scholarly journals MPC1 Deficiency Promotes CRC Liver Metastasis via Facilitating Nuclear Translocation of β-Catenin

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Guang-Ang Tian ◽  
Chun-Jie Xu ◽  
Kai-Xia Zhou ◽  
Zhi-Gang Zhang ◽  
Jian-Ren Gu ◽  
...  
Keyword(s):  
Tumor Metastasis ◽  
Nuclear Translocation ◽  
Tca Cycle ◽  
Mitochondrial Pyruvate Carrier ◽  
Human Sample ◽  
Metastatic Capacity ◽  
Tcga Dataset

Accumulating evidence has pointed out that metastasis is the leading cause of death in several malignant tumor, including CRC. During CRC, metastatic capacity is closely correlated with reprogrammed energy metabolism. Mitochondrial Pyruvate Carrier 1 (MPC1), as the carrier of transporting pyruvate into mitochondria, linked the glycolysis and TCA cycle, which would affect the energy production. However, the specific role of MPC1 on tumor metastasis in CRC remains unexplored. Here, by data mining of genes involved in pyruvate metabolism using the TCGA dataset, we found that MPC1 was significantly downregulated in CRC compared to nontumor tissues. Similar MPC1 expression pattern was also found in multiple GEO datasets. IHC staining in both human sample and AOM/DSS induced mouse CRC model revealed significant downregulation of MPC1. What is more, we found that MPC1 expression was gradually decreased in normal tissue, primary CRC, and metastasis CRC. Additionally, poor prognosis emerged in the MPC1 low expression patients, especially in patients with metastasis. Following, functional tests showed that MPC1 overexpression inhibited the motility of CRC cells in vitro and MPC1 silencing enhanced liver metastases in vivo. Furthermore, we uncovered that decreased MPC1 activated the Wnt/β-catenin pathway by promoting nuclear translocation of β-catenin to mediate the expression of MMP7, E-cadherin, Snail1, and myc. Collectively, our data suggest that MPC1 has the potential to be served as a promising biomarker for diagnosis and a therapeutic target in CRC.

scholarly journals Phaseolin Attenuates Lipopolysaccharide-Induced Inflammation in RAW 264.7 Cells and Zebrafish

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 420
Author(s):  
Su-Jung Hwang ◽  
Ye-Seul Song ◽  
Hyo-Jong Lee
Keyword(s):  
Nitric Oxide ◽  
Nuclear Translocation ◽  
Raw 264.7 Cells ◽  
Network Pharmacology ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Bioactive Constituents

Kushen (Radix Sophorae flavescentis) is used to treat ulcerative colitis, tumors, and pruritus. Recently, phaseolin, formononetin, matrine, luteolin, and quercetin, through a network pharmacology approach, were tentatively identified as five bioactive constituents responsible for the anti-inflammatory effects of S. flavescentis. However, the role of phaseolin (one of the primary components of S. flavescentis) in the direct regulation of inflammation and inflammatory processes is not well known. In this study, the beneficial role of phaseolin against inflammation was explored in lipopolysaccharide (LPS)-induced inflammation models of RAW 264.7 macrophages and zebrafish larvae. Phaseolin inhibited LPS-mediated production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), without affecting cell viability. In addition, phaseolin suppressed pro-inflammatory mediators such as cyclooxygenase 2 (COX-2), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in a dose-dependent manner. Furthermore, phaseolin reduced matrix metalloproteinase (MMP) activity as well as macrophage adhesion in vitro and the recruitment of leukocytes in vivo by downregulating Ninjurin 1 (Ninj1), an adhesion molecule. Finally, phaseolin inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB). In view of the above, our results suggest that phaseolin could be a potential therapeutic candidate for the management of inflammation.

scholarly journals Phosphorylation of Serine 11 and Serine 92 as New Positive Regulators of Human Snail1 Function: Potential Involvement of Casein Kinase-2 and the cAMP-activated Kinase Protein Kinase A

2010 ◽  
Vol 21 (2) ◽  
pp. 244-253 ◽  
Author(s):  
Matthew Reid MacPherson ◽  
Patricia Molina ◽  
Serhiy Souchelnytskyi ◽  
Christer Wernstedt ◽  
Jorge Martin-Pérez ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Tumor Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cop9 Signalosome ◽  
Mesenchymal Transition ◽  
Depth Analysis ◽  
Positive Regulators

