognostic biomarkers. Various microRNAs such as those in the miR-200 family, the miR-199/214 cluster, or the let-7 paralogs have potential as therapeutic targets for disseminated or chemoresistant ovarian tumors. Although many obstacles need to be overcome, microRNA therapy could be a powerful tool for ovarian cancer prevention and treatment. In this review, we discuss the emerging roles of microRNAs in various aspects of ovarian cancer.

Abstract 635: Role of Micro RNA-21 in Venous Neointimal Hyperplasia (VNH): Implications in Targeting MiR-21 For VNH Treatment

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Sreenivasulu Kialri ◽  
Binxia Yang ◽  
Deborah McCall ◽  
Sanjay Misra
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Neointimal Hyperplasia ◽  
Micro Rna ◽  
Coronary Artery Bypass Grafts ◽  
Myofibroblast Differentiation ◽  
Down Regulation ◽  
Tgf Β1

The exact molecular mechanisms involved in hemodialysis arteriovenous fistula (AVF) failure caused by venous neointimal hyperplasia (VNH) are not clear. It has been observed that there is an accumulation of extracellular matrix and up regulation of pro-fibrotic genes accompanied with presence of fibroblasts, smooth muscle cells, and inflammatory cells in the stenotic veins. Previous studies have demonstrated that adventitial and medial fibroblasts have a pivotal role(s) in VNH formation. MicroRNA-21 (miR-21) contributes to fibroblast to myofibroblast differentiation and dysregulation of miR-21 plays a pathological role in failure of coronary artery bypass grafts. The aim of the present study was to determine the role of miR-21 in VNH associated with AVF. We assessed miR-21 expression using qRT-PCR in the outflow veins of AVFs compared to control (contralateral jugular veins) veins in the C57BL/6J mice with chronic kidney disease (CKD). MiR-21 expression was upregulated accompanied with down regulation of miR-21 target genes; PPAR-α, PTEN and TIMP-3. In addition, gene expression of fibroblast specific protein (FSP) -1, TGF (transforming growth factor) -β1, matrix metalloproteinases (MMP)-2, -9, collagen-I, and IV were significantly increased at day 7 after AVF creation. Immunohistochemistry revealed that there was a significant increase in proliferating cell index (Ki-67) and fibroblast index (FSP-1) in the outflow veins of AVFs. Hypoxia has been shown to increase fibroblast to myofibroblast differentiation and this is predicted to be an early step in VNH formation. Therefore we assessed miR-21 expression in hypoxic (1%O 2 ) mouse pulmonary vein fibroblasts compared to normoxic cells in vitro and it was found that miR-21and TGF-β1 significantly elevated with down regulation of miR-21 target genes PTEN and TIMP-3. Furthermore, miR-21 knockdown in hypoxic fibroblasts attenuated TGF-β1 expression with a significant upregulation of genes targeted by miR-21 compared to controls. Together these results indicate that upregulation of miR-21 expression may result in fibroblast to myofibroblast differentiation resulting in VNH formation.

scholarly journals Suppressive Role of MicroRNA-148a in Cell Proliferation and Invasion in Ovarian Cancer Through Targeting Transforming Growth Factor-β-Induced 2

2016 ◽  
Vol 24 (5) ◽  
pp. 353-360 ◽  
Author(s):  
Min Zhao ◽  
Zhiying Su ◽  
Shiyang Zhang ◽  
Liangjin Zhuang ◽  
Yudi Xie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Underlying Mechanism ◽  
Protein Levels ◽  
Ovarian Epithelial Cells ◽  
Proliferation And Invasion

