Gene Summary

Gene:MMP2; matrix metallopeptidase 2
Aliases: CLG4, MONA, CLG4A, MMP-2, TBE-1, MMP-II
Summary:This gene is a member of the matrix metalloproteinase (MMP) gene family, that are zinc-dependent enzymes capable of cleaving components of the extracellular matrix and molecules involved in signal transduction. The protein encoded by this gene is a gelatinase A, type IV collagenase, that contains three fibronectin type II repeats in its catalytic site that allow binding of denatured type IV and V collagen and elastin. Unlike most MMP family members, activation of this protein can occur on the cell membrane. This enzyme can be activated extracellularly by proteases, or, intracellulary by its S-glutathiolation with no requirement for proteolytical removal of the pro-domain. This protein is thought to be involved in multiple pathways including roles in the nervous system, endometrial menstrual breakdown, regulation of vascularization, and metastasis. Mutations in this gene have been associated with Winchester syndrome and Nodulosis-Arthropathy-Osteolysis (NAO) syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:72 kDa type IV collagenase
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: MMP2 (cancer-related)

Akashi M, Hisaka T, Sakai H, et al.
Expression of Matrix Metalloproteinases in Intraductal Papillary Mucinous Neoplasm of the Pancreas.
Anticancer Res. 2019; 39(8):4485-4490 [PubMed] Related Publications
BACKGROUND/AIM: Intraductal papillary mucinous neoplasm (IPMN) has a variety of histological and morphological appearances. Matrix metalloproteinases (MMPs) have been considered to be associated with tumor progression or poor prognosis. The aim of this study was to elucidate the molecular basis of IPMN variation in different types of lesions.
MATERIALS AND METHODS: The expression of MMP-1,2,7,9 in 51 cases of IPMN were investigated. The MMP score was calculated as the sum of the score of staining distribution and the score of the intensity staining.
RESULTS: MMP scores were correlated with histological grade, histological subtype, and type of invasion. MMP high expression groups (MMP score ≥5) had worse prognosis than low-expression groups.
CONCLUSION: MMP expression varied between different types of IPMN, a result supporting differences in molecular basis of malignancies. These considerations may be helpful for optimal management or treatment according to various types of IPMN.

Wu TK, Chen CH, Pan YR, et al.
Cetrimonium Bromide Inhibits Cell Migration and Invasion of Human Hepatic SK-HEP-1 Cells Through Modulating the Canonical and Non-canonical TGF-β Signaling Pathways.
Anticancer Res. 2019; 39(7):3621-3631 [PubMed] Related Publications
BACKGROUND/AIM: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells.
MATERIALS AND METHODS: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis.
RESULTS: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), MMP-9, snail, slug, twist, vimentin, fibronectin, N-cadherin, Smad2, Smad3, Smad4, phosphoinositide-3-kinase (PI3K), p-PI3K, Akt, p-Akt, β-catenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3β. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-β (TGF-β) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-β signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K.
CONCLUSION: CTAB is involved in the suppression of TGF-β-mediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.

Kishore C, Sundaram S, Karunagaran D
Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.

Ou J, Guan D, Yang Y
Non-contact co-culture with human vascular endothelial cells promotes epithelial-to-mesenchymal transition of cervical cancer SiHa cells by activating the NOTCH1/LOX/SNAIL pathway.
Cell Mol Biol Lett. 2019; 24:39 [PubMed] Free Access to Full Article Related Publications
Background: The aim of this study was to investigate the effect of human umbilical vein endothelial cells on epithelial-to-mesenchymal transition of the cervical cancer cell line SiHa by studying the Notch1/lysyl oxidase (LOX)/SNAIL1 pathway.
Methods: Monocultures of SiHa cells, SiHa cells containing a control sequence, and
Results: Compared with monocultured SiHa cells, co-cultured SiHa cells showed a significant increase in their invasiveness and expression levels of vimentin, as well as of NOTCH 1, LOX, and SNAIL1, whereas their expression of E-cadherin was significantly reduced and protein activities of MMP-2 and MMP-9 were increased. Compared with SiHa, mono- and co-cultured
Conclusion: Co-culture with human umbilical vein endothelial cells promoted the epithelial-to-mesenchymal transition of SiHa cells by activating the NOTCH1/LOX/SNAIL1 pathway in SiHa cells, which enhanced their invasive and metastatic capacities. The results of this study may provide a new perspective on cervical cancer metastasis and a theoretical basis for clinical treatment.

Zhang L, Wan Y, Jiang Y, et al.
Overexpression of BP1, an isoform of Homeobox Gene DLX4, promotes cell proliferation, migration and predicts poor prognosis in endometrial cancer.
Gene. 2019; 707:216-223 [PubMed] Related Publications
The expression of homeobox gene DLX4 has been verified in some tumors, but not in endometrial cancer. We found that expression of DLX7, a splicing isoform of DLX4, did not show any significant difference in expression between endometrial cancer and endometrium. However, BP1, another splicing isoform of DLX4, was highly expressed in endometrial cancer, and its expression was positively correlated with patient prognosis, cancer pathological grade, tumor invasion and metastasis. Lentiviral-mediated expression of BP1 in HEC-1-B cells accelerated the cell cycle progression from G0/G1 into S phase, and promoted cell proliferation and migration both in vitro and in vivo. Real-time PCR and western blotting showed that the expression levels of p15, p21 and E-cadherin significantly decreased, and levels of cyclinD1 and MMP-2 increased in endometrial cancer cells. In conclusion, our results demonstrate that high expression of BP1 is associated with poor prognosis in patients with endometrial cancer and promotes cell proliferation and migration.

