scholarly journals Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 821
Author(s):  
Wanglong Qiu ◽  
Chia-Yu Kuo ◽  
Yu Tian ◽  
Gloria H. Su
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Critical Role ◽  
Genetic Mutations ◽  
Cancer Genetic ◽  
Dual Roles ◽  
Activin Signaling ◽  
Physiological Processes ◽  
Cancer Types ◽  
Related Proteins

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.

scholarly journals Circadian Clock Protein CRY Controls B-Cell Intrinsic Tolerance

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1029-1029 ◽  
Author(s):  
Qi Cao ◽  
Xuan Zhao ◽  
Sigal Gery ◽  
Zhengshan Chen ◽  
Ruishu Deng ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Signaling Pathway ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Adaptive Immune System ◽  
Cell Tolerance ◽  
Double Knockout ◽  
B Cell Tolerance ◽  
Physiological Processes

Abstract The circadian system regulates numerous physiological processes including adaptive immune system. Here we show that mice deficient for the circadian genes Cry1 and Cry2, (Cry double knockout [DKO]) display an autoimmune phenotype including higher serum IgG concentration than wild type (WT) mice, presence of serum anti-nuclear antibodies, precipitation of IgG, IgM and complement 3 (C3) in glomeruli, and massive infiltrations of leukocytes into the lung and kidney. A large panel of autoantigens demonstrated that the sera of the Cry DKO mice but not the WT mice, had autoantibodies covering most of the specificities reported to be present in patients with SLE, rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren's syndrome and other autoimmune disorders. Taken together, lost of the CRY circadian protein leds to severe autoimmunity. Furthermore, flow cytometry analysis of lymphoid organs showed lower pre-B cell numbers and higher mature recirculating B cells in the bone marrow as well as increased number of B2 B cells in the peritoneal cavity of Cry DKO mice. The BCR-proximal signaling pathway plays a critical role in peripheral B cell tolerance and activation. Activation of splenic B cells from the Cry DKO mice elicited markedly enhanced and prolonged tyrosine phosphorylation of cellular proteins compared to WT mice, suggesting that a very active BCR signaling pathway may contribute to impaired B cell tolerance in the Cry DKO mice. In summary, our results suggest that B cell development, as well as the intrinsic checkpoints of immune tolerance, are under direct circadian control. Disclosures No relevant conflicts of interest to declare.

scholarly journals Overexpressed WDR3 Induces the Activation of Hippo Pathway by Interacting with GATA4 in Pancreatic Cancer

2020 ◽  
Author(s):  
Wenjie Su ◽  
Shikai Zhu ◽  
Kai Chen ◽  
Hongji Yang ◽  
Mingwu Tian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Human Cancer ◽  
Critical Role ◽  
Biological Role ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Pancreatic Cancer Cells ◽  
Independent Functions

Abstract Background: WD repeat domain 3 (WDR3) is involved in a variety of cellular processes including gene regulation, cell cycle progression, signal transduction and apoptosis. However, the biological role of WDR3 in pancreatic cancer and the associated mechanism remains unclear. We seek to explore the immune-independent functions and relevant mechanism for WDR3 in pancreatic cancer.Methods: The GEPIA web tool was searched, and IHC assays were conducted to determine the mRNA and protein expression levels of WDR3 in pancreatic cancer patients. MTS, colony formation, and transwell assays were conducted to determine the biological role of WDR3 in human cancer. Western blot analysis, RT-qPCR, and immunohistochemistry were used to detect the expression of specific genes. An immunoprecipitation assay was used to explore protein-protein interactions.Results: Our study proved that overexpressed WDR3 was correlated with poor survival in pancreatic cancer and that WDR3 silencing significantly inhibited the proliferation, invasion and tumor growth of pancreatic cancer. Furthermore, WDR3 activated the Hippo signaling pathway by inducing yes association protein 1 (YAP1) expression, and the combination of WDR3 silencing and administration of the YAP1 inhibitor TED-347 had a synergistic inhibitory effect on the progression of pancreatic cancer. Finally, the upregulation of YAP1 expression induced by WDR3 was dependent on an interaction with GATA binding protein 4 (GATA4), the transcription factor of YAP1, in pancreatic cancer cells.Conclusions: We identified a novel mechanism by which WDR3 plays a critical role in promoting pancreatic cancer progression by activating the Hippo signaling pathway through an interaction with GATA4. Therefore, WDR3 is potentially a therapeutic target for pancreatic cancer treatment.

ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/β-catenin signaling pathway

2019 ◽  
Vol 40 (11) ◽  
pp. 1405-1414 ◽  
Author(s):  
Yehua Shen ◽  
Litao Xu ◽  
Zhouyu Ning ◽  
Luming Liu ◽  
Junhua Lin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Migration ◽  
Signaling Pathway ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Histone Deacetylase 2 ◽  
Pancreatic Cancer Cells

Abstract β-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway that mediates multiple cellular processes, such as cell migration and invasion. HDAC2 (histone deacetylase 2), a deacetylase that maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where β-catenin is bound, negatively regulating β-catenin activation. However, the regulation of HDAC2/β-catenin pathway remains unclear. Here, we report ARHGAP4 as a new regulator of the β-catenin pathway that regulates cell invasion and migration of pancreatic cancer as well as the downstream effector MMP2 and MMP9 expression in vitro. Mechanistically, ARHGAP4 interacts with and ubiquitinates HDAC2, which in turn inhibits β-catenin activation. Furthermore, treatment of CAY10683, an HDAC2 inhibitor, and XAV939, a Wnt/β-catenin pathway inhibitor, attenuated the effects of ARHGAP4 silencing on pancreatic cancer cells. Overall, our findings establish ARHGAP4 as a novel regulator of HDAC2/β-catenin pathway with a critical role in tumorigenesis.

