• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5925-5928
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• 2013

Objective: This study aimed to examine the relationship between expression of mammal target of rapamycin (mTOR) and phosphorylation of mTOR (p-mTOR) protein in the PI3K/Akt/mTOR signaling pathways in gastrointestinal stromal tumors and relatiuonships with clinical factors. Methods: Immunohistochemistry was used to detect the expression of the associated proteins mTOR, p-mTOR, and phosphorylation of the tumor suppressor genes PTEN, P27, VEGF, and EGFR in 40 cases of gastrointestinal stromal tumors, with division into a very low and low risk group as well as a moderate and high risk group. Results: The positive rate of mTOR and p-mTOR was significantly increased in the moderate and high risk group compared with the very low and low risk group. The difference was statistically significant (P<0.05). When grouped according to size, the positive mTOR expression rate exhibited a statistical difference (P<0.05), which was significantly increased in the group of tumors larger than 5 cm. The difference in the positive mTOR and p-mTOR expression rate exhibit no statistical significance among the PTEN, P27, VEGF, and EGFR expression subgroups (P>0.05). Conclusion: The different expressions of mTOR and p-mTOR in the signal transduction pathway of gastrointestinal stromal tumor in the different degree-of-risk groups suggested that the mTOR and p-mTOR of the signal transduction pathway serve an important function in the occurrence and development of gastrointestinal stromal tumors.

• Journal of Life Science
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• v.32 no.4
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• pp.271-278
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• 2022

The detailed mechanism by which cancer upregulated gene 2 (CUG2) overexpression induces cancer stem cell-like phenotypes is not fully understood. The downregulation of FBXW7 E3 ligase, a tumor suppressor known for its proteolytic regulation of oncogenic proteins such as cyclin E, c-Myc, Notch, and Yap1, has been frequently reported in several types of tumor tissues, including those in the large intestine, cervix, and stomach. Therefore, we investigated whether FBXW7 is involved in CUG2-induced oncogenesis. In this study, the decreased expression of FBXW7 was examined in human lung adenocarcinoma A549 (A549-CUG2) and human bronchial BEAS-2B cells (BEAS-CUG2) overexpressing CUG2 and compared with control cells stably expressing an empty vector (A549-Vec or BEAS-Vec). Treatment with MG132 (a proteosome inhibitor) prevented the degradation of FBXW7 and Yap1 proteins, which are substrates of the FBXW7 E3 ligase. To address the role of Fbxw7 in the development of cancer stem cell (CSC) phenotypes, we suppressed Fbxw7 protein levels using its siRNA. We observed that decreased levels of FBXW7 enhanced cell migration, invasion, and spheroid size and number in A549-Vec and BEAS-Vec cells. The enforced expression of FBXW7 produced the opposite results in A549-CUG2 and BEAS-CUG2 cells. Furthermore, the downregulation of FBXW7 elevated the activities of EGFR, Akt, and ERK1/2 and upregulated β-catenin, Yap1, and NEK2, while the enforced expression of FBXW7 generated the opposite results. We thus propose that FBXW7 downregulation induced by CUG2 confers CSC-like phenotypes through the upregulation of both the EGFR-ERK1/2 and β-catenin-Yap1-NEK2 signaling pathways.

• Molecular & Cellular Toxicology
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• v.5 no.3
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• pp.193-197
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• 2009

Suppressors of cytokine signaling (SOCS) proteins were originally identified as negative feedback regulators of cytokine signaling and include the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathways. Recent studies have shown that SOCS proteins negatively regulate the receptor tyrosine kinase (RTK) pathway including the insulin receptor (IR), EGFR, and KIT signaling pathways. In addition, SOCS1 and SOCS3 have been reported to have anti-tumor effects in human hepatocellular carcinoma (HCC). However, it is uncertain whether other members of the SOCS family are associated with tumor development and progression. In this study, to investigate whether SOCS6 is aberrantly regulated in HCC, we examined the expression level of SOCS6 in HCC by Western blot analysis and immunohistochemical staining. The results showed that SOCS6 was down-regulated in all examined HCCs compared to the corresponding normal tissues. In addition, expression of SOCS6 was observed in the cytoplasm of most normal and precancerous tissue, but not in the HCCs by immunohistochemical staining. This is first report to demonstrate that SOCS6 is aberrantly regulated in HCC. These findings suggest that underexpression of SOCS6 is involved in hepatocarcinogenesis, and SOCS6 may play a role, as a tumor suppressor, in HCC development and progression.

