scholarly journals Gankyrin Drives Malignant Transformation of Gastric Cancer and Alleviates Oxidative Stress via mTORC1 Activation

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Bo Huang ◽  
Weiyang Cai ◽  
Qian Wang ◽  
Feng Liu ◽  
Ming Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gastric Cancer ◽  
Malignant Transformation ◽  
Precancerous Lesions ◽  
Poor Overall Survival ◽  
Epithelial Tumor ◽  
Pathway Activation ◽  
Mtorc1 Pathway ◽  
Malignant Epithelial Tumor ◽  
Mtorc1 Activation

Gastric cancer, as a malignant epithelial tumor, is a major health threat leading to poor overall survival and death. It is usually diagnosed at an advanced stage due to asymptomatic or only nonspecific early symptoms. The present study demonstrated that gankyrin contributes to the early malignant transformation of gastric cancer and can be selected to predict the risk of gastric cancer in those patients harboring the precancerous lesions (dysplasia and intestinal metaplasia). In addition, a new insight into gastric cancer was provided, which stated that gankyrin alleviates oxidative stress via mTORC1 pathway activation. It can potentiate the mTORC1 by PGK1-AKT signaling that promotes the tumor process, and this phenomenon is not completely consistent with the previous report describing colorectal cancer.

Daily protein supplementation attenuates immobilization-induced blunting of postabsorptive muscle mTORC1 activation in middle age men

2021 ◽  
Author(s):  
Nina Zeng ◽  
Randall F. D'Souza ◽  
Caitlin L. Macrae ◽  
Vandre C. Figueiredo ◽  
Chantal A. Pileggi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Primary Objective ◽  
Protein Supplementation ◽  
Anabolic Resistance ◽  
Pathway Activation ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation

Disuse-induced muscle atrophy is accompanied by a blunted postprandial response of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Conflicting observations exist as to whether postabsorptive mTORC1 pathway activation is also blunted by disuse and plays a role in atrophy. It is unknown whether changes in habitual protein intake alters mTORC1 regulatory proteins and how they may contribute to the development of anabolic resistance. The primary objective of this study was to characterize the downstream responsiveness of skeletal muscle mTORC1 activation and its upstream regulatory factors, following 14 days of lower limb disuse in middle-aged men (45-60 years). The participants were further randomized to receive daily supplementation of 20g/d of protein (n=12; milk protein concentrate) or isocaloric carbohydrate placebo (n=13). Immobilization reduced postabsorptive skeletal muscle phosphorylation of the mTORC1 downstream targets, 4E-BP1, P70S6K and ribosomal protein S6 (RPS6), with phosphorylation of the latter two decreasing to a greater extent in the placebo, compared to the protein supplementation groups (37 ± 13 vs 14 ± 11% and 38 ± 20 vs 25 ± 8% respectively). Sestrin2 protein was also downregulated following immobilization irrespective of supplement group, despite a corresponding increase in its mRNA content. This decrease in Sestrin2 protein was negatively correlated with the immobilization induced change in the in-silico predicted regulator miR-23b-3p. No other measured upstream proteins were altered by immobilization or supplementation. Immobilization downregulated postabsorptive mTORC1 pathway activation and 20g/day of protein supplementation attenuated the decrease in phosphorylation of targets regulating muscle protein synthesis.

scholarly journals LncRNA coordinates Hippo and mTORC1 pathway activation in cancer

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Shugeng Zhang ◽  
Shuhang Liang ◽  
Dehai Wu ◽  
Hongrui Guo ◽  
Kun Ma ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Tumour Growth ◽  
Hippo Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Growth Control ◽  
Nuclear Accumulation ◽  
Control Functions ◽  
Pathway Activation ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation

AbstractThe Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant pathways that regulate tumour growth and metastasis. Therefore, we explored the potential crosstalk between these two functionally relevant pathways to coordinate their tumour growth-control functions. We found that a Hippo pathway-related long noncoding RNA, HPR, directly interacts with Raptor, an essential component of mTORC1, to upregulate mTORC1 activation by impairing the phosphorylation of Raptor by AMPK. Knockdown or knockout of HPR in breast cancer and cholangiocarcinoma cells led to a reduction in tumour growth. Compared with HPR WT cells, HPR-overexpressing cells exhibited nuclear accumulation of YAP1, and significantly blocked the downregulation of mTORC1 signalling induced by energy stress. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways in the control of tumour growth.

scholarly journals Gαq activation modulates autophagy by promoting mTORC1 signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sofía Cabezudo ◽  
Maria Sanz-Flores ◽  
Alvaro Caballero ◽  
Inmaculada Tasset ◽  
Elena Rebollo ◽  
...  
Keyword(s):  
Nutrient Status ◽  
Autophagy Induction ◽  
Pathway Activation ◽  
Mtorc1 Signaling ◽  
Different Types ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation ◽  
G Protein Coupled ◽  
Activation Status

AbstractThe mTORC1 node plays a major role in autophagy modulation. We report a role of the ubiquitous Gαq subunit, a known transducer of plasma membrane G protein-coupled receptors signaling, as a core modulator of mTORC1 and autophagy. Cells lacking Gαq/11 display higher basal autophagy, enhanced autophagy induction upon different types of nutrient stress along with a decreased mTORC1 activation status. They are also unable to reactivate mTORC1 and thus inactivate ongoing autophagy upon nutrient recovery. Conversely, stimulation of Gαq/11 promotes sustained mTORC1 pathway activation and reversion of autophagy promoted by serum or amino acids removal. Gαq is present in autophagic compartments and lysosomes and is part of the mTORC1 multi-molecular complex, contributing to its assembly and activation via its nutrient status-sensitive interaction with p62, which displays features of a Gαq effector. Gαq emerges as a central regulator of the autophagy machinery required to maintain cellular homeostasis upon nutrient fluctuations.

