Ezrin Ser66 phosphorylation regulates invasion and metastasis of esophageal squamous cell carcinoma cells by mediating filopodia formation

BackgroundEzrin, links the plasma membrane to the actin cytoskeleton, and plays an important role in the development and progression of human esophageal squamous cell carcinoma (ESCC). However, the roles of ezrin S66 phosphorylation in tumorigenesis of ESCC remain unclear.MethodsDistribution of ezrin in membrane and cytosol fractions was examined by analysis of detergent-soluble/-insoluble fractions and cytosol/membrane fractionation. Both immunofluorescence and live imaging were used to explore the role of ezrin S66 phosphorylation in the behavior of ezrin and actin in cell filopodia. Cell proliferation, migration and invasion of ESCC cells were investigated by proliferation and migration assays, respectively. Tumorigenesis, local invasion and metastasis were assessed in a nude mouse model of regional lymph node metastasis.ResultsEzrin S66 phosphorylation enhanced the recruitment of ezrin to the membrane in ESCC cells. Additionally, non-phosphorylatable ezrin (S66A) significantly prevented filopodia formation, as well as caused a reduction in the number, length and lifetime of filopodia. Moreover, functional experiments revealed that expression of non-phosphorylatable ezrin (S66A) markedly suppressed migration and invasion but not proliferation of ESCC cells in vitro, and attenuated local invasion and regional lymph node metastasis, but not primary tumor growth of ESCC cells in vivo.ConclusionEzrin S66 phosphorylation enhances filopodia formation, contributing to the regulation of invasion and metastasis of esophageal squamous cell carcinoma cells.     

Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin

EGFR is a potent stimulator of invasion and metastasis in head and neck squamous cell carcinomas (HNSCC). However, the mechanism by which EGFR may stimulate tumor cell invasion and metastasis still need to be elucidated. In this study, we showed that activation of EGFR by EGF in HNSCC cell line SCC10A enhanced cell migration and invasion, and induced loss of epitheloid phenotype in parallel with downregulation of E-cadherin and upregulation of N-cadherin and vimentin, indicating that EGFR promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition (EMT)-like phenotype change. Interestingly, activation of EGFR by EGF induced production of matrix metalloproteinase-9 (MMP-9) and soluble E-cadherin (sE-cad), and knockdown of MMP-9 by siRNA inhibited sE-cad production induced by EGF in SCC10A. Moreover, both MMP-9 knockdown and E-cadherin overexpression inhibited cell migration and invasion induced by EGF in SCC10A. The results indicate that EGFR activation promoted cell migration and invasion through inducing MMP-9-mediated degradation of E-cadherin into sE-cad. Pharmacologic inhibition of EGFR, MEK, and PI3K kinase activity in SCC10A reduced phosphorylated levels of ERK-1/2 and AKT, production of MMP-9 and sE-cad, cell migration and invasion, and expressional changes of EMT markers (E-cadherin and N-cadherin) induced by EGF, indicating that EGFR activation promotes cell migration and invasion via ERK-1/2 and PI3K-regulated MMP-9/E-cadherin signaling pathways. Taken together, the data suggest that EGFR activation promotes HNSCC SCC10A cell migration and invasion by inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin into sE-cad related to activation of ERK-1/2 and PI3K signaling pathways.     

RKIP inhibits the migration and invasion of human prostate cancer PC-3M cells through regulation of extracellular matrix

Raf kinase inhibitor protein (RKIP) plays a pivotal role in several intracellular signaling cascades and has been implicated as a metastasis suppressor in multiple cancer cells including prostate cancer cells, but the mechanism is not very clear. In this study, we investigated the effect of RKIP on cell proliferation, migration and invasion using human prostate cancer PC-3M cells as a model system. Our results indicate that RKIP does not effect cell proliferation in PC-3M cells, but inhibits both cell migration and cell invasion. In association with this inhibitory effect, RKIP down-regulates matrix metalloproteinases (MMP-2 and MMP-9), cathepsin B and urinary plasminogen activator (uPA). Also RKIP has the ability to regulate the expression of E-cadherin. But ectopic expression of RKIP does not affect the level of the Snail protein. As it has been indicated here, RKIP inhibits the migration and invasion ability of human prostate cancer cells through regulation of the extracellular matrix. These findings provide new mechanistic insight how RKIP suppresses metastasis in vitro.     

