OTAR3088/BioData-CL_Article-Sentences · Datasets at Hugging Face

PMCID string	Title string	Sentences string
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Each field of view corresponds to 0.2 mm × 0.2 mm Comparison of relative PDE3A mRNA expression and PDE3A protein expression in 23 GIST and 10 liposarcoma tissues.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Immunohistochemistry results were missing for three liposarcomas.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Three GISTs with intermediate staining were grouped in the strong staining category.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	A PDE3A mRNA expression was significantly higher in GISTs than in liposarcomas (p < 0.001).
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Examples of (B) PDE3A-negative and (C) PDE3A weak staining in liposarcomas.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Each field of view corresponds to 0.2 mm × 0.2 mm Finally, we investigated the association between PDE3A expression and clinicopathological factors and survival in the Helsinki Biobank series (Table 1).
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Tumors with low PDE3A expression had a 4 to 5 times lower mitotic count than those with intermediate or strong staining (p = 0.007).
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Low PDE3A expression was also more frequently associated with metastasis at diagnosis than in intermediate and strongly staining tumors (28.6% vs. 8.0% vs. 3.3%, respectively; p = 0.04).
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	In addition, PDE3A positive expression showed a strong correlation with CD117 (p < 0.001), but no significant association was present with sex, age at diagnosis, tumor location, mutation profile, or risk stratification category.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Of cases, 65% co-expressed PDE3A and SLFN12 without a significant association (p = 0.083; Fig. 1).
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Median follow-up time in the series was 7.5 years (range 1 day to 19.6 years) for overall survival and 5.1 years (range 24 days to 17.5 years) for metastasis-free survival.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	PDE3A expression was not associated with overall survival (p = 0.437) or metastasis-free survival (p = 0.298; Fig. 3).Fig.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	3Association of PDE3A staining intensity with (A) overall survival and (B) metastasis-free survival in GISTs Association of PDE3A staining intensity with (A) overall survival and (B) metastasis-free survival in GISTs Many studies indicate that PDE3A is a promising target for personalized GIST therapy, but its role as a diagnostic or prognostic biomarker has not yet been well established.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Here, we investigated PDE3A expression levels and immunohistochemical staining patterns using a novel PDE3A-specific antibody in 173 GIST samples.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	We observed homogeneous PDE3A staining in all GISTs (100%) with intermediate or high expression detected in 94%.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	In addition, low expression was associated with a lower mitotic count in tumor cells and an increased frequency of metastases at diagnosis but not with metastasis-free or overall survival.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	PDE3A is phosphodiesterase that regulates cellular levels of cyclic adenosine phosphate (cAMP).
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	It is expressed in several healthy tissues, including cardiac myocytes, vascular smooth muscles, platelets, and ICCs, where it contributes to heart contractility, vascular tone, platelet aggregation, and ICC network development .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	In our study, we observed high and frequent PDE3A expression, consistent with previous findings in GIST [10–12, 17].
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	PDE3A mRNA levels were also elevated and correlated with IHC staining intensity.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Strong staining was also detected in ICCs within colon tissue, while most surrounding tissue types, excluding neuroendocrine cells of colon villi, mast cells, and ganglia cells, showed little or no staining.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	A previous study reported widespread PDE3A staining in non-neoplastic colon epithelium and underlying connective tissue, but the authors suggested that this was likely non-specific staining .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	However, PDE3A positivity in ganglia and neuroendocrine cells has been confirmed in other studies.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	PDE3A mRNA expression has been detected earlier in superior cervical ganglia in rats , and protein expression is reported to be widespread in cells of the epithelial layer and sebaceous glands of labia, including interstitial or neuroendocrine cells .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Interestingly, we did not detect previously reported PDE3A staining in platelets or megakaryocytes .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	This discrepancy may result from differences in antibody clone specificity or detection thresholds for protein expression in IHC.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	A comparative analysis using different antibodies, as well as cell-specific detection of PDE3A using mRNA in situ hybridization or single-cell RNA sequencing, may be necessary to clarify these differences.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Since the primary anti-tumor effect of PDE3A modulators depends on drug-induced PDE3A–SLFN12 complex formation, assessing co-expression of both proteins is considered important for patient stratification.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	To address this, we assessed also SLFN12 expression using IHC and found co-expression in 65% of GISTs, which is notably lower than the 92% co-expression reported earlier .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	This discrepancy may also stem from differences in antibody clones and IHC protocols between studies.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Recent reports suggest that PDE3A expression alone may be a key determinant of therapeutic response, with PDE3A modulator efficacy observed even in tumors with SLFN12 expression below the detection limit of IHC or immunoblotting .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	One possible reason for the low SLFN12 detection rate is the inherently low basal expression of SLFN12 and its constant degradation in cells.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Therefore, mRNA in situ hybridization has been proposed as a potentially more reliable method for estimating SLFN12 expression in tumor tissue .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Although most GISTs appear to co-express PDE3A and SLFN12, and preclinical models have shown that these tumors are sensitive to PDE3A-targeting treatment, further research is needed to define PDE3A and SLFN12 expression thresholds that may predict drug response.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Additionally, the potential role of other biomarkers guiding therapy decisions, such as co-chaperon protein aryl hydrocarbon receptor-interacting protein (AIP) required for PDE3A-SLFN12 complex formation by DNMDP, remains unclear .
