Expression of MTA1 promotes motility and invasiveness of PANC-1 pancreatic carcinoma cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Hofer MD
PROVIDER: S-EPMC2409548 | biostudies-other | 2004 Jan
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, proving difficult to manage clinically. Wnt-11, a developmentally regulated gene producing a secreted protein, has been associated with various carcinomas but has not previously been studied in PDAC. The present study aimed to elucidate these aspects first in vitro and then in a clinical setting in vivo. Molecular analyses of Wnt-11 expression as well as other biomarkers involved qRT-PCR, RNA-seq and siRNA. Proliferation was measured by MTT; invasiveness was quantified by Boyden chamber (Matrigel) assay. Wnt-11 mRNA was present in three different human PDAC cell lines. Wnt-11 loss affected epithelial-mesenchymal transition and expression of neuronal and stemness biomarkers associated with metastasis. Indeed, silencing Wnt-11 in Panc-1 cells significantly inhibited their Matrigel invasiveness without affecting their proliferative activity. Consistently with the in vitro data, human biopsies of PDAC showed significantly higher Wnt-11 mRNA levels compared with matched adjacent tissues. Expression was significantly upregulated during PDAC progression (TNM stage I to II) and maintained (TNM stages III and IV). Wnt-11 is expressed in PDAC in vitro and in vivo and plays a significant role in the pathophysiology of the disease; this evidence leads to the conclusion that Wnt-11 could serve as a novel, functional biomarker PDAC.
| S-EPMC6895970 | biostudies-literature
Project description:As a tumor?associated microRNA (miR), miR?212 has dual functions; either as an oncogene or a tumor suppressor. A high expression level of miR?212 was reported to be associated with poor outcome in patients with esophageal squamous cell carcinoma (ESCC), however, its role in ESCC progression has not been explored. In the present study, an in vitro cell model of lentivirus?mediated gain?of?function demonstrated promotion of ESCC cell migration and invasion when miR?212 was overexpressed, and no effect on cell proliferation. miR?212 resulted in downregulation of the expression of E?cadherin, ??catenin, vimentin and Twist1. Moreover, it led to increased levels of extracellular matrix (ECM)?degrading enzymes, matrix metalloproteinase?9 and urokinase?type plasminogen activator. Furthermore, berberine inhibited miR?212?induced ESCC cell migration, unlike the PI3K inhibitor LY294002, rapamycin (mTOR inhibitor), 5?(Tetradecyloxy)?2?furoic acid (TOFA; an acetyl?CoA carboxylase 1 inhibitor), metformin and propranolol. These data suggest that miR?212 activates multiple signaling cascades and facilitates ESCC cell motility and invasion by promoting the epithelial?mesenchymal transition and degrading the ECM. Berberine may be a potential therapeutic agent against metastasis in patients with ESCC, who express high levels of miR?212.
| S-EPMC6755231 | biostudies-literature
Project description:Pancreatic cancer is an aggressive disease that responds poorly to conventional photon radiotherapy. Carbon-ion (C-ion) radiation has advantages compared with conventional radiotherapy, because it enables more accurate dose distribution and more efficient tumor cell killing. To elucidate the effects of local radiotherapy on the characteristics of metastatic tumors, it is necessary to understand the nature of motility in irradiated tumor cells; this will, in turn, facilitate the development of effective strategies to counter tumor cell motility, which can be used in combination with radiotherapy. The aim of the present study was to examine the invasiveness of pancreatic cancer cells exposed to C-ion irradiation. We found that C-ion irradiation suppressed the migration of MIAPaCa-2, BxPC-3 and AsPC-1; diminished the invasiveness of MIAPaCa-2; and tended to reduce the invasion of BxPC-3 and AsPC-1. However, C-ion irradiation increased the invasiveness of PANC-1 through the activation of plasmin and urokinase-type plasiminogen activator. Administration of serine protease inhibitor (SerPI) alone failed to reduce C-ion-induced PANC-1 invasiveness, whereas the combination of SerPI and Rho-associated coiled-coil forming protein kinase (ROCK) inhibitor suppressed it. Furthermore, PANC-1 showed mesenchymal-amoeboid transition when we treated with SerPI alone. In conclusion, C-ion irradiation is effective in suppressing the invasive potential of several pancreatic tumor cell lines, but not PANC-1; this is the first study showing that C-ion irradiation induces the invasive potential of a tumor cell line. Further in vivo studies are required to examine the therapeutic effectiveness of radiotherapy combined with inhibitors of both mesenchymal and amoeboid modes of tumor cell motility.