• BMB Reports
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• v.48 no.3
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• pp.159-165
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• 2015

Although the short isoform of ErbB3-binding protein 1 (Ebp1), p42 has been considered to be a potent tumor suppressor in a number of human cancers, whether p42 suppresses tumorigenesis of lung cancer cells has never been clarified. In the current study we investigated the tumor suppressor role of p42 in non-small cell lung cancer cells. Our data suggest that the expression level of p42 is inversely correlated with the cancerous properties of NSCLC cells and that ectopic expression of p42 is sufficient to inhibit cell proliferation, anchorage-independent growth, and invasion as well as tumor growth in vivo. Interestingly, p42 suppresses Akt activation and overexpression of a constitutively active form of Akt restores the tumorigenic activity of A549 cells that is ablated by exogenous p42 expression. Thus, we propose that p42 Ebp1 functions as a potent tumor suppressor of NSCLC through interruption of Akt signaling.

• Bioinformatics and Biosystems
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• v.2 no.1
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• pp.28-32
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• 2007

The protein phosphorylation is one of the important processes in the cell signaling pathway. A variety of protein kinase families are involved in this process, and each kinase family phosphorylates different kinds of substrate proteins. Many methods to predict the kinase-specific phosphoryrated sites or different types of phosphorylated residues (Serine/Threonine or Tyrosin) have been developed. We employed Supprot Vector Machine (SVM) to attempt the prediction of protein kinase specific phosphorylation sites. 10 different kinds of protein kinase families (PKA, PKC, CK2, CDK, CaM-KII, PKB, MAPK, EGFR) were considered in this study. We defined 9 residues around a phosphorylated residue as a deterministic instance from which protein kinases determine whether they act on. The subsets of PSI-BALST profile was converted to the numerical vectors to represent positive or negative instances. When SVM training, We took advantage of multiple SVMs because of the unbalanced training sets. Representative negative instances were drawn multiple times, and generated new traing sets with the same positive instances in the original traing set. When testing, the final decisions were made by the votes of those multiple SVMs. Generally, RBF kernel was used for the SVMs, and several parameters such as gamma and cost factor were tested. Our approach achieved more than 90% specificity throughout the protein kinase families, while the sensitivities recorded 60% on average.

• Journal of Ginseng Research
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• v.46 no.2
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• pp.206-213
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• 2022

Ginsenoside Rb2 is an active protopanaxadiol-type saponin, widely existing in the stem and leave of ginseng. Rb2 has recently been the focus of studies for pharmaceutical properties. This paper provides an overview of the preclinical and clinical pharmacokinetics for Rb2, which exhibit poor absorption, rapid tissue distribution and slow excretion through urine. Pharmacological studies indicate a beneficial role of Rb2 in the prevention and treatment of diabetes, obesity, tumor, photoaging, virus infection and cardiovascular problems. The underlying mechanism is involved in an inhibition of oxidative stress, ROS generation, inflammation and apoptosis via regulation of various cellular signaling pathways and molecules, including AKT/SHP, MAPK, EGFR/SOX2, TGF-β1/Smad, SIRT1, GPR120/AMPK/HO-1 and NF-κB. This work would provide a new insight into the understanding and application of Rb2. However, its therapeutic effects have not been clinically evaluated. Further studies should be aimed at the clinical treatment of Rb2.

• Annals of Pediatric Endocrinology and Metabolism
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• v.23 no.4
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• pp.204-209
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• 2018

Purpose: Growth hormone transduction defect (GHTD) is characterized by severe short stature, impaired STAT3 (signal transducer and activator of transcription-3) phosphorylation and overexpression of the cytokine inducible SH2 containing protein (CIS) and p21/CIP1/WAF1. To investigate the role of p21/CIP1/WAF1 in the negative regulation of the growth hormone (GH)/GH receptor and Epidermal Growth Factor (EGF)/EGF Receptor pathways in GHTD. Methods: Fibroblast cultures were developed from gingival biopsies of 1 GHTD patient and 1 control. The protein expression and the cellular localization of p21/CIP1/WAF1 was studied by Western immunoblotting and immunofluorescence, respectively: at the basal state and after induction with $200-{\mu}g/L$ human GH (hGH) (GH200), either with or without siRNA CIS (siCIS); at the basal state and after inductions with $200-{\mu}g/L$ hGH (GH200), $1,000-{\mu}g/L$ hGH (GH1000) or 50-ng/mL EGF. Results: After GH200/siCIS, the protein expression and nuclear localization of p21 were reduced in the patient. After successful induction of GH signaling (control, GH200; patient, GH1000), the protein expression and nuclear localization of p21 were reduced. After induction with EGF, p21 translocated to the cytoplasm in the control, whereas in the GHTD patient it remained located in the nucleus. Conclusion: In the GHTD fibroblasts, when CIS is reduced, either after siCIS or after a higher dose of hGH (GH1000), p21's antiproliferative effect (nuclear localization) is also reduced and GH signaling is activated. There also appears to be a positive relationship between the 2 inhibitors of GH signaling, CIS and p21. Finally, in GHTD, p21 seems to participate in the regulation of both the GH and EGF/EGFR pathways, depending upon its cellular location.