Saejia P, Lirdprapamongkol K, Svasti J, Paricharttanakul NM
Perfluorooctanoic Acid Enhances Invasion of Follicular Thyroid Carcinoma Cells Through NF-κB and Matrix Metalloproteinase-2 Activation.
Anticancer Res. 2019; 39(5):2429-2435 [PubMed] Related Publications
BACKGROUND/AIM: Perfluorooctanoic acid (PFOA) is one of the most common perfluorinated compounds widely used in several applications. Due to its persistence in the environment, PFOA has been associated with various diseases, including cancer. This study explored the effects of PFOA on follicular thyroid carcinoma cells (FTC133).
MATERIALS AND METHODS: Cell invasion, migration, adhesion and activity of matrix metalloproteinase-2 (MMP-2) were investigated using Transwell assays, adhesion assay and gelatin zymography, respectively. The underlying mechanism involved in the effects observed was evaluated by immunoblot analyses.
RESULTS: Treatment with PFOA did not affect cell migration, but enhanced cell invasion, adhesion and activity of MMP-2 in FTC133 cells. PFOA selectively enhanced the phosphorylation of nuclear factor kappa B (NF-κB) p65, as well as induced NF-κB nuclear translocation. Treatment with a NF-κB inhibitor (BAY 11-7085) was able to reverse PFOA-induced cell invasiveness.
CONCLUSION: PFOA promotes invasiveness of FTC133 cells mediated through the activation of NF-κB signaling.

Hung CY, Lee CH, Chiou HL, et al.
Praeruptorin-B Inhibits 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Invasion by Targeting AKT/NF-κB via Matrix Metalloproteinase-2/-9 Expression in Human Cervical Cancer Cells.
Cell Physiol Biochem. 2019; 52(6):1255-1266 [PubMed] Related Publications
BACKGROUND/AIMS: Praeruptorins, a seselin-type coumarin, possess anti-inflammatory and antitumor promoting properties. However, molecular mechanisms through which Praeruptorin-B (Pra-B) exerts an antimetastatic effect on cervical cancer cells remain unclear.
METHODS: Cell viability was examined using the MTT assay, whereas cell migration and invasion were examined using the Boyden chamber assay. Western blotting and RT-PCR were performed to investigate the inhibitory effect of Pra-B on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2/-9 (MMP-2/-9) expression in HeLa cells. The findings of the luciferase assay confirmed the inhibitory effect of Pra-B on TPA-induced transcriptional activity of MMP2/-9 in HeLa cells.
RESULTS: Pra-B inhibited TPA-induced metastatic ability of human cervical cancer cells without any significant toxicity. Pra-B suppressed TPA-induced mRNA and protein expression and transcriptional activity of MMP-2/-9 in HeLa cells. Furthermore, Pra-B inhibited AKT phosphorylation but did not affect the MAPK pathway. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 (a PI3K inhibitor) reduced cell invasion and MMP-2/-9 expression and transcriptional activity. In addition, Pra-B attenuated TPA-induced nuclear translocation of NF-κB-p65/-p50, which reduced Ikk-α phosphorylation in HeLa cells. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 reduced NF-κB nuclear translocation.
CONCLUSION: These results suggested that Pra-B-mediated inhibition of TPA-induced cell metastasis involved the suppression of p-AKT/NF-κB via MMP-2/-9 expression in HeLa cells. Pra-B can be a potential antimetastatic agent against cervical cancer.

Habel AF, Ghali RM, Bouaziz H, et al.
Common matrix metalloproteinase-2 gene variants and altered susceptibility to breast cancer and associated features in Tunisian women.
Tumour Biol. 2019; 41(4):1010428319845749 [PubMed] Related Publications
A role for matrix metalloproteinase polymorphisms in breast cancer development and progression was proposed, but with inconclusive results. We assessed the relation of matrix metalloproteinase-2 variants with breast cancer and related phenotypes in Tunisians. This case-control retrospective study involved 430 women with breast cancer and 498 healthy controls. Genotyping of matrix metalloproteinase-2 rs243866, rs243865, rs243864, and rs2285053 was analyzed by allelic exclusion. The minor allele frequency of rs2285053 was significantly lower in women with breast cancer cases as compared to control women; minor allele frequencies of the remaining single-nucleotide polymorphisms were similar between cases and control women. The distribution of rs243865 and rs2285053 genotypes was significantly different between breast cancer patients and control subjects. This persisted when key covariates were controlled for. None of the matrix metalloproteinase-2 variants were associated with estrogen receptor positivity, progesterone receptor positivity, or with double estrogen receptor-progesterone receptor positivity in breast cancer patients. Matrix metalloproteinase-2 rs243866, rs243865, and rs243864 were positively associated with menstrual irregularity and histological type, while rs243866 and rs2285053 were negatively associated with menarche and nodal status. In addition, rs2285053 was negatively associated with triple negativity, tumor size, distance metastasis, molecular type, and chemotherapy. Haploview analysis revealed high linkage disequilibrium between matrix metalloproteinase-2 variants. Four-locus Haploview analysis identified haplotypes GCTT and GTTC to be negatively associated with breast cancer, which remained statistically after controlling for key covariates. Matrix metalloproteinase-2 alleles and genotypes, along with four-locus haplotypes, are related to reduced susceptibility to breast cancer in Tunisian women, suggesting a protective effect.

Yu Y, Blokhuis BR, Garssen J, Redegeld FA
A Transcriptomic Insight into the Impact of Colon Cancer Cells on Mast Cells.
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells may modify MC function is still unclear. In this study, primary human MCs were generated from CD34⁺ progenitor cells and a 3D coculture model was developed to study the interplay between colon cancer cells and MCs. By comparing the transcriptomic profile of colon cancer-cocultured MCs versus control MCs, we identified a number of deregulated genes, such as MMP-2, VEGF-A, PDGF-A, COX2, NOTCH1 and ISG15, which contribute to the enrichment of cancer-related pathways. Intriguingly, pre-stimulation with a TLR2 agonist prior to colon cancer coculture induced upregulation of multiple interferon-inducible genes as well as MHC molecules in MCs. Our study provides an alternative approach to study the influence of colon cancer on MCs. The transcriptome signature of colon cancer-cocultured MCs may potentially reflect the mechanism of how colon cancer cells educate MCs to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal-e.g., TLR2 ligands-may modify their responses in the cancer milieu.