Ovarian cancer (OC) is one of the most common gynecological malignancies. MicroRNAs (miRs) play a crucial role in the development and progression of OC, but the underlying mechanism remains largely unclear. Our study investigated the regulatory role of miR-148a in OC cell proliferation and invasion. We found that miR-148a was significantly downregulated in OC tissues compared to their matched adjacent nontumor tissues. In addition, its expression was also reduced in OC cell lines (SKOV3, ES-2, OVCAR, and A2780) compared to normal ovarian epithelial cells. Overexpression of miR-148a caused a significant decrease in OC cell proliferation and invasion, as well as reduced MMP9 protein levels. Transforming growth factor-β-induced 2 (TGFI2) was further identified as a target gene of miR-148a, and its protein expression was downregulated in OC cells after miR-148a overexpression. Restoration of TGFI2 attenuated the suppressive effects of miR-148a on OC cell proliferation and invasion. Moreover, we found that TGFI2 was remarkably upregulated in OC tissues when compared with their matched adjacent nontumor tissues, and observed a reverse correlation between miR-148a and TGFI2 expression in OC tissues. On the basis of these findings, we suggest that miR-148a inhibits OC cell proliferation and invasion partly through inhibition of TGFI2. Therefore, our study highlights the importance of the miR-148a/TGFI2 axis in the malignant progression of OC.

scholarly journals Knockdown of Latent Transforming Growth Factor-β (TGF-β)-Binding Protein 2 (LTBP2) Inhibits Invasion and Tumorigenesis in Thyroid Carcinoma Cells

2017 ◽  
Vol 25 (4) ◽  
pp. 503-510 ◽  
Author(s):  
Fuqiang Wan ◽  
Li Peng ◽  
ChaoYu Zhu ◽  
XinFa Zhang ◽  
FangWen Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Thyroid Carcinoma ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Vital Role ◽  
Carcinoma Cells ◽  
Human Thyroid

Latent transforming growth factor-β (TGF-β)-binding protein 2 (LTBP2) is one of four proteins in the LTBP family of proteins (LTBP1‐4) and was shown to play a vital role in tumorigenesis. However, little is known regarding the functional role of LTBP2 in thyroid carcinoma. Therefore, the current study aimed to evaluate the effect of LTBP2 expression on the proliferation, invasion, and tumorigenesis in thyroid carcinoma cells and to explore the molecular mechanism of LTBP2 in tumor progression. Our results showed that the expression of LTBP2 is upregulated in human thyroid carcinoma and cell lines. Knockdown of LTBP2 inhibits the proliferation, invasion, and EMT phenotype in thyroid carcinoma cells. Furthermore, knockdown of LTBP2 attenuates thyroid carcinoma growth in nude mice. Finally, knockdown of LTBP2 inhibits activation of the PI3K/Akt pathway in thyroid carcinoma cells. In summary, the present study has provided further evidence that knockdown of LTBP2 inhibits invasion and tumorigenesis in thyroid carcinoma cells. Our findings may help to further elucidate the molecular mechanisms underlying thyroid carcinoma progression and provide candidate targets for the prevention and treatment of thyroid carcinoma.

scholarly journals Possible role of transforming growth factor β as a marker cytokine of type 3 T-helpers in atopic dermatitis pathogenesis

2004 ◽  
Vol 3 (3) ◽  
pp. 27-31
Author(s):  
N. A. Pronina ◽  
V. S. Sviridova ◽  
A. A. Denisov ◽  
V. V. Klimov ◽  
Ye. N. Kologrivova
Keyword(s):  
Atopic Dermatitis ◽  
Biological Activity ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Allergic Inflammation ◽  
Transforming Growth Factor Β ◽  
Cell Populations ◽  
Type 3

The role of transforming growth factor β (TGF-β) in atopic dermatitis pathogenesis is discussed basing on the analysis of existing data of cellular and molecular mechanisms of allergic inflammation. Up-to date data of the main T-helper (T-h) lymphocyte subpopulations including Tx1, Tx2, Tx3 has been presented. Functions of regulatory T-cell populations and produced cytokines have been described. The main attention has been accented on the TGF-β structure and biological activity as a main Tx3 cytokine. The current information of TGF-β influence on different cell populations and its biological activity realization mechanism is thoroughly discussed. Information relating to the mechanism of cytokine regulation during atopic dermatitis has been summarized. A deep analysis of possible participation of TGF-β in disbalance formation on Tx1 and Tx2 levels, in disturbances of histological derma structure and allergic inflammation timing has been made.

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