Browse
Submit Data
Databases
API
Help

Dataset Information

26 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Ral GTPase-activating protein regulates the malignancy of pancreatic ductal adenocarcinoma.

ABSTRACT: The small GTPases RalA and RalB are members of the Ras family and activated downstream of Ras. Ral proteins are found in GTP-bound active and GDP-bound inactive forms. The activation process is executed by guanine nucleotide exchange factors, while inactivation is mediated by GTPase-activating proteins (GAPs). RalGAPs are complexes that consist of a catalytic α1 or α2 subunit together with a common β subunit. Several reports implicate the importance of Ral in pancreatic ductal adenocarcinoma (PDAC). However, there are few reports on the relationship between levels of RalGAP expression and malignancy in PDAC. We generated RalGAPβ-deficient PDAC cells by CRISPR-Cas9 genome editing to investigate how increased Ral activity affects malignant phenotypes of PDAC cells. RalGAPβ-deficient PDAC cells exhibited several-fold higher Ral activity relative to control cells. They had a high migratory and invasive capacity. The RalGAPβ-deficient cells grew more rapidly than control cells when injected subcutaneously into nude mice. When injected into the spleen, the RalGAPβ-deficient cells formed larger splenic tumors with more liver metastases, and unlike controls, they disseminated into the abdominal cavity. These results indicate that RalGAPβ deficiency in PDAC cells contributes to high activities of RalA and RalB, leading to enhanced cell migration and invasion in vitro, and tumor growth and metastasis in vivo.

SUBMITTER: Yoshimachi S

PROVIDER: S-EPMC8353909 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages.

Project description:The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.

| S-EPMC4659838 | biostudies-other

MRGBP as a potential biomarker for the malignancy of pancreatic ductal adenocarcinoma.

Project description:MORF4-related gene-binding protein (MRGBP), which is also known as chromosome 20 open reading frame 20 (C20orf20), is commonly highly expressed in several types of malignant tumors and tumor progression. However, the expression pattern and underlying mechanism of MRGBP in pancreatic ductal adenocarcinoma (PDAC) remain unknown. In the study, we found that MRGBP was frequently upregulated in PDAC tissues and cell lines. In addition, the upregulation of MRGBP was positively associated with TNM stage, T classification, and poor prognosis. Knockdown of MRGBP in the PDAC cell lines ASPC-1 and Mia PaCa-2 by transiently transfected with small interfering RNA (siRNA) drastically attenuated the proliferation, migration, and invasion of those cells, whereas ectopic MRGBP overexpression in BxPC-3 cells produced exactly the opposite effect. Furthermore, we also found that overexpression of MRGBP remarkably led to cell morphological changes and induced an increased expression of mesenchymal marker Vimentin, whereas a decreased expression of epithelial marker E-cadherin. Taken together, this study indicates that MRGBP acts as a tumor oncogene in PDAC and is a promising target of carcinogenesis.

| S-EPMC5609997 | biostudies-literature

κB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRasG12D-driven PDAC, loss of κB-Ras accelerates tumour development and shortens median survival. κB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. κB-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of κB-Ras proteins and highlight low κB-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling.

| S-EPMC7343838 | biostudies-literature

SKA1 regulates actin cytoskeleton remodelling via activating Cdc42 and influences the migration of pancreatic ductal adenocarcinoma cells.

Project description:OBJECTIVES:Spindle and kinetochore-associated protein 1(SKA1), originally identified as a protein essential for proper chromosome segregation, has been recently linked to multiple malignancies. This study aimed to explore the biological, clinical role and molecular mechanism of SKA1 in pancreatic carcinogenesis. MATERIALS AND METHODS:SKA1 expression was detected in 145 pancreatic ductal adenocarcinoma (PDAC) specimens by immunohistochemistry. Biological behaviour assays were used to determine the role of SKA1 in PDAC progression in vitro and in vivo. Using isobaric tags for relative and absolute quantitation (iTRAQ), SKA1's downstream proteins were examined. Moreover, cytochalasin B and ZCL278 were used to explore the changes of SKA1-induced signalling and cell morphology, with further confirmation by immunoblotting and immunofluorescence assays. RESULTS:Increased SKA1 expression was significantly correlated with tumour size and cellular differentiation degree in PDAC tissues. Furthermore, elevated levels of SKA1 reflected shorter overall survival (P = .019). As for biological behaviour, SKA1 acted as a tumour promotor in PDAC, overexpression of SKA1 facilitates cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, we demonstrated that SKA1 enhanced pancreatic cancer aggressiveness by inhibiting G2/M arrest and regulating actin cytoskeleton organization via activating Cdc42. CONCLUSIONS:This study revealed novel roles for SKA1 as an important regulator of actin cytoskeleton organization and an oncogene in PDAC cells, which may provide insights into developing novel therapeutics.