Xu J, Wang Y, Li Z, et al.
Ultrasound-Targeted Microbubble Destruction (UTMD) Combined with Liposome Increases the Effectiveness of Suppressing Proliferation, Migration, Invasion, and Epithelial- Mesenchymal Transition (EMT) via Targeting Metadherin (MTDH) by ShRNA.
Med Sci Monit. 2019; 25:2640-2648 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Reports show that ultrasound-targeted microbubble destruction (UTMD) is a promising method of gene therapy, and metadherin (MTDH) is related to the development of breast cancer. Thus, we investigated the role of MTDH in breast cancer and compared the effect of suppressing MTDH by shRNA using liposome, UTMD, or the combination of these 2 methods. MATERIAL AND METHODS Graphing of survival curves of MTDH was analyzed by bioinformatics. UTMD was conducted using an ultrasonic therapeutic apparatus. Cell counting kit-8 (CCK-8) assay was used to measure cell viability. Migration and invasion rates were measured by wound healing test and Transwell invasion assay, respectively. The expression of MTDH, E-cadherin, metastasis-associated protein-1 (MTA-1), matrix metalloproteinase (MMP)-2, and MMP-9 were measured by Western blot and qPCR. RESULTS The prognosis of breast cancer can be decreased by the high expression of MTDH, and elevated expression of MTDH was discovered in MCF-7, MCF-10A, and T47D cell lines. UTMD combined with liposome is most efficient in transfecting shRNA, clearly suppressing the expression of MTDH and thereby decreasing cell viability, migration, invasion rate, and epithelial- mesenchymal transition (EMT) processes in the MCF-7 cell line. CONCLUSIONS UTMD combined with liposome could be used as a more efficient way to transfect shRNA into cells to suppress the expression of MTDH and thus lead to the downregulation of proliferation, migration, and EMT processes of the MCF-7 cell line, showing the potential for use in gene therapy.

Li QH, Liu Y, Chen S, et al.
circ-CSPP1 promotes proliferation, invasion and migration of ovarian cancer cells by acting as a miR-1236-3p sponge.
Biomed Pharmacother. 2019; 114:108832 [PubMed] Related Publications
Circular RNAs are known to participate in tumorigenesis through a variety of pathways, and as such, have potential to serve as molecular markers in tumor diagnosis and treatment. Here, using quantitative reverse transcription (qRT)-PCR, we showed that circ-CSPP1 is highly expressed in ovarian cancer (OC) tissues. Particularly, we detected circ-CSPP1 expression in three OC cell lines; of which, OVCAR3 and A2780 demonstrated higher levels of circ-CSPP1 expression, and CAOV3 showed lower circ-CSPP1 expression level. Subsequent silencing of circ-CSPP1 in OVCAR3 and A2780 cell lines revealed decreased cell growth, migration and invasion, while overexpression of circ-CSPP1 caused opposite results We also found that miR-1236-3p is a target of circ-CSPP1. Circ-CSPP1 silencing increased the expression of miR-1236-3p, and circ-CSPP1 overexpression decreased miR-1236-3p expression. MiR-1236-3p reportedly plays a tumor-suppressor role in OC by targeting zinc finger E-box binding homeobox 1 (ZEB1). In agreement with this, we showed that silencing circ-CSPP1 significantly decreased ZEB1 expression at both RNA and protein levels, and epithelial-mesenchymal transition (EMT) related markers (E-cadherin and N-cadherin) varied with ZEB1 expression. Circ-CSPP1 silencing also caused decreased expression of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor A (VEGFA), both of which are related to tumorigenesis. Overexpression of circ-CSPP1 had opposite effects. In addition, we indicated that the tumor-promoting effect was inhibited after we transfected miR-1236-3p into circ-CSPP1 overexpressing OC cells. Altogether, our findings suggest that by acting as a miR-1236-3p sponge, circ-CSPP1 impairs the inhibitory effect of miR-1236-3p on ZEB1, which subsequently promotes EMT and OC development.

Zhang Y, Zhao Z, Li S, et al.
Inhibition of miR‑214 attenuates the migration and invasion of triple‑negative breast cancer cells.
Mol Med Rep. 2019; 19(5):4035-4042 [PubMed] Free Access to Full Article Related Publications
Triple‑negative breast cancer (TNBC) is a subtype of breast cancer. MicroRNA (miR)‑214 is closely associated with controlling the development of tumor cells; therefore, in the present study, the target gene and effects of miR‑214 on TNBC cells were explored. Luciferase activity was examined by luciferase reporter assay. The viability, invasion and migration of MDA‑MB‑231 TNBC cells were measured using Cell Counting kit‑8, Transwell and wound‑healing assays, respectively. The expression levels of various factors were determined using reverse transcription‑quantitative polymerase chain reaction and western blotting. The results demonstrated that the expression levels of miR‑214 were higher and the levels of α1‑antitrypsin (α1‑AT) were lower in TNBC tissues compared with in normal tissues. Subsequently, α1‑AT was revealed to be a target of miR‑214. Furthermore, inhibition of miR‑214 decreased cell viability, invasion and migration, enhanced the expression of E‑cadherin and tissue inhibitor of metalloproteinases‑2, and reduced the expression of metastatic tumour antigen 1 and matrix metalloproteinase‑2. Inhibition of miR‑214 also significantly downregulated the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and markedly downregulated that of phosphoinositide 3‑kinase (PI3K); however, the expression levels of total PI3K, Akt and mTOR remained stable in all groups. Taken together, these findings indicated that α1‑AT may be a target of miR‑214. Downregulation of miR‑214 markedly suppressed the viability, migration and invasion of MDA‑MB‑231 cells, and inhibited the PI3K/Akt/mTOR pathway. These findings suggested that miR‑214 targeting α1‑AT may be a potential mechanism underlying TNBC development.