PKM2-regulated STAT3 promotes esophageal squamous cell carcinoma progression via TGF-β1-induced EMT

Recent studies have demonstrated pleiotropic roles of pyruvate kinase isoenzyme type M2 (PKM2) in tumor progression. However, the precise mechanisms underlying the effects of PKM2 on esophageal squamous cell carcinoma (ESCC) metastasis and transforming growth factor β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) remain to be established. In this study, we observed upregulation of PKM2 in ESCC tissues that was markedly associated with lymph node metastasis and poor prognosis. High PKM2 expression in tumor tissues frequently coincided with the high pSTAT3Tyr705 expression and low E-cadherin expression. Furthermore, altered PKM2 expression was significantly associated with proliferation, migration, and invasion of ESCC cells, in addition to expression patterns of EMT markers (Snail, E-cadherin, and vimentin) and pSTAT3^Tyr705/STAT3 ratio. Overexpression of STAT3 significantly attenuated the effects of PKM2 knockdown on cell proliferation and motility as well as expression of pSTAT3 ^Tyr705 and EMT markers. Consistently, stable short hairpin RNA (shRNA)-mediated silencing of PKM2 reversed the effects of TGF-β1 treatment, specifically, upregulation of PKM2, phosphorylation of STAT3 at Tyr705, and increased EMT, migration, and invasion. We propose that PKM2 regulates cell proliferation, migration, and invasion via phosphorylation of STAT3 through TGF-β1-induced EMT. Our findings collectively provide mechanistic insights into the tumor-promoting role of PKM2, supporting its prognostic value and the therapeutic utility of PKM2 inhibitors as potential antitumor agents in ESCC.     

IGHMBP2过表达促进食管鳞癌细胞的侵袭和迁移

IGHMBP2(Immunoglobulin mu binding protein 2)基因编码一种解旋酶,参与DNA的复制和修复,并且作为转录调节因子在基因转录中发挥重要作用。IGHMBP2基因定位于11q13.2,该染色体区段在食管鳞癌中扩增频率较高。为了探讨IGHMBP2基因在食管鳞癌中的扩增情况及其在食管鳞癌中的作用,文章对本实验室前期报道的59例食管鳞癌原发肿瘤array-CGH数据进行分析,结果显示IGHMBP2基因扩增频率为28.9%(17/59)。进一步利用荧光原位杂交(FISH)和Western blot技术,发现食管鳞癌细胞系KYSE30、KYSE180、KYSE510和KYSE150中存在IGHMBP2基因扩增/增益以及蛋白高表达。敲降IGHMBP2后,KYSE30和KYSE150细胞的侵袭迁移能力明显降低(P<0.001),侵袭迁移相关蛋白E-cadherin的表达水平升高;敲降后转染IGHMBP2质粒,回复其蛋白表达后,细胞的侵袭迁移能力又得以恢复(P<0.01)。上述结果表明,IGHMBP2过表达可能通过降低E-cadherin的表达从而增强食管鳞癌细胞的侵袭迁移能力。     

RASSF6-TRIM16 axis promotes cell proliferation,migration and invasion in esophageal squamous cell carcinoma

Ras-association(RA) domain family number 6(RASSF6) is a member of the Ras-association domain protein family.It is epigenetically inactive and negatively regulates the malignant progression of some tumors.However,its precise role in esophageal squamous cell carcinoma(ESCC) has not been reported.In this study,we performed immunohistochemistry(IHC) assay.The results show that RASSF6 is upregulated in ESCC and that the elevated expression level of RASSF6 is associated with lymph node metastasis and poor survival of ESCC patients.Consistent with the clinical obse rvations,the upregulation of RASSF6 greatly promotes ESCC cell proliferation,migration and invasion as well as the cell cycle transition to Gl/S phase in vitro.According to models in vivo,the downregulation of RASSF6 considerably inhibits ESCC tumor growth and lung metastasis.Mechanistically,RASSF6 negatively regulates the tumor suppressor tripartite-motif-containing protein 16(TRIM16) by promoting its ubiquitination-dependent degradation and eventually activates pathways associated with the cell cycle and epithelialmesenchymal transition(EMT).Together,these results indicate that the RASSF6-TRIM16 axis is a key effector in ESCC progression and that RASSF6 serves as a potential target for the treatment of ESCC.     

