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Objective:To investigate the expression of stanniocalcin-2 (STC-2) and cellular-mesenchymal epithelial transition factor (C-met) in tumor tissues of cervical cancer patients and their clinical significance.Methods:A total of 110 cervical cancer patients were selected in Foshan First People′s Hospital from January 2014 to December 2018. Patients′ cancer tissue samples and normal tissue samples were collected during modified radical resection to determine and compare the expression levels of STC-2 mRNA and C-met mRNA in the two tissues, and to analyze the correlation between the expression levels of STC-2, C-met and the clinicopathological characteristics of the patients as well as the multivariate analysis of tumor metastasis and recurrence in the patients. The correlation between the expression of STC-2 and C-met and the time of postoperative tumor metastasis and recurrence in cervical cancer patients were analyzed after 24 months of follow-up.Results:The expression levels of C-met mRNA and STC-2 mRNA in cancer tissues were higher than those in adjacent normal tissues: 4.51 ± 1.21 vs. 3.97 ± 1.14, 2.57 ± 0.21 vs. 2.12 ± 0.24, there were statistical differences ( t = 3.41, 14.80, P<0.05). The expression of STC-2 and C-met in cancer tissues had no significant difference with age, pathological type, federation international of gynecology and obstetrics (FIGO) stage and tumor size ( P>0.05), but had significant difference with tumor recurrence or metastasis ( P<0.05). The results of Logistic multivariate analysis showed that vascular emboli, lymph node metastasis, TNM stage, depth of tumor invasion, C-met expression and STC-2 expression were independent risk factors affecting the prognosis of cervical cancer patients ( P<0.05). The expression of STC-2 and C-met were negatively correlated with the time of tumor metastasis in patients with cervical cancer ( r = - 0.663, P<0.001; r = - 0.747, P<0.001). Conclusions:The expression levels of STC-2 and C-met in cancer tissues of cervical cancer patients are higher than those in adjacent normal tissues, and the expression levels of STC-2 and C-met are negatively correlated with the time of metastasis. The expression of C-met, the expression of STC-2, vascular emboli, lymph node metastasis, TNM stage, and the depth of tumor invasion are all independent risk factors affecting the prognosis of cervical cancer patients.
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ObjectiveTo investigate the effect and mechanism of Wumeiwan against Lewis lung cancer in mice with syndrome of cold and heat in complexity based on hepatocyte growth factor/mesenchymal-epithelial transition factor （HGF/C-Met） signaling pathway. MethodTwenty healthy male mice were classified into blank group， model group （equivalent volume of distilled water， ig）， cisplatin group （4.0 mg·kg-1 cisplatin， ip）， and Wumeiwan group （12.5 mL·kg-1 Wumeiwan， ig）， with 5 in each group. Lewis lung cancer with the syndrome of cold and heat in complexity was induced in mice except the blank group by gavage of propylthiouracil， Zhimu Shigaotang， and Fanxieye， ice-water swimming， and subcutaneous injection of dry yeast suspension and Lewis cell suspension under the right armpit. After modeling， administration began and lasted 6 weeks. After the experiment， the tumor weight， tumor volume， tumor inhibition rate， and lung cancer metastasis-inhibiting proportion were measured and calculated. The pathological morphology of lung tissue was observed based on hematoxylin and eosin （HE） staining. The growth state of tumor tissue was analyzed by immunohistochemistry. The mRNA expression of HGF and C-Met was detected by Real-time polymerase chain reaction （PCR）， and the protein expressions of HGF， C-Met， survivin， and X-linked inhibitor of apoptosis protein （XIAP） by Western blot. ResultCompared with the blank group， the model group showed high mRNA expression of HGF and C-Met and protein expression of HGF， C-Met， surviving， and XIAP （P<0.01）. Compared with the model group， Wumeiwan group displayed low proportion of positive cells， positive cell density， positive score （P<0.05）， histochemical score， tumor weight， tumor volume （P<0.01）， mRNA expression of HGF and C-Met （P<0.01）， and protein expression of HGF， C-Met， surviving， and XIAP （P<0.01）. Compared with the model group， the cisplatin group displayed decrease in the proportion of positive cells， density of positive cells （P<0.05）， positive score， tumor weight， tumor volume （P<0.01）， mRNA expression of HGF and C-Met （P<0.01）， and protein expression of HGF， C-Met， surviving， and XIAP （P<0.01）， and insignificant variation in the histochemical score. Wumeiwan group had high mRNA expression of HGF （P<0.01）， and insignificant variation in the proportion of positive cells， positive cell density， histochemical score， positive score， tumor weight， tumor volume， mRNA expression of C-Met， and protein expression of HGF， C-Met， surviving， and XIAP. ConclusionWumeiwan can slow down the progression of Lewis lung cancer in mice with syndrome of cold and heat I complexicity by inhibiting HGF/C-Met signaling pathway.