Guo Y, Cui W, Pei Y, Xu D
Platelets promote invasion and induce epithelial to mesenchymal transition in ovarian cancer cells by TGF-β signaling pathway.
Gynecol Oncol. 2019; 153(3):639-650 [PubMed] Related Publications
OBJECTIVE: To test whether platelets could increase invasion potential and initiate EMT in ovarian cancer cells via a TGF-β signaling pathway.
METHODS: Blood samples were collected in 69 patients with ovarian cancer, 16 patients with benign ovarian tumor and 64 healthy donors. SK-OV-3 and OVCAR-3 ovarian cancer cells were treated with platelets. Transwell assays were used to analyze the invasive capacity, and EMT was assessed by microarray analysis, quantitative real-time PCR (qPCR) and Western blotting. Activation of TGF-β pathway was examined by ELISA and Western blotting. TGF-β type I receptor (TβR I) inhibitor A83-01 was used to confirm the role of TGF-β pathway in vitro and in vivo.
RESULTS: Clinical data showed ovarian cancer patients with elevated platelet counts had a higher incidence of advanced stages. Treatment with platelets increased the invasive properties of both cell lines. Mesenchymal markers (snail family transcriptional repressor-1, vimentin, neural cadherin, fibronectin-1 and matrix metalloproteinase-2) were up-regulated in platelet-treated cells, while the epithelial marker (epithelial cadherin) was down-regulated. Higher TGF-β level was observed in patients with elevated platelet counts when compared to the subjects. Higher levels of TGF-β were also found in culture medium treated with platelets, and cells treated with platelets also showed increased phosphorylation of Smad2. TβR I inhibitor A83-01 reversed the EMT-like alterations and inhibited platelet-induced invasion in vitro and in vivo.
CONCLUSION: Platelet increased invasion potential and induced EMT in ovarian cancer cells in a TGF-β dependent pathway. Platelet-derived TGF-β may be useful as a new target treatment for ovarian cancer.

Wang D, Wu C, Liu D, et al.
Ginsenoside Rg3 Inhibits Migration and Invasion of Nasopharyngeal Carcinoma Cells and Suppresses Epithelial Mesenchymal Transition.
Biomed Res Int. 2019; 2019:8407683 [PubMed] Free Access to Full Article Related Publications
Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer. Distant metastasis becomes the predominant mode of treatment failure in NPC patients. Ginsenoside Rg3 (Rg3), an active pharmaceutical component extracted from traditional Chinese medicine ginseng, shows antitumor effects in various cancers. In this study, we aimed to determine whether Rg3 inhibits the migration and invasion activity of NPC cells and to explore the possible mechanisms. Our results revealed that Rg3 hampers cell migration and invasion in both HNE1 and CNE2 cell lines. A reduced level of matrix metalloproteinase-2 (MMP-2) and MMP-9 was induced by Rg3 treatment. In addition, Rg3 significantly altered the expression of epithelial mesenchymal transition (EMT) markers with increased E-cadherin but decreased Vimentin and N-cadherin expression. Transforming growth factor

Ding Q, Li X, Sun Y, Zhang X
Schizandrin A inhibits proliferation, migration and invasion of thyroid cancer cell line TPC-1 by down regulation of microRNA-429.
Cancer Biomark. 2019; 24(4):497-508 [PubMed] Related Publications
OBJECTIVE: Schizandrin A (SchA) exerts anticancer potential. However, the effects of SchA on thyroid cancer (TC) have not been clear illuminated. Therefore, we investigated the effects of SchA on TC cell line TPC-1 and the underlying mechanisms.
METHODS: TPC-1 cells were treated with SchA and/or transfected with miR-429 mimic, anti-miR-429 and their corresponding negative controls (NC). Cell viability, proliferation, migration, invasion and cell apoptosis were examined by CCK-8 assay, bromodeoxyuridine, modified two-chamber migration assay, Millicell Hanging Cell Culture and flow cytometry analysis, respectively. The expression of miR-429, p16, Cyclin D1, cyclin-dependent kinases 4 (CDK4), matrix metalloprotein (MMP)-2, MMP-9 and Vimentin was detected by qRT-PCR. All protein expression was examined by western blot.
RESULTS: SchA inhibited cell proliferation, metastasis and induced cell apoptosis. Moreover, SchA negatively regulated miR-429 expression. Treatment with miR-429 mimic and SchA reversed the results led by SchA and NC. Furthermore, the phosphorylation β-catenin, mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) were statistically down-regulated by SchA while co-treatment with miR-429 mimic and SchA led to the opposite trend. Moreover, miR-429 knockdown showed contrary results.
CONCLUSION: SchA inhibits cell proliferation, migration, invasion and inactivates Wnt/β-catenin and MEK/ERK signaling pathways by down regulating miR-429.

Afshar E, Hashemi-Arabi M, Salami S, et al.
Screening of acetaminophen-induced alterations in epithelial-to-mesenchymal transition-related expression of microRNAs in a model of stem-like triple-negative breast cancer cells: The possible functional impacts.
Gene. 2019; 702:46-55 [PubMed] Related Publications
Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44

Wang Y, Shi L, Li J, et al.
Long-term cadmium exposure promoted breast cancer cell migration and invasion by up-regulating TGIF.
Ecotoxicol Environ Saf. 2019; 175:110-117 [PubMed] Related Publications
Cadmium (Cd) is a known human carcinogen. Previous studies have demonstrated that Cd exposure promoted migration and invasion of breast cancer cells. However, the molecular mechanisms underlying this process have not yet been clearly addressed. The purpose of this study was to investigate whether TG-interacting factor (TGIF) was involved in long-term Cd exposure-induced migration and invasion of breast cancer cells. Human breast cancer cells were continuously exposed to Cd for eight weeks. Western blot and qRT-PCR assays were performed to measure the expression of protein and mRNA. Migration and invasion assays were performed to assess the migratory and invasive ability of human breast cancer cells. Our data indicated that long-term Cd exposure obviously increased the expression of TGIF protein and mRNA in human breast cancer cells. Long-term Cd exposure increased the ability of migration and invasion of human breast cancer cells, which could be inhibited by transfection of small interfering RNA (siRNA) targeting TGIF. We also observed that the long-term Cd exposure-induced up-regulation of MMP2 mRNA expression was modulated by TGIF. In conclusion, our findings suggested that TGIF/MMP2 signaling axis might be involved in malignant progression stimulated by long-term Cd exposure in human breast cancer.