Copper transporter Ctr1 contributes to enhancement of the sensitivity of cisplatin in esophageal squamous cell carcinoma

Increasing evidence has demonstrated that Ctr1 plays a crucial role in the regulation of cisplatin uptake in a variety of tumors. The purpose of this study was to investigate its role in mediating cisplatin sensitivity in ESCC cells. Immunohistochemistry (IHC), In situ hybridization (ISH) and semi-quantitative RT-PCR were used to detect Ctr1 expressions in ESCC tissues. qRT-PCR and Western blot was performed to investigate the levels of Ctr1 mRNA and protein in ESCC cells. CCK-8, Flow cytometry and Transwell chamber assay were carried out to examine cell proliferation, apoptosis, migration and invasion abilities in ESCC cells. We found that ESCC tissues and cells had higher Ctr1 level than normal tissues and Het-1A cell. Ctr1 expression was correlated with histological grade, invasion depth, TNM staging and lymph node metastasis in ESCC patients. Ctr1 depletion reduced the suppressive role of proliferation, migration and invasion as well as the inductive role of cell apoptosis and Caspase-3 activity evoked by cisplatin, whereas Ctr1 upregulation combined with cisplatin exerted the synergistic role in regulation of proliferation, apoptosis, Caspase-3 activity, migration and invasion in ESCC. In conclusion, Ctr1 is implicated in ESCC development and progression and its expression may be a novel predictor for assessment of cisplatin sensitivity in ESCC.     

Up-regulating ribonuclease inhibitor inhibited epithelial-to-mesenchymal transition and metastasis in murine melanoma cells

Human ribonuclease inhibitor (RI) is a cytoplasmic acidic protein. RI is constructed almost entirely of leucine rich repeats, which might be involved in unknown biological effects except inhibiting RNase A and angiogenin activities. We previously reported that up-regulating RI inhibited the growth and metastasis of melanoma cells. Epithelial-mesenchymal transition (EMT) is a critical event of cancer cells that triggers invasion and metastasis. However, the role of RI in the EMT process remains unknown. Here we hypothesize that RI might inhibit melanoma invasion and metastasis by regulating EMT. We found that over-expression of RI induced up-regulation of E-cadherin, accompanied with decreased expressions of proteins associated with EMT such as N-cadherin, Snail, Slug, Vimentin and Twist both in vitro and in vivo. Furthermore, RI restrained matrix metalloproteinase MMP-2 and MMP-9 secretions in B16 and B16-F10 melanoma cells. In addition, we also found that up-regulation of RI inhibited cell proliferation, migration and invasion as well as changed cell morphology, adhesion and rearranged cytoskeleton in vitro. Finally, the effects of RI on phenotype and invasiveness translated into suppressing metastasis by the experimental metastasis models of melanoma with lighter lung weight, a fewer metastasis nodules and a lower incidence rate, with respect to the control groups. Taken together, our data highlight, for the first time, that RI plays a novel role in inhibiting development and progression of murine melanoma cells through regulating EMT. These results suggest that RI could be a therapeutic target protein for melanoma and may be of biological importance.     

Overexpression of Aurora-A enhances invasion and matrix metalloproteinase-2 expression in esophageal squamous cell carcinoma cells