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	While patient stratification might not be necessary in GISTs due to a high co-expression rate, exploring diagnostics approaches could be beneficial for other tumor types, such as soft-tissue sarcomas, melanoma, and ovarian carcinoma, where PDE3A expression is less frequent [10–12].
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Our study has some limitations.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Although we observed a statistically significant association between PDE3A expression and both the number of mitoses and the presence of metastatic disease, these results should be interpreted with caution.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Only seven GISTs in our series showed weak PDE3A positivity.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Therefore, the findings should be validated in a larger, independent GIST cohort.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	An additional large sample cohort would also help assess whether staining differences could arise due to variations in sample fixation across different pathology laboratories.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	In conclusion, PDE3A is uniformly expressed in the majority of GIST samples and that its protein expression can be reliably assessed using the monoclonal mouse antibody clone 230-F8-G1 and immunohistochemistry in FFPE tissue samples.
PMC12647229	Phosphodiesterase 3 A expression in gastrointestinal stromal tumors	Future studies are warranted to define expression thresholds and to determine the frequency of PDE3A expression across various cancer types, which may help to identify patients most likely to benefit from PDE3A-targeting therapies should these modulators enter clinical use.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Gastrointestinal stromal tumors (GISTs) are typical gastrointestinal tract neoplasms.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Imatinib is the first-line therapy for GIST patients.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Drug resistance limits the long-term effectiveness of imatinib.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	The regulatory effect of insulin-like growth factor 2 (IGF2) has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	To further investigate the mechanism of IGF2 specific to GISTs.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	IGF2 was screened and analyzed using Gene Expression Omnibus (GEO: GSE225819) data.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	After IGF2 knockdown or overexpression by transfection, the phenotypes (proliferation, migration, invasion, apoptosis) of GIST cells were characterized by cell counting kit 8, Transwell, and flow cytometry assays.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition (EMT)-associated proteins.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Data from the GEO indicated that IGF2 expression is high in GISTs, associated with liver metastasis, and closely related to drug resistance.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	GIST cells with high expression of IGF2 had increased proliferation and migration, invasiveness and EMT.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Knockdown of IGF2 significantly inhibited those activities.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	In addition, OE-IGF2 promoted GIST metastasis in vivo in nude mice.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	IGF2 activated IGF1R signaling in GIST cells, and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Moreover, 2-deoxy-D-glucose (a glycolysis inhibitor) treatment reversed IGF2 overexpression-mediated imatinib resistance in GISTs.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Core Tip: Our study found that insulin-like growth factor 2 (IGF2) regulated metastasis and imatinib resistance in gastrointestinal stromal tumors (GISTs).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	IGF2 interacted with IGF1R to regulate glycolysis.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Our results confirm that IGF2 targeting of IGF1R signaling inhibited metastasis and improved imatinib chemosensitivity by driving glycolysis in GISTs and indicated that IGF2 might be used to reverse imatinib resistance in GIST patients.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Primary gastrointestinal stromal tumors (GISTs) account for 2% of gastrointestinal tumors.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	GISTs are encoded by the receptor tyrosine kinase gene KIT or PDGFRA.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	These mutations cause ligand-dependent activation and constitutive activation of signal transduction mediated by PDGFRA or KIT.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	The downstream molecular pathways of the KIT mutation include PI3K/AKT, JAK-STAT, Src family kinases, and Ras-ERK).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Activation of molecular pathways follows KIT activation and leads to the occurrence of GISTs tumors by activation of cell proliferation and inhibition of apoptosis signals .
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Imatinib remains the primary treatment of GIST patients with advanced or metastatic tumors.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Imatinib significantly improves the prognosis of patients in the advanced stages of the disease, but those undergoing imatinib treatment often encounter challenges associated with both primary and secondary drug resistance, which, unfortunately, restricts long-term efficacy.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Insulin-like growth factor 2 (IGF2) is a genomic imprinting gene in growth on the chromosome 11 short arm.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	IGF2 overexpression is observed in a variety.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	of cancers and is related to chemotherapy resistance and a worse prognosis[12-14].