Snail1 is a major factor for epithelial-mesenchymal transition (EMT), an important event in tumor metastasis and in other pathologies. Snail1 is tightly regulated at transcriptional and posttranscriptional levels. Control of Snail1 protein stability and nuclear export by GSK3β phosphorylation is important for Snail1 functionality. Stabilization mechanisms independent of GSK3β have also been reported, including interaction with LOXL2 or regulation of the COP9 signalosome by inflammatory signals. To get further insights into the role of Snail1 phosphorylation, we have performed an in-depth analysis of in vivo human Snail1 phosphorylation combined with mutational studies. We identify new phosphorylation sites at serines 11, 82, and 92 and confirmed previously suggested phosphorylations at serine 104 and 107. Serines 11 and 92 participate in the control of Snail1 stability and positively regulate Snail1 repressive function and its interaction with mSin3A corepressor. Furthermore, serines 11 and 92 are required for Snail1-mediated EMT and cell viability, respectively. PKA and CK2 have been characterized as the main kinases responsible for in vitro Snail1 phosphorylation at serine 11 and 92, respectively. These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality.

scholarly journals Inhibition of Calcineurin/NFAT Signaling Blocks Oncogenic H-Ras Induced Autophagy in Primary Human Keratinocytes

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuangshuang Wang ◽  
Hua Qian ◽  
Liwei Zhang ◽  
Panpan Liu ◽  
Dexuan Zhuang ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Human Keratinocytes ◽  
Primary Human Keratinocytes ◽  
Activated T Cells ◽  
Ras Pathway ◽  
Ras Family ◽  
Interfering Rna

Mutations of H-Ras, a member of the RAS family, are preferentially found in cutaneous squamous cell carcinomas (SCCs). H-Ras has been reported to induce autophagy, which plays an essential role in tissue homeostasis in multiple types of cancer cells and in fibroblasts, however, the potential role of H-Ras in regulating autophagy in human keratinocytes has not been reported. In this study, we found that the stable expression of the G12V mutant of H-RAS (H-RasG12V) induced autophagy in human keratinocytes, and interestingly, the induction of autophagy was strongly blocked by inhibiting the calcineurin/nuclear factor of activated T cells (NFAT) pathway with either a calcineurin inhibitor (Cyclosporin A) or a NFAT inhibitor (VIVIT), or by the small interfering RNA (siRNA) mediated knockdown of calcineurin B1 or NFATc1 in vitro, as well as in vivo. To characterize the role of the calcineurin/NFAT pathway in H-Ras induced autophagy, we found that H-RasG12V promoted the nuclear translocation of NFATc1, an indication of the activation of the calcineurin/NFAT pathway, in human keratinocytes. However, activation of NFATc1 either by the forced expression of NFATc1 or by treatment with phenformin, an AMPK activator, did not increase the formation of autophagy in human keratinocytes. Further study revealed that inhibiting the calcineurin/NFAT pathway actually suppressed H-Ras expression in H-RasG12V overexpressing cells. Finally, chromatin immunoprecipitation (ChIP) assays showed that NFATc1 potentially binds the promoter region of H-Ras and the binding efficiency was significantly enhanced by the overexpression of H-RasG12V, which was abolished by treatment with the calcineurin/NFAT pathway inhibitors cyclosporine A (CsA) or VIVIT. Taking these data together, the present study demonstrates that the calcineurin/NFAT signaling pathway controls H-Ras expression and interacts with the H-Ras pathway, involving the regulation of H-Ras induced autophagy in human keratinocytes.

scholarly journals GPR87 Promotes Metastasis through the AKT-eNOS-NO Axis in Lung Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 19
Author(s):  
Hye-Mi Ahn ◽  
Eun-Young Choi ◽  
Youn-Jae Kim
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
The Public ◽  
Adenocarcinoma Cells ◽  
No Signaling ◽  
Tcga Dataset ◽  
Patient Prognosis

Lung adenocarcinoma is one of the leading causes of cancer-related deaths. Despite the availability of advanced anticancer drugs for lung cancer treatment, the prognosis of patients still remains poor. There is a need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. The functional experiments in vitro and in vivo were performed to evaluate the role of GPR87 expression on lung adenocarcinoma metastasis. The public lung adenocarcinoma TCGA dataset was used to determine the clinical relevance of GPR87 expression in patients with lung adenocarcinoma. GPR87 is upregulated in various cancer; however, the biological function of GPR87 has not yet been established in lung adenocarcinoma. In this study, we found that GPR87 expression is upregulated in lung adenocarcinoma and is associated with poor patient prognosis. Additionally, we showed that GPR87 overexpression promotes invasiveness and metastasis of lung adenocarcinoma cells. Furthermore, we demonstrated that AKT-eNOS-NO signaling is a novel downstream pathway of GPR87 in lung adenocarcinoma. Conversely, we confirmed that silencing of GPR87 expression suppressed these phenotypes. Our results reveal the oncogenic function of GPR87 in cancer progression and metastasis through the activation of eNOS as a key mediator. Therefore, we propose that targeting eNOS could be a novel therapeutic strategy to improve the clinical treatment of lung adenocarcinoma.