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers, and metastasis is the principal cause of death in ESCC patients. It has been shown that amplification and overexpression of mitotic serine/threonine kinase Aurora-A occur in several types of human tumors, including ESCC. Moreover, increase in expression levels of Aurora-A has been predicted to correlate with the grades of tumor differentiation and invasive capability. However, the mechanisms by which Aurora-A mediates its invasive effects still remain elusive. In this article, we showed that Aurora-A overexpression significantly increased cell migration and invasion as well as secretion and expression of matrix metalloproteinase-2 (MMP-2). Conversely, siRNA-mediated knockdown of Aurora-A expression in human ESCC cells led to inhibition of cell invasiveness as well as secretion and expression of MMP-2. In addition, Aurora-A overexpression increased phosphorylation levels of p38 mitogen-activated protein kinase (MAPK) and Akt, and the knockdown of Aurora-A by siRNA decreased the activity of p38 MAPK and Akt. Moreover, the blocking of the activity of above kinases using chemical inhibitors suppressed the ability of Aurora-A to induce MMP-2 secretion and expression as well as cell invasion. These data show that overexpression of Aurora-A contributes to the malignancy development of ESCC by enhancing tumor cell invasion as well as MMP-2 activity and expression, which can occur through signaling pathways involving p38 MAPK and Akt protein kinases. Taken together, these studies provide a molecular basis for promoting the role of Aurora-A in malignancy development of ESCC.     

Intestinal trefoil factor promotes invasion in non-tumorigenic Rat-2 fibroblast cell

Intestinal trefoil factor (TFF3) is essential in regulating cell migration and maintaining mucosal integrity in gastrointestinal tract. We previously showed that TFF3 was overexpressed in gastric carcinoma. Whether TFF3 possesses malignant potential is not fully elucidated. We sought to investigate the effects of inducting TFF3 expression in a non-malignant rat fibroblast cell line (Rat-2) on the cell proliferation, invasion and the genes regulating cell invasion. Invasiveness and proliferation of transfected Rat-2 cell line were assessed using in vitro invasion chamber assay and colorimetric MTS assay. Differential mRNA expressions of invasion-related genes, namely, metalloproteinases (MMP-9), tissue inhibitors of metalloproteinases (TIMP-1), beta-catenin and E-cadherin, were determined by quantitative real-time polymerase chain reaction (PCR). We showed that TFF3 did not inhibit the proliferation of Rat-2 cells. We also demonstrated that transfection of TFF3 significantly promoted invasion of Rat-2 cells by 1.4- to 2.2-folds. There was an upregulation of beta-catenin (13.1-23.0%) and MMP-9 (43.4-92.2%) mRNA expression levels, and downregulation of E-cadherin (25.6-33.8%) and TIMP-1 (31.5-37.8%) in TFF3-transfected cells compared to controls during 48-h incubation. Our results suggested that TFF3 possesses malignant potential through promotion of cell invasiveness and alteration of invasion-related genes.     

Association of matrix metalloproteinases-9 gene polymorphisms with genetic susceptibility to esophageal squamous cell carcinoma

Matrix metalloproteinases-9 (MMP-9) plays important roles in tumor invasion and metastasis by degrading extracellular matrix components. Variations in the DNA sequence in the MMP-9 gene may lead to altered MMP-9 production and/or activity, and so this may modulate an individual's susceptibility to esophageal squamous cell carcinoma (ESCC). To test this hypothesis, we investigated the association of the MMP-9 polymorphisms and their haplotypes with the risk of ESCC in a Chinese population. There were significant differences in the genotype and allele distribution of P574R polymorphism of the MMP-9 gene among cases and controls. The P574R GG genotypes were associated with a significantly increased risk of ESCC as compared with the CC genotypes (odds ratio [OR] = 4.08; 95% confidence interval [CI]: 1.58-10.52; p = 0.00). Compared with 279R-574P haplotype, 279R-574R (OR = 3.52; 95% CI: 1.99-6.25) and 279Q-574P (OR = 2.16; 95% CI: 1.07-4.35) haplotypes can increase the onset risk of ESCC statistically, but the role of 279R-574R haplotype is more obvious. MMP-9 P574R polymorphisms and P574R-R279Q haplotype are significantly associated with the risk of ESCC. Our study shows for the first time that MMP-9 gene P574R polymorphism may contribute to a genetic risk factor for ESCC in a Chinese population.     