scholarly journals CXCR4 is a Novel Biomarker Correlated With Malignant Transformation and Immune Infiltrates in Gastric Precancerous Lesions

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaotao Jiang ◽  
Junhui Zheng ◽  
Lanxing Liu ◽  
Kailin Jiang ◽  
Yi Wen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Malignant Transformation ◽  
Immune Cells ◽  
Prognostic Model ◽  
Precancerous Lesions ◽  
Precancerous Lesion ◽  
Functional Enrichment ◽  
Effector Memory ◽  
Hub Genes ◽  
Gene Modules

Background: As early gastric cancer (EGC) has a far better prognosis than advanced gastric cancer (GC), early diagnosis and treatment are essential. However, understanding the mechanism of the process from gastric precancerous lesion (GPL) becoming EGC has made little advances. Besides, biomarkers that can monitor the progression of GPL-to-GC are still much insufficient.Methods: Key gene modules associated with GPL progression to EGC were identified by integrating two GPL-related data sets, GSE55696 and GSE130823, using the WGCNA method. Combining with the TCGA-STAD cohort, hub genes were identified. Immunofluorescence was conducted to validate the expression. To explore the implication of hub genes in GPL malignant transformation, a correlation test was conducted to identify their co-expression genes, co-expression cytokines, and co-expression immune cells. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to shrink CXCR4-related predictors and construct a prognostic model. Functional enrichment was applied for exploring the potential mechanism.Results: The green module in GSE55696 and the yellow module in GSE130823 were regarded as key gene modules associated with GPL progression to EGC, and 219 intersection genes from them were mainly enriched in critical immune biological processes. Combining with the TCGA-STAD cohort, CXCR4 was identified as a novel biomarker correlated with the malignant transformation of GPL, the positive rate of which was increased with GPL progression according to immunofluorescence. CXCR4 co-expression genes were found mainly involved in regulation of actin. CXCR4 co-expression cytokines were enriched in regulation of chemotaxis, cell chemotaxis, mononuclear cell migration, leukocyte chemotaxis, etc. As for co-expression immune cells, the expression level of CXCR4 was positively correlated with the abundance of macrophages but negatively correlated with that of effector memory T cells and NKT cells during GPL malignant transformation. In addition, the CXCR4-related prognostic model was able to predict the prognosis of GC and serve as an independent predictor for overall survival (OS).Conclusions: CXCR4 was a novel biomarker correlated with malignant transformation of GPL and played a vital role in the control of tumor immunity. CXCR4 is possible to serve as a therapeutic target for malignant transformation of GPL.

scholarly journals Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis

2021 ◽  
Vol 16 (1) ◽  
pp. 537-543
Author(s):  
Mei Zhang ◽  
Jing Yuan ◽  
Rong Dong ◽  
Jingjing Da ◽  
Qian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Tubular Injury ◽  
Jnk Pathway ◽  
Pathway Activation

Abstract Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

scholarly journals Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 194
Author(s):  
Jutta Ries ◽  
Abbas Agaimy ◽  
Falk Wehrhan ◽  
Christoph Baran ◽  
Stella Bolze ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Malignant Transformation ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Precancerous Lesions ◽  
Death Receptor ◽  
Oral Leukoplakia ◽  
Significant Difference

Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (pE = 0.001; pS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.

scholarly journals Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yuyun Wu ◽  
Ningbo Hao ◽  
Suming Wang ◽  
Xin Yang ◽  
Yufeng Xiao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Noncoding Rna ◽  
Tumor Metastasis ◽  
Cancer Metastasis ◽  
Survival Rates ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Low Expression ◽  
Overall Survival Rates

Gastric cancer (GC) is one of the most common malignancies worldwide, and the tumor metastasis leads to poor outcomes of GC patients. Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules that play a crucial role in tumor metastasis. However, the biological function and underlying mechanism of numerous lncRNAs in GC metastasis remain largely unclear. Here, we report a novel lncRNA, lnc-TLN2-4:1, whose expression is decreased in GC tissue versus matched normal tissue, and its low expression is involved in the lymph node and distant metastases of GC, as well as poor overall survival rates of GC patients. We further found that lnc-TLN2-4:1 inhibits the ability of GC cells to migrate and invade but does not influence GC cell proliferation and confirmed that lnc-TLN2-4:1 is mainly located in the cytoplasm of GC cells. We then found that lnc-TLN2-4:1 increases the mRNA and protein expression of TLN2 in GC cells and there is a positive correlation between the expression of lnc-TLN2-4:1 and TLN2 mRNA in GC tissue. Collectively, we identified a novel lncRNA, lnc-TLN2-4:1, in GC, where lnc-TLN2-4:1 represses cell migration and invasion. The low expression of lnc-TLN2-4:1 is associated with poor overall survival rates of GC patients. These suggest that lnc-TLN2-4:1 may be a tumor suppressor during GC metastasis.

scholarly journals Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1

2015 ◽  
Vol 309 (10) ◽  
pp. C639-C649 ◽  
Author(s):  
Hui-Hua Chang ◽  
Steven H. Young ◽  
James Sinnett-Smith ◽  
Caroline Ei Ne Chou ◽  
Aune Moro ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pancreatic Cancer ◽  
Prostaglandin E2 ◽  
Human Pancreatic Cancer ◽  
Pancreatic Carcinoma Cell Line ◽  
Pancreatic Cancer Cells ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Pka Pathway ◽  
Mtorc1 Activation

Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca2+-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca2+ response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca2+ signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.

Sign in / Sign up

Export Citation Format

Share Document