| S-EPMC7162805 | biostudies-literature

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance.

Project description:Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

| S-EPMC5238727 | biostudies-literature

Apoptosis-associated speck-like protein containing a CARD regulates the growth of pancreatic ductal adenocarcinoma

Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan–Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.

| S-EPMC8595714 | biostudies-literature

Pancreatic ductal adenocarcinoma

Project description:Pancreatic ductal adenocarcinoma

| PRJNA432344 | ENA

hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma.

Project description:hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking.hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (?-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-Kras(G12D/+),LSL-Trp53(R175H/+) transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled ?-hERG1-MoAb.(i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the ?-hERG1-MoAb could detect PDAC in vivo.hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo.

| S-EPMC4366888 | biostudies-other

Ral and Rheb GTPase activating proteins integrate mTOR and GTPase signaling in aging, autophagy, and tumor cell invasion.

Project description:Diverse environmental cues converge on and are integrated by the mTOR signaling network to control cellular growth and homeostasis. The mammalian Tsc1-Tsc2 GTPase activating protein (GAP) heterodimer is a critical negative regulator of Rheb and mTOR activation. The RalGAP?-RalGAP? heterodimer shares sequence and structural similarity with Tsc1-Tsc2. Unexpectedly, we observed that C. elegans expresses orthologs for the Rheb and RalA/B GTPases and for RalGAP?/?, but not Tsc1/2. This prompted our investigation to determine whether RalGAPs additionally modulate mTOR signaling. We determined that C. elegans RalGAP loss decreased lifespan, consistent with a Tsc-like function. Additionally, RalGAP suppression in mammalian cells caused RalB-selective activation and Sec5- and exocyst-dependent engagement of mTORC1 and suppression of autophagy. Unexpectedly, we also found that Tsc1-Tsc2 loss activated RalA/B independently of Rheb-mTOR signaling. Finally, RalGAP suppression caused mTORC1-dependent pancreatic tumor cell invasion. Our findings identify an unexpected crosstalk and integration of the Ral and mTOR signaling networks.

| S-EPMC3955741 | biostudies-literature

Avarol induces apoptosis in pancreatic ductal adenocarcinoma cells by activating PERK-eIF2?-CHOP signaling.

Project description:Avarol is a sesquiterpenoid hydroquinone with potent cytotoxicity. Although resolving endoplasmic reticulum (ER) stress is essential for intracellular homeostasis, erratic or excessive ER stress can lead to apoptosis. Here, we reported that avarol selectively induces cell death in pancreatic ductal adenocarcinomas (PDAC), which are difficult to treat owing to the availability of few chemotherapeutic agents. Analyses of the molecular mechanisms of avarol-induced apoptosis indicated upregulation of ER stress marker BiP and ER stress-dependent apoptosis inducer CHOP in PDAC cells but not in normal cells, suggesting that avarol selectively induces ER stress responses. We also showed that avarol activated the PERK-eIF2? pathway but did not affect the IRE1 and ATF6 pathways. Moreover, CHOP downregulation was significantly suppressed by avarol-induced apoptosis. Thus, the PERK-eIF2?-CHOP signaling pathway may be a novel molecular mechanism of avarol-induced apoptosis. The present data indicate that avarol has potential as a chemotherapeutic agent for PDAC and induces apoptosis by activating the PERK-eIF2? pathway.

| S-EPMC4413216 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data