Aspirin inhibits matrix metalloproteinase-2 activity, increases E-cadherin production, and inhibits in vitro invasion of tumor cells

Aspirin (acetylsalicylic acid) is a widely used anti-inflammatory drug. Recently, aspirin was shown to reduce the risk of development of cancer and mortality from it. Tumor metastasis is the most important cause of cancer death. The aim of the present study was to investigate if aspirin affects the invasion of cancer cells. Matrix metalloproteinases (MMPs) and cell adhesion molecules play important roles in the modulation of tumor invasion. Gelatin-based zymography assay showed that aspirin inhibited MMP-2 activity of SK-Hep-1 cancer cells. Matrigel-based chemoinvasion assay showed that aspirin inhibited in vitro invasion of SK-Hep-1 cancer cells. Aspirin treatment also increased the production of the cell adhesion molecule, E-cadherin, in Hep G2 cancer cells. Aspirin is a cyclooxygenase (COX) inhibitor. Treatment of cells with another COX inhibitor, sulindac, also inhibited MMP-2 activity and increased E-cadherin production of cells. These results indicate that aspirin can modulate both MMP-2 and E-cadherin production and therein may possess antimetastatic effect.     

S-Allylcysteine reduces breast tumor cell adhesion and invasion

Previous studies show that aqueous garlic extract and its derivatives (e.g. S-allylcysteine [SAC]) prevent carcinogen-induced breast tumorigenesis. However, investigations testing the effect of SAC on later stages of breast tumorigenesis and/or metastasis have produced mixed results. Here we show that SAC significantly reduced anchorage-dependent and -independent growth of MDA-MB-231 breast tumor cells in a dose- and time-dependent fashion, and sub-lethal SAC-treatment altered mammary tumor cell adhesion and invasion through components of the extracellular matrix. We provide evidence to suggest increased expression of E-cadherin and reduced MMP-2 expression and activity are partially responsible for inhibition of mammary tumor cell invasion by SAC. Because E-cadherin and MMP-2 are important in cancer metastasis, these results suggest a link between SAC induction of E-cadherin and reduction of MMP2 activity with the inhibition of cell motility and invasion; thus providing evidence that events leading to breast cancer metastasis are repressed by sub-lethal SAC-treatment.     

A novel role of ribonuclease inhibitor in regulation of epithelial-to-mesenchymal transition and ILK signaling pathway in bladder cancer cells

Human ribonuclease inhibitor (RI) is a cytoplasmic acidic protein possibly involved in biological functions other than the inhibition of RNase A and angiogenin activities. We have previously shown that RI can inhibit growth and metastasis in some cancer cells. Epithelial-mesenchymal transition (EMT) is regarded as the beginning of invasion and metastasis and has been implicated in the metastasis of bladder cancer. We therefore postulate that RI regulates EMT of bladder cancer cells. We find that the over-expression of RI induces the up-regulation of E-cadherin, accompanied with the decreased expression of proteins associated with EMT, such as N-cadherin, Snail, Slug, vimentin and Twist and of matrix metalloprotein-2 (MMP-2), MMP-9 and Cyclin-D1, both in vitro and in vivo. The up-regulation of RI inhibits cell proliferation, migration and invasion, alters cell morphology and adhesion and leads to the rearrangement of the cytoskeleton in vitro. We also demonstrate that the up-regulation of RI can decrease the expression of integrin-linked kinase (ILK), a central component of signaling cascades controlling an array of biological processes. The over-expression of RI reduces the phosphorylation of the ILK downstream signaling targets p-Akt and p-GSK3β in T24 cells. We further find that bladder cancer with a high-metastasis capability shows higher vimentin, Snail, Slug and Twist and lower E-cadherin and RI expression in human clinical specimens. Finally, we provide evidence that the up-regulation of RI inhibits tumorigenesis and metastasis of bladder cancer in vivo. Thus, RI might play a novel role in the development of bladder cancer through regulating EMT and the ILK signaling pathway.     

Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis

E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell-cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin-mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin-expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin-expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin-expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin-expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin-expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin-expressing cells.     