| S-EPMC7713567 | biostudies-literature
Project description:Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor ? (TGF?) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGF? signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy.
| S-EPMC3161761 | biostudies-literature
Project description:Pancreatic cancer (PC) is one of the deadliest cancers and remains a major challenge due to its invasive and metastatic nature. Increased levels of CCR5 and CCL5 have established indicators for disease status in various cancers, including PC. However, their role in invasion and metastasis of PC is not known. Here we conducted immunohistochemistry of PC tissues and found elevated epithelial staining for CCR5 and CCL5 in metastatic PC tissues compared to non-neoplastic. In vitro experiments, such as flow cytometry, immunofluorescence and western blotting with human PC cell lines (AsPc-1, BxPc-3 and MIA PaCa-2), showed higher expression levels of CCR5. The CCL5 activation of PC cells expressing CCR5 increased their invasive potential, while treatment with CCR5 inhibitor maraviroc inhibited the CCL5 activation. CCL5 induced proliferation of PC cells was mediated through F-actin polymerization, while there was marked reduction when the cells were treated with maraviroc. The direct interaction of CCR5 with CCL5 was verified using a calcium mobilization assay. Taken together, our results demonstrate that CCR5 and CCL5 are potential markers for metastatic PC cancer, and their interaction leads to the increased PC cell invasion. Thus, blocking CCR5/CCL5 axis might prove beneficial to prevent metastasis and provide a more therapeutic strategy to control PC progression.
| S-EPMC5778036 | biostudies-literature
Project description:The Plexins family of proteins are well-characterized transmembrane receptors of semaphorins, axon guidance cue molecules, that mediate the cell attraction or repelling effects for such cues. Plexins and their ligands are involved in numerous cellular activities, such as motility, invasion, and adhesion to the basement membrane. The detachment of cells and the gain in motility and invasion are hallmarks of the cancer metastasis cascade, thus generating interest in exploring the role of plexins in cancer metastasis. Semaphorin-plexin complexes can act as tumor promoters or suppressors, depending upon the cancer type, and are under investigation for therapeutic purposes. Our group has identified Semaphorin-5A (SEMA5A)/Plexin-B3 as an attractive targetable complex for pancreatic cancer (PC) metastasis. However, our understanding of the Plexin-B3 function and pathological expression in PC is limited, and our present study delineates the role of Plexin-B3 in PC malignancy. We examined the pathological expression of Plexin-B3 in PC tumors and metastasis using a human tissue microarray, disease progression model of PDX-Cre-Kras(G12D) (KC) mice, and different metastatic sites obtained from the KrasG12D; Trp53R172H; Pdx1-Cre (KPC) mice model. We observed a higher Plexin-B3 expression in PC tumor cores than the normal pancreas, and different metastatic sites were positive for Plexin-B3 expression. However, in the KC mice model, the Plexin-B3 expression increased initially and then decreased with the disease progression. Next, to evaluate the functional role of Plexin-B3, we utilized T3M-4- and CD18/HPAF-Control and -Plexin B3 knockdown cells for different in vivo and in vitro studies. The knockdown of Plexin-B3 enhanced the in vitro cellular migration, invasiveness, and impaired colony formation in three-dimensional culture, along with an increase in cellular spread and remodeling of the actin filaments. We also observed a higher metastasis in nude mice injected with T3M-4- and CD18/HPAF-shPlexin-B3 cells compared to their respective control cells. Furthermore, we observed a lower number of proliferating Ki-67-positive cells and higher ALDH1-A1-positive cells in the tumors formed by Plexin-B3 knockdown cells compared to tumors formed by the control cells. Together, our data suggest that the loss of Plexin-B3 is associated with the interference of cell division machinery and the induction of stem cell-like characteristics in PC cells.