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Studies of IGF1R have increased recently.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Insulin-like growth factor (IGF) is comprised of the two ligands IGF1 and IGF2, their target tyrosine kinase receptors, IGF1 receptor (IGF1R) and the insulin receptor, as well as the IGF2 receptor (IGF2R) and IGF-binding proteins that regulate IGF ligand availability.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	IGF1R, is a tyrosine kinase receptor with binding affinity for both IGF1 and IGF2 ligands.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Upon ligand binding, the activated tyrosine kinase domain initiates signaling cascades that specifically activate the GPTase Ras-Raf-ERK/MAPK and PI3K-AKT/mTOR pathways.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	These pathways, regulate the proliferation rate and apoptosis of cancer cells.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	The IGF pathway family gene expression (such as IGF1, IGF2, and IGF1R) has been reported to distinguish subsets of GISTs wild type for KIT and PDGFRA.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Although data on IGF1R in GISTs have been reported[20-22], further research on the mechanisms of IGF2 and IGF1R in GISTs is needed.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Sequencing data from the Gene Expression Omnibus (GEO) database (GSE225819 and GSE155880) were examined by bioinformatics.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	We found that IGF2 acted as a cancer-promoting factor and was involved in cell proliferation, apoptosis, liver metastasis, and epithelial-mesenchymal transition (EMT) in GISTs.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Moreover, the role of IGF2 in GIST cells and the IGF2-IGF1R regulatory axis contributed to imatinib resistance of GISTs by regulating glycolysis and represents a target for GISTs therapy.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Gene expression data based on RNA sequencing were obtained from the GEO.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Two eligible datasets (GSE225819, GSE155880) were combined.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	The aligned reads were calculated by FeatureCounts (subread/2.0, http://subread.sourceforge.net/) and differentially expressed genes (DEGs) were analyzed by the R package DESeq2/3.1.0 (https://bioconductor.org/packages/release/bioc/html/DESeq2.html).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	A total of 2578 DEGs (1398 downregulated, and 1188 upregulated) were identified by screening GSE225819, including 20 normal samples and 20 GISTs samples with liver metastasis (\|log2FC\| > 1; P < 0.05) (Supplementary Table 1).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Based on Deseq2, 1386 DEGs (939 downregulated, and 447 upregulated) were identified by screened GSE155880 including seven Imatinib-sensitive samples and seven imatinib-resistant GIST patients (\|log2FC\| > 1; P < 0.05) (Supplementary Table 2).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	RGM-1 normal human gastric mucosal cells, GIST882, and GIST-T1 cells were cultured in Iscove's modified Dulbecco's medium containing10% fetal bovine serum and 1% antibiotics, The culture temperature was 37 °C with 5% CO2.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	The imatinib concentration was increased from 1 nM to 100 nM over 10 mon and repeated to obtain imatinib-resistant GIST882 (GIST882-R) and GISTT1 (GISTT1R) cells.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	GIST882 and GIST-T1 cells were transfected with OE-IGF2, sh-IGF2 plasmids and sh-NC, OE-NC negative controls (RiboBio, Beijing, China) using Lipofectamine 3000 (Invitrogen, Waltham, MA, United States) and cultured for 2 d. Transfection efficiency was determined by western blotting.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Imatinib mesylate was purchased from Selleckchem (Houston, TX, United States).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	GIST-T1 and GIST-882 cells were treated with serial dilutions of 1 μM imatinib in dimethyl sulfoxide for 4 h. We lysed transfected cells with RIPA buffer, the total protein was purified, and the protein concentration was determined with bicinchoninic kits (ThermoFisher Scientific, Waltham, MA, United States).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	The proteins were resolved by 10% SDS-PAGE and transferred to PVDF membranes for incubation with anti-IGF2 (1:1000, ab177467; Abcam, Cambridge, United Kingdom), anti-vimentin (1:1000, ab92547; Abcam), anti-N-cadherin (1:1000, ab76011; Abcam), anti-E-cadherin (1:1000, ab40772; Abcam), anti-Twist1 (1:1000, ab50887; Abcam), anti-IGF1R (1:1000, ab182408; Abcam), anti-p-IGF1R (1:1000, ab39398; Abcam), anti-PI3K (1:1000, ab302958; Abcam), anti-AKT (1:1000, MA5-14916; Invitrogen), anti-phospho-AKT (1:1000, PA5-95669; Invitrogen), and anti-β-actin (1:1000, ab8227; Abcam) primary antibodies overnight at 4 °C after blocking with skimmed milk (5%).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	After washing the primary antibodies away, the proteins were incubated with the anti-rabbit secondary antibody (1:5000; SA00001-2; SanYing Biotechnology Inc, Wuhan, China) for 1 h. The protein bands were visualized using an ECL chemiluminescence system, and the protein blots were quantified with Image J. The concentration of IGF2 was measured using ELISA kits (Abcam) according to the manufacturer′s instructions.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	The samples were prepared from cell culture supernatants and the IGF2 concentration was measured at 450 nm using a microplate reader.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	We determined GIST cell proliferation by cell counting kit-8 (CCK-8) assay.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	OE-IGF2- or sh-IGF2-transfected GIST882 and GIST-T1 cells were added to 96-well plates (1 × 10/well).
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	After 1 d, we added CCK-8 reagent (10 μL, Catalog No. AD10; Dojindo Molecular Technologies, Kumamoto, Japan) to each well at room temperature.
PMC11334037	Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors	Absorbance was monitored at 0, 24, 48, 72, and 96 h and the half inhibitory concentration of imatinib was determined at 450 nm.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Each field of view corresponds to 0.2 mm × 0.2 mm Comparison of relative PDE3A mRNA expression and PDE3A protein expression in 23 GIST and 10 liposarcoma tissues.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Immunohistochemistry results were missing for three liposarcomas.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Three GISTs with intermediate staining were grouped in the strong staining category.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