scholarly journals Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 122 ◽  
Author(s):  
Xiu He ◽  
Shi Chen ◽  
Chao Li ◽  
Jiaqi Ban ◽  
Yungeng Wei ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Alveolar Macrophages ◽  
Nuclear Translocation ◽  
Protective Role ◽  
Crystalline Silica ◽  
Autophagic Flux ◽  
Lysosomal System

Silicosis is an occupational lung disease characterized by persistent inflammation and irreversible fibrosis. Crystalline silica (CS) particles are mainly phagocytized by alveolar macrophages (AMs), which trigger apoptosis, inflammation, and pulmonary fibrosis. Previously, we found that autophagy-lysosomal system dysfunction in AMs was involved in CS-induced inflammation and fibrosis. Induction of autophagy and lysosomal biogenesis by transcription factor EB (TFEB) nuclear translocation can rescue fibrotic diseases. However, the role of TFEB in silicosis is unknown. In this study, we found that CS induced TFEB nuclear localization and increased TFEB expression in macrophages both in vivo and in vitro. However, TFEB overexpression or treatment with the TFEB activator trehalose (Tre) alleviated lysosomal dysfunction and enhanced autophagic flux. It also reduced apoptosis, inflammatory cytokine levels, and fibrosis. Both pharmacologically inhibition of autophagy and TFEB knockdown in macrophages significantly abolished the antiapoptotic and anti-inflammatory effects elicited by either TFEB overexpression or Tre treatment. In conclusion, these results uncover a protective role of TFEB-mediated autophagy in silicosis. Our study suggests that restoration of autophagy-lysosomal function by Tre-induced TFEB activation may be a novel strategy for the treatment of silicosis.

scholarly journals TGF-βRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Fanglong Wu ◽  
Shimeng Wang ◽  
Qingxiang Zeng ◽  
Junjiang Liu ◽  
Jin Yang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Oral Cancer ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Metabolic Reprogramming ◽  
Cancer Associated Fibroblasts

AbstractCancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-β signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-βRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-βRII in CAFs glucose metabolism and suggests that targeting TGF-βRII in CAFs might represent a therapeutic approach for oral cancer.

LINC01956 Promotes Metastasis and M2 Polarization of Tumor-Associated Macrophages in Glioblastoma Via The FUS/β-Catenin Signaling Pathway

2021 ◽  
Author(s):  
fengfei lu ◽  
fa jin
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Nuclear Translocation ◽  
Hypoxic Conditions ◽  
M2 Polarization ◽  
Rna Immunoprecipitation ◽  
First Time

Abstract Background:Long noncoding RNAs (lncRNAs) can drive cancer progression. Here, we studied the role of a novel lncRNA, LINC01956, in glioblastoma (GBM). Methods:RT-PCR assay was used to examine LINC01956 expression levels. Colony-formation, MTT, cell-cycle and in-vivo tumorigenesis assays were used to examine the role of LINC01956 in cell growth in vitro and in vivo. Boyden assay was used to examine cell invasion ability in vitro. RNA immunoprecipitation and RNA-protein pull-down assays were used to examine the interaction between LINC01956 and FUS protein.ChIP assay was used to examine HIF1-binding sites in the LINC01956 promoter.Results:The level of LINC01956 was elevated in GBM cell lines and tissues. LINC01956 downregulation suppressed the migration and proliferation of GBM cells. M2 polarization of macrophages induced by exosomes derived from glioma cells overexpressing LINC01956 further accelerated GBM progression. Mechanistically, we found that FUS interacted with both LINC01956 and β-catenin. LINC01956 bound to FUS and reduced its ubiquitination. LINC01956 evoked nuclear translocation of phosphorylated (p)-β-catenin by recruiting FUS. Furthermore, under hypoxic conditions, LINC01956 was regulated by HIF-1α. Conclusion:Taken together, our data revealed for the first time that LINC01956 exerts protumor effects via FUS-dependent activation of the WNT/β-catenin signaling pathway.

scholarly journals CDX2 inhibits epithelial–mesenchymal transition in colorectal cancer by modulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression

2020 ◽  
Vol 124 (1) ◽  
pp. 270-280
Author(s):  
Junhui Yu ◽  
Shan Li ◽  
Zhengshui Xu ◽  
Jing Guo ◽  
Xiaopeng Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Pten Expression ◽  
Invasion And Metastasis ◽  
Snail Expression ◽  
Mesenchymal Transition