Chen C, Shan H
Keratin 6A gene silencing suppresses cell invasion and metastasis of nasopharyngeal carcinoma via the β‑catenin cascade.
Mol Med Rep. 2019; 19(5):3477-3484 [PubMed] Free Access to Full Article Related Publications
Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer. This study aimed to study the mechanisms of ectopic keratin 6A (KRT6A) in NPC. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were performed to detect KRT6A levels in NPC cell lines (C666‑1, 5‑8F and SUNE‑1) and a nasopharyngeal epithelial cell line (NP69, as a control). After SUNE‑1 NPC cells had been silenced by KRT6A, cell viability, metastasis and invasion were determined using Cell Counting Kit‑8, wound healing and Transwell assays, respectively. KRT6A levels, metastasis‑associated factors and the Wnt/β‑catenin pathway were measured using RT‑qPCR and western blotting. It was demonstrated that KRT6A was upregulated in all detected NPC cells, among which KRT6A was the highest in SUNE‑1 cells. In SUNE‑1 cells, cell viability was inhibited at 24 and 48 h, and that cell metastasis and invasion were demonstrated to be suppressed by KRT6A silencing. Both the mRNA and protein levels of KRT6A, matrix metalloproteinase (MMP)‑2, MMP‑9, β‑catenin, lymphoid enhancer binding factor 1 and T‑cell specific factor 4 were reduced in the small interfering (si)KRT6A group. However, the results demonstrated that the levels of epithelial‑cadherin and tissue inhibitor of metalloproteinase‑2 (TIMP‑2) were promoted in the siKRT6A group. The activation of the Wnt/β‑catenin pathway by lithium chloride reversed the effect of si‑KRT6A by modulating the expression of MMP‑2/9 and TIMP2. It was observed that KRT6A silencing suppressed cell invasion and metastasis of NPC via the β‑catenin cascade. Together these results provide important insights into a novel approach for the diagnosis and treatment of NPC.

Zhang H, Dong R, Zhang P, Wang Y
Songorine suppresses cell growth and metastasis in epithelial ovarian cancer via the Bcl‑2/Bax and GSK3β/β‑catenin signaling pathways.
Oncol Rep. 2019; 41(5):3069-3079 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) is the most frequent cause of cancer‑associated mortality among all types of gynecological cancer. The high recurrence rate and the poor 5‑year survival rate indicate that more effective therapeutic strategies are required. The aim of the present study was to investigate the role and potential mechanisms of songorine in treating EOC. EOC cells were cultured with different concentrations of songorine, following which MTT and flow cytometric analyses were conducted to measure cell viability and apoptosis. Wound healing and Transwell assays were used to detect cell migration and invasion abilities. Furthermore, associated molecules in the glycogen synthase kinase (GSK)‑3β/β‑catenin and B‑cell lymphoma 2 (Bcl‑2)/Bcl‑2‑associated X (Bax) signaling pathways were semi‑quantified by western blotting. Finally, tumor size measurements, pathological observations, western blot analysis and toxicological evaluations were performed in SKOV‑3 tumor‑bearing BALB/c nude mice to investigate the efficacy and safety of songorine. As expected, songorine inhibited EOC cell survival, invasion and migration, promoted EOC cell apoptosis and suppressed mammalian EOC tumorigenic behavior. In particular, GSK3β inhibitor treatment restored the songorine‑induced regulation of the GSK3β/β‑catenin signaling pathway. Furthermore, in the in vitro and in vivo experiments, songorine consistently downregulated the expression of N‑cadherin, vimentin, matrix metalloproteinase (MMP)‑2, MMP‑9, phosphorylated‑GSK3β, β‑catenin and Bcl‑2, and upregulated the expression of E‑cadherin, cleaved caspase‑3, cleaved caspase‑9 and Bax. In conclusion, songorine exerted its anticancer effect through the GSK3β/β‑catenin and Bcl‑2/Bax signaling pathways. These results highlight the potential use of songorine as a novel therapeutic agent for EOC.

Sun L, Jin X, Xie L, et al.
Swainsonine represses glioma cell proliferation, migration and invasion by reduction of miR-92a expression.
BMC Cancer. 2019; 19(1):247 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Swainsonine is a natural indolizidine alkaloid, its anti-tumor activity has been widely reported in varied cancers. This study aimed to investigate whether Swainsonine exerted anti-tumor impact on glioma cells, likewise uncovered the relative molecular mechanisms.
METHODS: After administration with diverse concentrations of Swainsonine, cell growth, migration and invasion in U251 and LN444 cells were appraised by the common-used CCK-8, BrdU, flow cytometry and Transwell assays. MiR-92a mimic, inhibitor and the correlative NC were transfected into U251 and LN444 cells, and assessment of miR-92a expression was by utilizing qRT-PCR. Functions of miR-92a in above-mentioned cell biological processes were analyzed again in Swainsonine-treated cells. The momentous proteins of cell cycle, apoptosis and PI3K/AKT/mTOR pathway were ultimately examined by western blot.
RESULTS: Swainsonine significantly hindered cell proliferation through decreasing cell viability, declining the percentage of BrdU cells, down-regulating CyclinD1 and up-regulating p16 expression. Enhancement of percentage of apoptotic cells was presented in Swainsonine-treated cells via activating cleaved-Caspase-3 and cleaved-Caspase-9. Additionally, Swainsonine impeded the abilities of migration and invasion by decreasing MMP-2, MMP-9, Vimentin and E-cadherin. Repression of miR-92a was observed in Swainsonine-treated cells, and miR-92a overexpression overturned the anti-tumor activity of Swainsonine in glioma cells. Finally, western blot assay displayed that Swainsonine hindered PI3K/AKT/mTOR pathway via regulating miR-92a.
CONCLUSIONS: These discoveries corroborated that Swainsonine exerted anti-tumor impacts on glioma cells via repression of miR-92a, and inactivation of PI3K/AKT/mTOR signaling pathway.