A PDE3A mRNA expression was significantly higher in GISTs than in liposarcomas (p < 0.001).

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Examples of (B) PDE3A-negative and (C) PDE3A weak staining in liposarcomas.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Each field of view corresponds to 0.2 mm × 0.2 mm Finally, we investigated the association between PDE3A expression and clinicopathological factors and survival in the Helsinki Biobank series (Table 1).

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Tumors with low PDE3A expression had a 4 to 5 times lower mitotic count than those with intermediate or strong staining (p = 0.007).

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Low PDE3A expression was also more frequently associated with metastasis at diagnosis than in intermediate and strongly staining tumors (28.6% vs. 8.0% vs. 3.3%, respectively; p = 0.04).

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

In addition, PDE3A positive expression showed a strong correlation with CD117 (p < 0.001), but no significant association was present with sex, age at diagnosis, tumor location, mutation profile, or risk stratification category.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Of cases, 65% co-expressed PDE3A and SLFN12 without a significant association (p = 0.083; Fig. 1).

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Median follow-up time in the series was 7.5 years (range 1 day to 19.6 years) for overall survival and 5.1 years (range 24 days to 17.5 years) for metastasis-free survival.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

PDE3A expression was not associated with overall survival (p = 0.437) or metastasis-free survival (p = 0.298; Fig. 3).Fig.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

3Association of PDE3A staining intensity with (A) overall survival and (B) metastasis-free survival in GISTs Association of PDE3A staining intensity with (A) overall survival and (B) metastasis-free survival in GISTs Many studies indicate that PDE3A is a promising target for personalized GIST therapy, but its role as a diagnostic or prognostic biomarker has not yet been well established.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Here, we investigated PDE3A expression levels and immunohistochemical staining patterns using a novel PDE3A-specific antibody in 173 GIST samples.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

We observed homogeneous PDE3A staining in all GISTs (100%) with intermediate or high expression detected in 94%.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

In addition, low expression was associated with a lower mitotic count in tumor cells and an increased frequency of metastases at diagnosis but not with metastasis-free or overall survival.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

PDE3A is phosphodiesterase that regulates cellular levels of cyclic adenosine phosphate (cAMP).