| S-EPMC7919786 | biostudies-literature
Project description:Although the roles and underlying mechanisms of other PDK family members (i.e., PDK1, PDK2 and PDK3) in tumor progression have been extensively investigated and are well understood, the functions and underlying molecular mechanisms of pyruvate dehydrogenase kinase 4 (PDK4) in the tumorigenesis and progression of various cancers [including hepatocellular carcinoma (HCC)] remain largely unknown. In this study, we examined the expression profile of PDK4 in HCC clinical tissue specimens and the roles of PDK4 in the proliferation, tumorigenicity, motility and invasion of HCC cells. The immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) results revealed that PDK4 was significantly downregulated in the cohort of HCC clinical specimens. Additionally, PDK4 protein was found in both the nucleus and cytoplasm of HCC cells based on an immunofluorescence (ICC) assay, and PDK4 protein was also found in the nucleus and cytoplasm of cancer cells contained in HCC clinical specimens based on IHC. The CCK-8 assay and cell colony formation assay demonstrated that stable depletion of endogenous PDK4 by lentivirus-mediated RNA interference (RNAi) markedly promoted the proliferation of HCC cell lines (i.e., BEL-7402 and BEL-7404 cells) in vitro, while PDK4 silencing significantly enhanced the tumorigenic ability of BEL-7404 cells in vivo. In addition to enhance proliferation and tumorigenesis induced by PDK4 silencing, additional studies demonstrated that knockdown of PDK4 led to increase migration and invasion of BEL-7402 and BEL-7404 cells in vitro. Taken together, these findings suggest that the loss of PDK4 expression contributes to HCC malignant progression.
| S-EPMC7255379 | biostudies-literature
Project description:Exosomes are important intercellular communicators, where tumor exosomes (TEX) severely influence hematopoiesis and premetastatic organ cells. With the extracellular matrix (ECM) being an essential constituent of non-transformed tissues and tumors, we asked whether exosomes from a metastatic rat tumor also affect the organization of the ECM and whether this has consequences on host and tumor cell motility. TEX bind to individual components of the ECM, the preferential partner depending on the exosomes' adhesion molecule profile such that high CD44 expression is accompanied by hyaluronic acid binding and high ?6?4 expression by laminin (LN) 332 binding, which findings were confirmed by antibody blocking. TEX can bind to the tumor matrix already during exosome delivery but also come in contact with distinct organ matrices. Being rich in proteases, TEX modulate the ECM as demonstrated for degradation of collagens, LNs, and fibronectin. Matrix degradation by TEX has severe consequences on tumor and host cell adhesion, motility, and invasiveness. By ECM degradation, TEX also promote host cell proliferation and apoptosis resistance. Taken together, the host tissue ECM modulation by TEX is an important factor in the cross talk between a tumor and the host including premetastatic niche preparation and the recruitment of hematopoietic cells. Reorganization of the ECM by exosomes likely also contributes to organogenesis, physiological and pathologic angiogenesis, wound healing, and clotting after vessel disruption.
| S-EPMC3730040 | biostudies-literature
Project description:We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1), MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression.
| S-EPMC4524119 | biostudies-literature
Project description:BackgroundHigh levels of S100A6 have been associated with poor outcome in pancreatic cancer patients. The functional role of S100A6 is, however, poorly understood.MethodsImmunoprecipitation followed by two-dimensional gel electrophoresis and mass spectrometry were undertaken to identify S100A6 interacting proteins in pancreatic cancer cells. Immunohistochemistry and coimmunofluorescence were performed to examine expression or colocalisation of proteins. siRNA was used to deplete specific proteins and effects on motility were measured using Boyden Chamber and wound healing assays.ResultsOur proteomic screen to identify S100A6 interacting proteins revealed annexin 11, annexin 2, tropomyosin beta and a candidate novel interactor lamin B1. Of these, annexin 2 was considered particularly interesting, as, like S100A6, it is expressed early in the development of pancreatic cancer and overexpression occurs with high frequency in invasive cancer. Reciprocal immunoprecipitation confirmed the interaction between annexin 2 and S100A6 and the proteins colocalised, particularly in the plasma membrane of cultured pancreatic cancer cells and primary pancreatic tumour tissue. Analysis of primary pancreatic cancer specimens (n=55) revealed a strong association between high levels of cytoplasmic S100A6 and the presence of annexin 2 in the plasma membrane of cancer cells (P=0.009). Depletion of S100A6 was accompanied by diminished levels of membrane annexin 2 and caused a pronounced reduction in the motility of pancreatic cancer cells.ConclusionThese findings point towards a functional role for S100A6 that may help explain the link between S100A6 expression in pancreatic cancer and aggressive disease.
| S-EPMC2768105 | biostudies-literature