Xiong Y, He L, Shay C, et al.
Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer.
J Exp Clin Cancer Res. 2019; 38(1):122 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastatic lung cancer is a life-threatening condition that develops when cancer in another area of the body metastasizes, or spreads, to the lung. Despite advances in our understanding of primary lung oncogenesis, the biological basis driving the progression from primary to metastatic lung cancer remains poorly characterized.
METHODS: Genetic knockdown of the particular genes in cancer cells were achieved by lentiviral-mediated interference. Invasion potential was determined by Matrigel and three-dimensional invasion. The secretion of matrix metalloproteinase 2 (MMP2) and MMP9 were measured by ELISA. Protein levels were assessed by Western blotting and immunohistochemistry. Protein-protein interactions were determined by immunoprecipitation. An experimental mouse model was generated to investigate the gene regulation in tumor growth and metastasis.
RESULTS: Nck-associated protein 1 (NAP1/NCKAP1) is highly expressed in primary non-small-cell lung cancer (NSCLC) when compared with adjacent normal lung tissues, and its expression levels are strongly associated with the histologic tumor grade, metastasis and poor survival rate of NSCLC patients. Overexpression of NAP1 in lowly invasive NSCLC cells enhances MMP9 secretion and invasion potential, whereas NAP1 silencing in highly invasive NSCLC cells produces opposing effects in comparison. Mechanistic studies further reveal that the binding of NAP1 to the cellular chaperone heat shock protein 90 (HSP90) is required for its protein stabilization, and NAP1 plays an essential role in HSP90-mediated invasion and metastasis by provoking MMP9 activation and the epithelial-to-mesenchymal transition in NSCLC cells.
CONCLUSIONS: Our insights demonstrate the importance and functional regulation of the HSP90-NAP1 protein complex in cancer metastatic signaling, which spur new avenues to target this interaction as a novel approach to block NSCLC metastasis.

Jin C, Chen Z, Shi W, Lian Q
Tropomodulin 3 promotes liver cancer progression by activating the MAPK/ERK signaling pathway.
Oncol Rep. 2019; 41(5):3060-3068 [PubMed] Related Publications
Tropomodulin 3 (TMOD3) is a member of the pointed‑end capping protein family that contributes to invasion and metastasis in several types of malignancies. TMOD3 has been found to be crucial for membranous skeleton and embryonic development; however, little is known regarding the role of TMOD3 in liver cancer progression. In addition, to the best of our knowledge, no previous studies have investigated the mechanism underlying the TMOD3‑regulated promotion of liver cancer. The aim of the present study was to determine whether TMOD3 is associated with liver cancer progression. TMOD3 expression was found to be elevated in liver cancer cells and tissues. In the in vitro experiments, liver cancer cell proliferation, invasion and migration were inhibited by TMOD3 knockdown and promoted by ectopic expression of TMOD3. Furthermore, mechanistic analysis indicated that TMOD3 overexpression activated mitogen‑activated protein kinase (MAPK)/extracellular signal‑regulated kinase (ERK) signaling and increased the levels of other targets of this pathway, including matrix metalloproteinase (MMP)2, MMP9 and cyclin D1. TMOD3 overexpression was associated with changes in liver cancer cell morphology and altered expression of epithelial and mesenchymal markers. High TMOD3 expression was hypothesized to promote epithelial‑to‑mesenchymal transition in liver cancer cells. In conclusion, TMOD3 was shown to promote liver cancer cell growth, invasion and migration through the MAPK/ERK signaling pathway, and it may serve as a candidate biomarker and therapeutic target in liver cancer.

Chen W, Xin B, Pang H, et al.
Downregulation of estrogen receptor β inhibits lung adenocarcinoma cell growth.
Oncol Rep. 2019; 41(5):2967-2974 [PubMed] Related Publications
Estrogen receptor β (ERβ) is an important ER subtype in lung adenocarcinoma. However, the functions and mechanisms of ERβ have not been fully elucidated. The aim of the present study was to investigate the biological effects and relevant mechanisms of ERβ in lung adenocarcinoma. The protein expression of ERβ was found to be higher in lung adenocarcinoma tissues compared with that in adjacent non‑cancerous tissues (n=75, P<0.001). Of note, ERβ protein expression was significantly correlated with tumor size (P=0.018), lymph node metastasis (P=0.041), clinical stage (P=0.041) and differentiation (P<0.001). In addition, ERβ protein expression in A549 cells was found to be higher compared with that in human bronchial epithelial cells (HBEs). Furthermore, knockdown of ERβ expression inhibited colony formation and cell invasion in vitro, whereas the number of metastatic tumors in the lungs of mice was decreased in vivo. Western blot analysis demonstrated that the expression of phosphorylated extracellular signal‑regulated kinase (pERK), matrix metalloproteinase (MMP)‑2 and MMP‑9 was decreased by downregulation of ERβ. Therefore, ERβ may play an important role in lung adenocarcinoma progression via the MEK/ERK signaling axis, and it may represent a novel therapeutic target for lung adenocarcinoma in the future.