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

It is expressed in several healthy tissues, including cardiac myocytes, vascular smooth muscles, platelets, and ICCs, where it contributes to heart contractility, vascular tone, platelet aggregation, and ICC network development .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

In our study, we observed high and frequent PDE3A expression, consistent with previous findings in GIST [10–12, 17].

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

PDE3A mRNA levels were also elevated and correlated with IHC staining intensity.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Strong staining was also detected in ICCs within colon tissue, while most surrounding tissue types, excluding neuroendocrine cells of colon villi, mast cells, and ganglia cells, showed little or no staining.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

A previous study reported widespread PDE3A staining in non-neoplastic colon epithelium and underlying connective tissue, but the authors suggested that this was likely non-specific staining .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

However, PDE3A positivity in ganglia and neuroendocrine cells has been confirmed in other studies.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

PDE3A mRNA expression has been detected earlier in superior cervical ganglia in rats , and protein expression is reported to be widespread in cells of the epithelial layer and sebaceous glands of labia, including interstitial or neuroendocrine cells .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Interestingly, we did not detect previously reported PDE3A staining in platelets or megakaryocytes .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

This discrepancy may result from differences in antibody clone specificity or detection thresholds for protein expression in IHC.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

A comparative analysis using different antibodies, as well as cell-specific detection of PDE3A using mRNA in situ hybridization or single-cell RNA sequencing, may be necessary to clarify these differences.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Since the primary anti-tumor effect of PDE3A modulators depends on drug-induced PDE3A–SLFN12 complex formation, assessing co-expression of both proteins is considered important for patient stratification.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

To address this, we assessed also SLFN12 expression using IHC and found co-expression in 65% of GISTs, which is notably lower than the 92% co-expression reported earlier .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

This discrepancy may also stem from differences in antibody clones and IHC protocols between studies.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Recent reports suggest that PDE3A expression alone may be a key determinant of therapeutic response, with PDE3A modulator efficacy observed even in tumors with SLFN12 expression below the detection limit of IHC or immunoblotting .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

One possible reason for the low SLFN12 detection rate is the inherently low basal expression of SLFN12 and its constant degradation in cells.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Therefore, mRNA in situ hybridization has been proposed as a potentially more reliable method for estimating SLFN12 expression in tumor tissue .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Although most GISTs appear to co-express PDE3A and SLFN12, and preclinical models have shown that these tumors are sensitive to PDE3A-targeting treatment, further research is needed to define PDE3A and SLFN12 expression thresholds that may predict drug response.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Additionally, the potential role of other biomarkers guiding therapy decisions, such as co-chaperon protein aryl hydrocarbon receptor-interacting protein (AIP) required for PDE3A-SLFN12 complex formation by DNMDP, remains unclear .

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

While patient stratification might not be necessary in GISTs due to a high co-expression rate, exploring diagnostics approaches could be beneficial for other tumor types, such as soft-tissue sarcomas, melanoma, and ovarian carcinoma, where PDE3A expression is less frequent [10–12].

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Our study has some limitations.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Although we observed a statistically significant association between PDE3A expression and both the number of mitoses and the presence of metastatic disease, these results should be interpreted with caution.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Only seven GISTs in our series showed weak PDE3A positivity.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Therefore, the findings should be validated in a larger, independent GIST cohort.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

An additional large sample cohort would also help assess whether staining differences could arise due to variations in sample fixation across different pathology laboratories.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

In conclusion, PDE3A is uniformly expressed in the majority of GIST samples and that its protein expression can be reliably assessed using the monoclonal mouse antibody clone 230-F8-G1 and immunohistochemistry in FFPE tissue samples.

PMC12647229

Phosphodiesterase 3 A expression in gastrointestinal stromal tumors

Future studies are warranted to define expression thresholds and to determine the frequency of PDE3A expression across various cancer types, which may help to identify patients most likely to benefit from PDE3A-targeting therapies should these modulators enter clinical use.

PMC11334037