• Korean Journal of Food Science and Technology
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• v.48 no.1
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• pp.66-71
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• 2016

Delphinidin is a blue-red pigment and one of the major anthocyanins in plants. It plays an important role in anti-oxidant, anti-inflammatory, anti-mutagenic and anti-cancer properties. In this study, we investigated the inhibitory effects of delphinidin on vascular endothelial growth factor (VEGF) gene expression, an important factor involved in angiogenesis and tumor progression in human prostate cancer. Delphinidin decreased levels of epidermal growth factor (EGF)-induced VEGF mRNA expression in PC-3M cells. The expression of the EGF-induced hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) and signaling transducer and activator of transcription 3 (STAT3) proteins, which are the major transcription factors for VEGF, were inhibited by delphinidin. In addition, delphinidin decreases HRE-promoter reporter gene activity, suggesting that delphinidin can suppress the transcription of HIF-$1{\alpha}$ under EGF induction, leading to a decrease in the expression of VEGF. Delphinidin specifically suppressed the phosphorylation of Akt, p70S6K, and 4EBP1, but not the phosphorylation of EGFR. Therefore, our results suggest that delphinidin may inhibit human prostate cancer progression and angiogenesis by inhibiting HIF-$1{\alpha}$, STAT3 and VEGF gene expression.

• BMB Reports
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• v.34 no.6
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• pp.537-543
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• 2001

In the present study, an in vitro ELISA system to assess the interaction between Src homology (SH)2 domains and phosphotyrosine that contain peptides was established using purified GST-conjugated SH2 proteins and synthetic biotinylated phosphotyrosine that contain oligopeptides. The SH2 domains bound the relevant phosphopeptides that were immobilized in the streptavidin-coated microtiter plate in a highly specific and dose-dependent manner. The epidermal growth factor receptor (EGFR)-, T antigen (T Ag)-, and platelet-derived growth factor receptor (PDGFR)-derived phosphopeptides interacted with the growth factor receptor binding protein (Grb)2/SH2, Lck/SH2, and phosphatidyl inositol 3-kinase (PI3K) p85/SH2, respectively. No cross-reactions were observed. Competitive inhibition experiments showed that a short phosphopeptide of only four amino acids was long enough to determine the binding specificity. Optimal concentrations of the GST-SH2 fusion protein and phosphopeptide in this new ELISA system for screening the binding blockers were chosen at 2nM and 500nM, respectively. When two candidate compounds were tested in our ELISA system, they specifically inhibited the Lck/SH2 and/or p85/SH2 binding to the relevant phosphopeptides. Our results indicate that this ELISA system could be used as an easy screening method for the discovery of specific binding blockers of protein-protein interactions via SH2 domains.

• Journal of Physiology & Pathology in Korean Medicine
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• v.38 no.1
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• pp.22-26
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• 2024

The purpose of this study was to identify the applicability, main compounds, and target genes of Cnidii Fructus (CF) in the treatment of gastritis using network pharmacology. The compounds in CF were searched in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and a database of medicinal materials and chemical compounds in Northeast Asian traditional medicine (TM-MC). The target gene information of the compounds was collected from pubchem and cross-compared with the gastritis-related target gene information collected from Genecard to derive the target genes. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on the derived target genes. Afterwards, network analysis between compounds and disease target genes was performed using cytoscape. We identified 121 active compounds and 139 target genes associated with gastritis. Pathways derived from the GO biological process and KEGG pathway DB primarily focus on target genes related to inflammation (IL-6, IL-8, TNF production, NF-κB transcription factor activity, and NF-κB signaling pathway) and cell death (PI3K-Akt, FoxO). Major targets for CF treatment of gastritis include TP53, TNF, BCL2, EGFR, NFKB1, ABCB1, PPARG, PTGS2, IL6, IL1B, and SOD1, along with major compounds such as coumarin, osthol, hexadecanoic acid, oleic acid, linoleic acid, and stigmasterol. This study provided CF's applicability for gastritis, related compounds, and target information. Evaluating CF's effectiveness in a preclinical gastritis model suggests its potential use in clinical practice for digestive system diseases.