Wang J, Sun Z, Yan S, Gao F
Effect of miR‑145 on gastric cancer cells.
Mol Med Rep. 2019; 19(5):3403-3410 [PubMed] Free Access to Full Article Related Publications
Gastric cancer is one of the most common malignant tumors in the world. Due to the lack of early diagnosis and effective treatment, the outcome of treatment and prognosis is poor. MicroRNA‑145 (miR‑145) is downregulated in various cancer types. In the present study, miR‑145 expression was detected by reverse transcription‑quantitative polymerase chain reaction in gastric cancer cell lines and normal gastric epithelial cells. The function of miR‑145 in the gastric cancer cell line SGC‑7901 was investigated. The present results demonstrated that the expression of miR‑145 was downregulated in gastric cancer cells. Further analysis identified that upregulation of miR‑145 significantly suppressed SGC‑7901 cell proliferation, increased cellular apoptosis and blocked the cell cycle in the G1 phase. Additionally, overexpression of miR‑145 reduced SGC‑7901 cell invasion and metastasis in vitro. Western blot analysis demonstrated that overexpression of miR‑145 downregulated Myc proto‑oncogene protein, phosphoinositide 3‑kinase/protein kinase B and matrix metalloproteinase 2/9, and upregulated p21 in SGC‑7901 cells. The present results revealed potential signaling pathways that miR‑145 may use to regulate gastric cancer cell proliferation, apoptosis and metastasis. Collectively, the present results suggest that miR‑145 is a tumor suppressor for gastric cancer and it may be a potential therapeutic target for gastric cancer treatment.

Hsu PC, Pei JS, Chen CC, et al.
Association of
Anticancer Res. 2019; 39(3):1185-1190 [PubMed] Related Publications
BACKGROUND/AIM: The association of matrix metalloproteinase-2 (MMP-2) genotypes with adult leukemia has been reported only once, but never for childhood leukemia. This study aimed to determine the role of MMP-2 promoter -1306 (rs243865) and -735 (rs2285053) genotypes in childhood leukemia risk.
MATERIALS AND METHODS: This case-control study included 266 patients and 266 age- and gender-matched healthy controls. The polymorphic sites of MMP-2 were genotyped by typical polymerase chain reaction-restriction fragment length polymorphism.
RESULTS: The CC, CT and TT of rs243865 genotype were 75.2, 23.7 and 1.1% in the case group and 69.2, 28.9 and 1.9% in the control group, respectively. The CT and TT genotypes caused a 0.75- and 0.55-fold increase in the risk of childhood leukemia, respectively. There was no differential distribution of rs2285053 genotypes. Allelic frequency analysis showed that the T allele of MMP-2 promoter -1306 and -735 conferred lower susceptibility than the C allele.
CONCLUSION: The MMP-2 promoter genotypes play a minor role in determining personal susceptibility to childhood leukemia among the Taiwanese.

Jia W, Deng F, Fu W, et al.
Curcumin suppresses wilms' tumor metastasis by inhibiting RECK methylation.
Biomed Pharmacother. 2019; 111:1204-1212 [PubMed] Related Publications
Wilms' tumor (WT) is the most common kidney tumor of children. The transformation suppressor gene RECK, which codes membrane-anchored glycoprotein, frequently downregulates multiple matrix metalloproteinases in tumors. And curcumin, which is a polyphenlic compound separated from turmeric, has antitumor effects on various cancers. However, the correlation of WT, RECK and curcumin is still unrevealed. In this study, we evaluated that the methylation degree of RECK was much higher in WT than in adjacent non-tumor tissues. And RECK methylation was closely associated with tumor metastasis in WT patients. After curcumin treatment, the level of RECK methylation was decreased significantly. And the expression of MMP2 and MMP9 was reduced consequently. Moreover, the proliferation, invasion and migration ability of WT cells were suppressed after curcumin treatment. Meanwhile, the apoptosis rate of WT cells was increased simultaneously. In nude mice model, curcumin restrained ability of tumorigenicity and promoted apoptosis of WT cells. Together, our results suggest that the RECK methylation can serve as a prognostic biomarker of WT. Moreover, curcumin could inhibit RECK methylation, thereby abates the expression of MMPs, and suppresses the tumor progression and metastasis of WT.

Wang G, Yin L, Peng Y, et al.
Insulin promotes invasion and migration of KRAS
Cell Prolif. 2019; 52(3):e12575 [PubMed] Related Publications
OBJECTIVES: Hyperinsulinemia is a risk factor for pancreatic cancer, but the function of insulin in carcinogenesis is unclear, so this study aimed to elucidate the carcinogenic effects of insulin and the synergistic effect with the KRAS mutation in the early stage of pancreatic cancer.
MATERIALS AND METHODS: A pair of immortalized human pancreatic duct-derived cells, hTERT-HPNE E6/E7/st (HPNE) and its oncogenic KRAS
RESULTS: The migration and invasion ability of HPNE cells was increased after the introduction of the mutated KRAS gene, together with an increased expression of MMP-2. These effects were further enhanced by the simultaneous administration of insulin. The use of MMP-2 siRNA confirmed that MMP-2 was involved in the regulation of cell invasion. Furthermore, there was a concentration- and time-dependent increase in gelatinase activity after insulin treatment, which could be reversed by an insulin receptor tyrosine kinase inhibitor (HNMPA-(AM)
CONCLUSIONS: Taken together, these results suggest that insulin induced migration and invasion in HPNE and HPNE-mut-KRAS through PI3K/AKT and ERK1/2 activation, with MMP-2 gelatinolytic activity playing a vital role in this process. These findings may provide a new therapeutic target for preventing carcinogenesis and the evolution of pancreatic cancer with a background of hyperinsulinemia.