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Targeted therapy is an important therapeutic method for advanced non-small cell lung cancer with driver gene alteration.However,resistance to targeted therapy will inevitably happen in clinical practice,which has become a major issue demanding prompt solution.Studies have demonstrated that bypass resistance mediated by the activation of hepatocyte growth factor(HGF)/mesenchymal-epithelial transition factor(MET)signaling pathway is a common cause of resistance to targeted therapy.Presently,relevant studies have accumulated rich experience in the specific mechanisms.To be brief,HGF/MET is an important target for overcoming the resistance to targeted therapy and promises to be a leading biomarker for judging and observing the occurrence of resistance.This paper introduces the recent studies concerning the effects and mechanisms of HGF/MET signaling pathway on resistance to targeted therapy.
Subject(s)
Humans , Carcinoma, Non-Small-Cell Lung/genetics , Epithelial-Mesenchymal Transition , Hepatocyte Growth Factor , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-met/metabolism , Signal TransductionABSTRACT
Increasing HER-2/neu resistance in gastric carcinoma has encouraged search for new biomarkers for targeted therapy. Cellular mesenchymal epithelial transition (C-MET) is one such tyrosine kinase inhibitor proposed for personalized salvage treatment. We determined frequency of C-MET gene copy number variation (CNV) by Fluorescent in-situ hybridization (FISH) in gastric adenocarcinoma (GAC) and sought its correlation with conventional clinicopathologic parameters. Dual-coloured FISH was done on 32 GAC cases. C-MET gene and centromere 7 signals were counted under fluorescent microscope and ratio was calculated for each case. Correlation between C-MET CNV and conventional clinic-pathologic parameters was done by Fischer exact test. CNV was identified in the form of amplification and polysomy (3.1% each) and associated with poorer prognostic parameters. Our pilot study highlights limited subset of patients that may benefit from anti-C-MET-targeted therapy and thus could be a novel biomarker for targeted intervention in GAC.
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Introducción: La metástasis del cáncer es la transferencia de células tumorales de un órgano a otro mediante una serie de multipasos secuenciales interrelacionados. Este proceso es uno de los principales retos en el tratamiento del cáncer debido a su heterogeneidad biológica. El proceso de metástasis es considerado la principal causa de muerte en esta enfermedad, reportándose que más de 90 por ciento de las muertes por cáncer son debidos a esta etapa. Objetivo: Actualizar los conocimientos sobre metástasis en tumores sólidos y su asociación con transición epitelial-mesenquimal (EMT) en relación a la evolución y emergencia del cáncer. Método: Se realizó una revisión, no sistemática, de los estudios más significativos sobre el tema, publicados en la Web of Science, Pubmed, Ebsco, Scopus e Infomed. Conclusiones: La metástasis es la principal causa de muerte del cáncer, por lo que entender las bases del mecanismo de la formación de tumores metastásicos permitirá realizar terapias más eficaces para tratar el cáncer(AU)
Introduction: Cancer metastasis is the transfer of tumor cells from one organ to another through a series of interrelated sequential multi-steps. This process is one of the main challenges in cancer treatment due to the biological heterogeneity. The metastasis process is considered the main cause of death in this disease, accounting for more than 90 percent of cancer deaths. Objective: To identify the most recent advances on solid tumor metastasis and the association with epithelial-mesenchymal transition (EMT) in relation to the evolution and emergence of cancer. Method: A non-systematic review was carried out of the most significant studies on the subject, published in Web of Science, Pubmed, Ebsco, Scopus and Infomed. Conclusions: Metastasis is the main cause of cancer death, so understanding the bases of the mechanism for metastatic tumor formation will allow for more effective therapies(AU)
Subject(s)
Humans , Male , Female , Epithelial-Mesenchymal Transition/physiology , Neoplasm Metastasis/pathology , Neoplasm Metastasis/prevention & control , Health Knowledge, Attitudes, Practice , Prospective StudiesABSTRACT
Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Alk (containing parasitic fungi Hypomyces hyalines (Schw.) Tul.). Here, we initially found, by wound healing assay and Transwell assay in vitro, that verticillin A possesses an inhibitory effect against the migration and invasion of the human colon cancer cell. Subsequently, c-mesenchymal-epithelial transition factor (c-Met) was identified as a molecular target of verticillin A by screening key genes related to cell migration. Verticillin A-mediated c-Met suppression is at the transcriptional level. Further study demonstrated that verticillin A suppressed c-MET phosphorylation and decreased c-MET protein level. In addition, verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma (Ras)-associated factor (Raf), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell. More importantly, verticillin A also inhibited cancer cell metastasis in vivo. Thus, verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase (MEK)/ERK signaling pathways. Therefore, we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.