Identification of metastasis candidate proteins among HCC cell lines by comparative proteome and biological function analysis of S100A4 in metastasis in vitro

Widespread metastasis of hepatocellular carcinoma (HCC) was a complex cascade of events, which is still beyond full appreciation. Screening key proteins, which play a critical role in metastasis, using high-throughput proteomics approach help discover valuable biomarkers and elucidate the mechanism of metastasis. This study was to find out some metastasis candidate proteins among HCC cell lines with various metastatic potential by comparative proteomics, and then further validate the biological function of these proteins in metastasis in vitro. The protein profiles of metastatic HCC cell lines (MHCC97H and MHCC97L) displayed obvious differences compared with nonmetastatic ones (Hep3B). Twenty-six metastasis candidate proteins, which were identified by on-line LC-ESI-MS/MS, such as S100 calcium-binding protein A4 (S100A4), annexin 1, etc., might have much application in diagnostic procedures and prognosis evaluation. S100A4, as a leading different metastasis candidate protein, which overexpressed only in the metastatic cells, was selected for further investigation. A series of assays related to invasion and metastasis in vitro, including cell motility, invasion, and matrix metalloproteinases (MMPs) secretion, were performed in MHCC97H/antisense recombinant plasmid to S100A4 (pcDNA3.1(+) AS S100A4) and the mock controls. All the data in the present study suggested that S100A4 might contribute to HCC invasion and metastasis through two paths of matrix metalloproteinase (MMP9) secretion regulation and strengthened motility and invasion properties.     

Effect of tumor-associated mutant E-cadherin variants with defects in exons 8 or 9 on matrix metalloproteinase 3

Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. The cell adhesion molecule E-cadherin is frequently down-regulated or mutated in tumors. In addition to down-regulation of cell adhesion, degradation of the extracellular matrix by matrix metalloproteinases is necessary for tumor cell spread. To investigate a possible link between E-cadherin and matrix metalloproteinase 3 (MMP-3), we examined expression of MMP-3 in human MDA-MB-435S cells transfected with wild-type (wt) or three different tumor-associated mutant E-cadherin variants with alterations in exons 8 or 9, originally identified in gastric carcinoma patients. In the presence of wt E-cadherin, the MMP-3 protein level was decreased in cellular lysates and in the supernatant where a secreted form of the protein is detectable. Down-regulation of MMP-3 was not found in MDA-MB-435S transfectants expressing mutant E-cadherin variants which indicates that E-cadherin mutations interfere with the MMP-3 suppressing function of E-cadherin. The mechanism of regulation of MMP-3 by E-cadherin is presently not clear. We have previously found that cell motility is enhanced by expression of the mutant E-cadherin variants used in this study. Here, we found that application of the synthetic inhibitor of MMP-3 NNGH and small interfering RNA (siRNA) directed against MMP-3 reduce mutant E-cadherin-enhanced cell motility. Taken together, our results point to a functional link between MMP-3 and E-cadherin. MMP-3 is differentially regulated by expression of wt or mutant E-cadherin. On the other hand, MMP-3 plays a role in the enhancement of cell motility by mutant E-cadherin. Both observations may be highly relevant for tumor progression since they concern degradation of the extracellular matrix and tumor cell spread.     

Selection of peptide inhibitor to matrix metalloproteinase-2 using phage display and its effects on pancreatic cancer cell lines PANC-1 and CFPAC-1

Despite tremendous advances in cancer treatment and survival rates, pancreatic cancer remains one of the most deadly afflictions and the fourth leading cause of cancer deaths in the world. Matrix Metalloproteinases (MMPs) are thought to be involved in cancer progression. Matrix metalloproteinase (MMP)-2 is known to play a pivotal role in tumor invasion, metastasis and angiogenesis, and validated to be the anticancer target. Inhibition of MMP-2 activity is able to reduce the cancer cell invasion and suppress tumor growth in vivo. Two novel peptides, M204C4 and M205C4, which could specially inhibit MMP-2 activity, were identified by a phage display library screening. We showed that M204C4 and M205C4 inhibited the activity of MMP-2 in a dose dependent manner in vitro. Two peptides reduced MMP-2 mediated invasion of the pancreatic cancer cell lines PANC-1 and CFPAC-1, but not affected the expression and release of MMP-2. Furthermore, these two peptides could suppress tumor growth in vivo. Our results indicated that two peptides selected by phase display technology may be used as anticancer drugs in the future.