scholarly journals Overexpressed WDR3 induces the activation of Hippo pathway by interacting with GATA4 in pancreatic cancer

2021 ◽  
Author(s):  
Wenjie Su ◽  
Shikai Zhu ◽  
Kai Chen ◽  
Hongji Yang ◽  
Mingwu Tian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Biological Role ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Pancreatic Cancer Cells ◽  
Independent Functions

Abstract Background: WD repeat domain 3 (WDR3) is involved in a variety of cellular processes including gene regulation, cell cycle progression, signal transduction and apoptosis. However, the biological role of WDR3 in pancreatic cancer and the associated mechanism remains unclear. We seek to explore the immune-independent functions and relevant mechanism for WDR3 in pancreatic cancer.Methods: The GEPIA web tool was searched, and IHC assays were conducted to determine the mRNA and protein expression levels of WDR3 in pancreatic cancer patients. MTS, colony formation, and transwell assays were conducted to determine the biological role of WDR3 in human cancer. Western blot analysis, RT-qPCR, and immunohistochemistry were used to detect the expression of specific genes. An immunoprecipitation assay was used to explore protein-protein interactions.Results: Our study proved that overexpressed WDR3 was correlated with poor survival in pancreatic cancer and that WDR3 silencing significantly inhibited the proliferation, invasion, and tumor growth of pancreatic cancer. Furthermore, WDR3 activated the Hippo signaling pathway by inducing yes association protein 1 (YAP1) expression, and the combination of WDR3 silencing and administration of the YAP1 inhibitor TED-347 had a synergistic inhibitory effect on the progression of pancreatic cancer. Finally, the upregulation of YAP1 expression induced by WDR3 was dependent on an interaction with GATA binding protein 4 (GATA4), the transcription factor of YAP1, which interaction induced the nuclear translocation of GATA4 in pancreatic cancer cells.Conclusions: We identified a novel mechanism by which WDR3 plays a critical role in promoting pancreatic cancer progression by activating the Hippo signaling pathway through the interaction with GATA4. Therefore, WDR3 is potentially a therapeutic target for pancreatic cancer treatment.

scholarly journals Overexpressed WDR3 induces the activation of Hippo pathway by interacting with GATA4 in pancreatic cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wenjie Su ◽  
Shikai Zhu ◽  
Kai Chen ◽  
Hongji Yang ◽  
Mingwu Tian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Critical Role ◽  
Biological Role ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Pancreatic Cancer Cells ◽  
Independent Functions

Abstract Background WD repeat domain 3 (WDR3) is involved in a variety of cellular processes including gene regulation, cell cycle progression, signal transduction and apoptosis. However, the biological role of WDR3 in pancreatic cancer and the associated mechanism remains unclear. We seek to explore the immune-independent functions and relevant mechanism for WDR3 in pancreatic cancer. Methods The GEPIA web tool was searched, and IHC assays were conducted to determine the mRNA and protein expression levels of WDR3 in pancreatic cancer patients. MTS, colony formation, and transwell assays were conducted to determine the biological role of WDR3 in human cancer. Western blot analysis, RT-qPCR, and immunohistochemistry were used to detect the expression of specific genes. An immunoprecipitation assay was used to explore protein-protein interactions. Results Our study proved that overexpressed WDR3 was correlated with poor survival in pancreatic cancer and that WDR3 silencing significantly inhibited the proliferation, invasion, and tumor growth of pancreatic cancer. Furthermore, WDR3 activated the Hippo signaling pathway by inducing yes association protein 1 (YAP1) expression, and the combination of WDR3 silencing and administration of the YAP1 inhibitor TED-347 had a synergistic inhibitory effect on the progression of pancreatic cancer. Finally, the upregulation of YAP1 expression induced by WDR3 was dependent on an interaction with GATA binding protein 4 (GATA4), the transcription factor of YAP1, which interaction induced the nuclear translocation of GATA4 in pancreatic cancer cells. Conclusions We identified a novel mechanism by which WDR3 plays a critical role in promoting pancreatic cancer progression by activating the Hippo signaling pathway through the interaction with GATA4. Therefore, WDR3 is potentially a therapeutic target for pancreatic cancer treatment.

Targeting the Akt/PI3K Signaling Pathway as a Potential Therapeutic Strategy for the Treatment of Pancreatic Cancer

2017 ◽  
Vol 24 (13) ◽  
Author(s):  
Safieh Ebrahimi ◽  
Mina Hosseini ◽  
Soodabeh Shahidsales ◽  
Mina Maftouh ◽  
Gordon A. Ferns ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Pi3k Signaling ◽  
Pi3k Signaling Pathway

scholarly journals CHN1 promotes epithelial–mesenchymal transition via the Akt/GSK-3β/Snail pathway in cervical carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haoqi Zhao ◽  
Lan Wang ◽  
Shufang Wang ◽  
Xihua Chen ◽  
Min Liang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lymph Node ◽  
Signaling Pathway ◽  
Cervical Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Xenograft Tumor ◽  
Mesenchymal Transition ◽  
Gsk 3Β ◽  
Related Proteins

Abstract Background Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial–mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified. Methods The expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting. Results CHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002. Conclusion These results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.

scholarly journals PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8298
Author(s):  
Hugo Christian Monroy-Ramirez ◽  
Marina Galicia-Moreno ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Arturo Santos ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Metabolic Regulation ◽  
Structural Changes ◽  
Critical Role ◽  
The Body ◽  
Molecular Characteristics ◽  
Signal Pathways ◽  
Virus Infections ◽  
Physiological Processes ◽  
Hepatic Level

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

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