Abstract Background Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, fewer studies focus on the role of CDX2 during the induction of epithelial–mesenchymal transition (EMT) in colorectal cancer (CRC). Methods Immunohistochemical analysis of CDX2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of CDX2 in the invasion and metastasis of CRC. Results CDX2 was downregulated in CRC tissues and reduced CDX2 correlated with poor prognosis. Knockdown of CDX2 promoted colon cancer cell invasion in vitro and facilitated liver metastasis in vivo with inducing EMT phenotypes. Further investigation indicated that CDX2 retarded Akt and GSK-3β phosphorylation, and thereby diminished Snail expression, β-catenin stabilisation and nuclear translocation. The depletion of β-catenin neutralised the regulation of Slug and ZEB1 by CDX2 knockdown. Mechanistically, CDX2 antagonised PI3K/Akt activity in CRC by modulating PTEN expression. CDX2 directly bound to the promoter of PTEN and transactivated its expression. Conclusions Our study first uncovered that CDX2 inhibits EMT and metastasis of CRC by regulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression.

scholarly journals Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vikrant Borse ◽  
Matthew Barton ◽  
Harry Arndt ◽  
Tejbeer Kaur ◽  
Mark E. Warchol
Keyword(s):  
Inner Ear ◽  
Cellular Localization ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Hippo Signaling ◽  
Supporting Cells ◽  
The Hippo Pathway

AbstractThe Hippo signaling pathway is a key regulator of tissue development and regeneration. Activation of the Hippo pathway leads to nuclear translocation of the YAP1 transcriptional coactivator, resulting in changes in gene expression and cell cycle entry. Recent studies have demonstrated the nuclear translocation of YAP1 during the development of the sensory organs of the inner ear, but the possible role of YAP1 in sensory regeneration of the inner ear is unclear. The present study characterized the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after HC injury. During neonatal development, YAP1 expression was observed in the cytoplasm of supporting cells, and was transiently expressed in the cytoplasm of some differentiating hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle after short periods in organotypic culture. However, little or no nuclear translocation of YAP1 was observed in the utricles of neonatal or mature mice after ototoxic injury. In contrast, substantial YAP1 nuclear translocation was observed in the chicken utricle after streptomycin treatment in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may partially account for the differing regenerative abilities of the avian vs. mammalian inner ear.

scholarly journals RCAN1.4 attenuates renal fibrosis through inhibiting calcineurin-mediated nuclear translocation of NFAT2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jianjian Zhang ◽  
Hui Chen ◽  
Xiaodong Weng ◽  
Hao Liu ◽  
Zhiyuan Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Renal Fibrosis ◽  
Nuclear Translocation ◽  
Protein Accumulation ◽  
Adeno Associated Virus ◽  
Over Expression ◽  
Related Proteins

AbstractChronic kidney disease (CKD) is thus deemed to a global health problem. Renal fibrosis, characterized by accumulation of extracellular matrix (ECM) components in the kidney, is considered a common pathway leading to CKD. Regulator of calcineurin1 (RCAN1), identified as a competitive endogenous inhibitor of the phosphatase calcineurin, participates in ECM deposition in various organs. However, the role of RCAN1 in renal fibrosis remains unclear. Here, unilateral ureteral obstruction (UUO), a well-known model to induce renal fibrosis in vivo, was performed on mice for a week. To overexpress RCAN1.4 in vivo, recombinant adeno-associated virus 9-packed RCAN1.4 over-expression plasm was employed in mice kidney. Lentivirus-packed RCAN1.4 over-expression plasm was employed to transfer into HK-2 and NRK-49F cells in vitro. The results indicated that RCAN1.4 expression was impaired both in UUO-induced renal fibrosis in vivo and TGF-β1-induced renal fibrosis in vitro. However, knocking in of RCAN1.4 suppressed the production of extracellular matrix (ECM) both in vivo and in vitro. Furthermore, in vitro, the apoptosis-related proteins, including the ratio of Bax/Bcl-2 and cleaved-caspase3, were elevated in cells transfected with RCAN1.4 overexpression plasmid. In addition, we found that RCAN1.4 could rugulated NFAT2 nuclear distribution by inhibiting calcineurin pathway. So overexpression of RCAN1.4 could reverse renal fibrosis, attenuate ECM related protein accumulation, promote apoptosis of myofibroblast via inhibiting Calcineurin/NFAT2 signaling pathway. Taken together, our study demonstrated that targeting RCAN1.4 may be therapeutic efficacy in renal fibrosis.

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