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Kidney is one of the most important organs of the body and the mammalian kidney development is essential for kidney unit formation. The key process of kidney development is metanephric development, where mesenchymal-epithelial transition (MET) plays a crucial role. Here we investigated the biological function of PPP3CA in metanephric mesenchyme (MM) cells. qRT-PCR and Western blotting were used to detect PPP3CA and MET makers expression in mK3, mK4 cells respectively at mRNA and protein level. Subsequently, PPP3CA was stably knocked down via lentivirus infection in mK4 cells. Flow cytometry, EdU/CCK-8 assay, wound healing assay were conducted to clarify the regulation of PPP3CA on cell apoptosis, proliferation and migration respectively. PPP3CA was expressed higher in epithelial-like mK4 cells than mesenchyme-like mK3 cells. Thus, PPP3CA was silenced in mK4 cells and PPP3CA deficiency promoted E-cadherin expression, cell apoptosis. Moreover, PPP3CA knock down attenuated cell proliferation and cell migration in mK4 cell. The underlying mechanism was associated with the dephosphorylation of PPP3CA on ERK1/2. Taken together, our results indicated that PPP3CA mediated MET process and cell behaviors of MM cells, providing new foundation for analyzing potential regulator in kidney development process.
Subject(s)
Animals , Mice , Apoptosis/genetics , Cell Line , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , Gene Silencing , Mesenchymal Stem Cells/cytology , MesodermABSTRACT
Background: C-ros oncogene 1, receptor tyrosine kinase (ROS 1) proto-oncogene 1, receptor tyrosine kinase (ROS-1) fusions are potent oncogenic drivers and these re-arrangements promote signal transduction programs leading to uninhibited cell survival and proliferation identified in 1–2% of cases of nonsmall-cell lung cancer. Mesenchymal epithelial transition factor (MET) receptor tyrosine kinase and its ligand are predominantly involved in epithelial mesenchymal transition and tissue regeneration. The MET amplification and overexpression is oncogenic in 3–7% cases. The objectives of this study were to identify the frequency of ROS-1 and c-MET protein expression in adenocarcinoma lung and to correlate it with the clinicopathological parameters and to analyze the histomorphology of cases that harbor the characteristic mutations (c-MET and ROS-1). Materials and Methods: Study group comprised a prospective cases series of 90 cases of adenocarcinoma lung. ROS-1 protein expression was determined by immunohistochemistry using the D4D6 rabbit monoclonal antibody (Cell Signaling, Danvers, MA) and c-MET protein expressed was analyzed using the SP-44 clone (Ventana Medical Systems). Results: c-MET protein expression was identified in 33.33% cases (n = 30/90) with statistically significant thyroid transcription factor-1 (TTF-1) positivity. ROS-1 protein expression was detected in 3.33% cases (n-3/90), in biopsies from the respiratory tree with TTF-1 expression. Conclusion: This is the first study from the Indian subcontinent to identify the frequency of ROS-1 re-arrangements and MET amplification in the Indian population. The availability of targeted therapy that has a significant impact on survival makes it essential to detect these less frequent mutations.