Fan HW, Ni Q, Fan YN, et al.
C-type lectin domain family 5, member A (CLEC5A, MDL-1) promotes brain glioblastoma tumorigenesis by regulating PI3K/Akt signalling.
Cell Prolif. 2019; 52(3):e12584 [PubMed] Related Publications
OBJECTIVES: Glioblastoma is the most common malignant glioma of all brain tumours. It is difficult to treat because of its poor response to chemotherapy and radiotherapy and high recurrence rate after treatment. The aetiology of glioblastoma is a result of disorders of multiple factors. Depending on cell signal transduction, these glioblastoma-associated factors lead to cell proliferation, differentiation and apoptosis. Therefore, investigation of the potential factors which involved in the development of glioblastoma could provide a new target for the treatment of glioblastoma.
MATERIALS AND METHODS: We analysed the transcript expression of CLEC5A in glioblastoma by accessing The Cancer Genome Atlas (TCGA). qRT-PCR was performed to detect the RNA expression of genes in cells and tissues, and Western blot was used to measure the protein levels (Cyclin D1, Bcl-2, BAX, PCNA, MMP2, MMP9, Akt and Akt phosphorylation) in tissues and cells. Cell proliferation, migration, invasion, cycle and apoptosis were measured by CCK-8, transwell and flow cytometry assays, respectively. Ki67 level and lung metastasis were determined by immunochemistry and H&E staining.
RESULTS: In this study, we found that CLEC5A was highly upregulated in glioblastoma compared to normal brain tissues, which had an opposite relation with the overall patient survival. Downregulation of CLEC5A could inhibit cell proliferation, migration and invasion via promoting apoptosis and G1 arrest. In contrast, overexpression of CLEC5A stimulated cell proliferation, migration and invasion. In addition, we found that CLEC5A level was positively correlated with Akt phosphorylation level. Akt inhibitor or agonist could reverse the modulation effects of CLEC5A in glioblastoma. Moreover, In vivo results suggested that inhibition of CLEC5A significantly reduced tumour size, weight, cell proliferation ability and lung metastasis via inhibition of phosphorylation Akt.
CONCLUSION: Both in vitro and in vivo evidences supported that CLEC5A was involved in glioblastoma pathogenesis via regulation of PI3K/Akt pathway. Thus, CLEC5A might serve as a potential therapeutic target in the treatment of glioblastoma in the future.

Zhu L, Xi PW, Li XX, et al.
The RNA binding protein RBMS3 inhibits the metastasis of breast cancer by regulating Twist1 expression.
J Exp Clin Cancer Res. 2019; 38(1):105 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Metastasis remains the biggest obstacle for breast cancer treatment. Therefore, identification of specific biomarker of metastasis is very necessary. The RNA binding protein 3 (RBMS3) acts as a tumor suppressor in various cancers. Whereas, its role and underlying molecular mechanism in breast cancer is far from elucidated.
METHODS: Quantitative real-time PCR and western blots were carried out to determine the expression of RBMS3 in breast cancer cells and tissues. Transwell and in vivo metastasis assay were conducted to investigate the effects of RBMS3 on migration, invasion and metastasis of breast cancer cells. Transcriptome sequencing was applied to screen out the differential gene expression affected by RBMS3. RNA immunoprecipitation assay combined with luciferase reporter assay were performed to explore the direct correlation between RBMS3 and Twist1 mRNA.
RESULTS: RBMS3 was downregulated in breast cancer and ectopic expression of RBMS3 contributed to inhibition of cell migration, invasion in vitro and lung metastasis in vivo. Furthermore, RBMS3 negatively regulated Twsit1 expression via directly binding to 3'-UTR of Twist1 mRNA, and thereby decreased Twist1-induced expression of matrix metalloproteinase 2 (MMP2). Additionally, Twist1-induced cell migration, invasion and lung metastasis could be reversed by the upregulation of RBMS3.
CONCLUSIONS: In summary, our study revealed a novel mechanism of the RBMS3/Twsit1/MMP2 axis in the regulation of invasion and metastasis of breast cancer, which may become a potential molecular marker for breast cancer treatment.

Wang W, Gao W, Zhang L, et al.
Deoxypodophyllotoxin inhibits cell viability and invasion by blocking the PI3K/Akt signaling pathway in human glioblastoma cells.
Oncol Rep. 2019; 41(4):2453-2463 [PubMed] Related Publications
Deoxypodophyllotoxin (DPT) is a natural chemical that has been demonstrated to inhibit cellular viability and motility in various cancer cell types. Although previous studies have indicated that programmed cell death and cell cycle arrest are involved in the suppression of glioma development by DPT, the underlying mechanism has not been fully explored. Different methods were used to the elucidate the mechanisms of DPT that inhibit the malignant behavior of glioma cells. Cellular viability was assessed by MTT assay. Relative protein and mRNA expression levels were detected by western blot analysis and reverse transcription‑quantitative polymerase chain reaction analyses, respectively. Cell cycle distribution and the apoptosis rate were detected by flow cytometry. Hochest 33258 staining was also performed to detect apoptosis. Transwell assays without and with Matrigel were used to assess migration and invasion abilities, respectively. It was determined that DPT suppressed cellular viability by inducing cell cycle arrest at the G1/S phase by targeting the phosphatidylinositol 4,5‑bisphosphate 3‑kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (Akt)‑cyclin‑dependent kinase inhibitor 1‑cyclin‑dependent kinase 2/cyclin E signaling cascades. Additionally, DPT significantly enhanced apoptosis by attenuating the PI3K/Akt‑mediated suppression of Bcl‑2‑associated agonist of cell death expression, which was accompanied by an increased apoptosis regulator BAX/apoptosis regulator Bcl‑2 ratio. Furthermore, DPT downregulated the invasiveness of glioma cells by hindering PI3K/Akt‑matrix metalloproteinase (MMP)9/MMP2 signaling pathways. In conclusion, DPT effectively inhibited the expression of PI3K and downregulated PI3K/Akt‑mediated signaling pathways to prevent glioblastoma progression.

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