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BACKGROUND: The mesenchymal-epithelial transition factor (MET) receptor can be overexpressed in solid tumors, including small cell lung cancer (SCLC). However, the molecular mechanism regulating MET stability and turnover in SCLC remains undefined. One potential mechanism of MET regulation involves the C-terminus of Hsp70-interacting protein (CHIP), which targets heat shock protein 90-interacting proteins for ubiquitination and proteasomal degradation. In the present study, we investigated the functional effects of CHIP expression on MET regulation and the control of SCLC cell apoptosis and invasion. METHODS: To evaluate the expression of CHIP and c-Met, which is a protein that in humans is encoded by the MET gene (the MET proto-oncogene), we examined the expression pattern of c-Met and CHIP in SCLC cell lines by western blotting. To investigate whether CHIP overexpression reduced cell proliferation and invasive activity in SCLC cell lines, we transfected cells with CHIP and performed a cell viability assay and cellular apoptosis assays. RESULTS: We found an inverse relationship between the expression of CHIP and MET in SCLC cell lines (n=5). CHIP destabilized the endogenous MET receptor in SCLC cell lines, indicating an essential role for CHIP in the regulation of MET degradation. In addition, CHIP inhibited MET-dependent pathways, and invasion, cell growth, and apoptosis were reduced by CHIP overexpression in SCLC cell lines. CONCLUSION: CHIP is capable of regulating SCLC cell apoptosis and invasion by inhibiting MET-mediated cytoskeletal and cell survival pathways in NCI-H69 cells. CHIP suppresses MET-dependent signaling, and regulates MET-mediated SCLC motility.
Subject(s)
Humans , Apoptosis , Blotting, Western , Cell Line , Cell Proliferation , Cell Survival , Heat-Shock Proteins , Lung Neoplasms , Small Cell Lung Carcinoma , Ubiquitin , UbiquitinationABSTRACT
Objective To detect the mRNA expression of mesenchymal-epithelial transition factor (MET)gene in patients with non-small cell lung cancer (NSCLC),and to investigate the relationship and clinical significance between the mRNA expression of MET gene and clinical pathological characteristics. Methods From June 201 1 to November 201 3,48 patients with pathologically confirmed NSCLC in Chinese People′s Liberation Army General Hospital were selected.All patients included in the study were not treated before surgery.The branched DNA liquid chip technology was used to detect mRNA expression of MET gene in tumor tissues.The relationship between mRNA expression of MET gene and clinical pathological characteristics was analyzed.Results The constituent ratios of low,moderate and high mRNA expression level of MET gene were 22.9%,50.0% and 27.1 % respectively,mainly for the moderate expression.The mRNA expression of MET gene was related to the pathologic type (χ2 =7.1 83,P =0.020)and TNM stage (χ2 =24.566,P =0.01 7)of the patients;but it was not related to the gender (χ2 =0.566,P =0.754),age (χ2 =1 .857,P =0.395),smoking history (χ2 =4.959,P =0.084),degrees of differentiation (χ2 =5.749,P =0.067), lymph node metastasis (χ2 =1 .631 ,P =0.442)and distant metastasis (χ2 =4.261 ,P =0.1 1 9).Conclusion mRNA expression of MET gene is more likely to present moderate and higher level in NSCLC patients.MET gene can also be used as a biomarker for judging tumor pathological type.
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Currently, it is considered that the tumor cells get abnormal activity by EMT (epithelial-mesenchymal transition) activation, inducing the generation and survival of CTCs (circulating tumor cells). After dissemination of CTCs through the blood, MET (mesenchymal-epithelial transition) occurs to form secondary tumor metastasis. Given that EMT is a key factor to induce CTCs to promote tumor metastasis, more and more attention was paid on CTCs in prognosis and targeted therapy of tumors. This review is mainly involved the current progress in the role of EMT in generation and survival of CTCs and the role of MET in metastasis formation from EMT-derived CTCs, and discusses the problem of the clinical application of detection of CTCs-EMT phenotype. Copyright © 2013 by TUMOR.