{"gene":"PRRX2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2022,"finding":"CircLRFN5 binds directly to PRRX2 protein and promotes its degradation via a ubiquitin-mediated proteasomal pathway; PRRX2 transcriptionally upregulates GCH1 expression in glioma stem cells, suppressing ferroptosis by generating the antioxidant tetrahydrobiopterin (BH4).","method":"RNA immunoprecipitation, RNA pull-down assay, ubiquitination assay, dual-luciferase reporter assay, chromatin immunoprecipitation assay, shRNA knockdown/overexpression in glioma stem cells","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, pulldown, ChIP, ubiquitination assay) in a single lab","pmids":["36266731"],"is_preprint":false},{"year":2021,"finding":"PRRX2 functions as a transcription factor for IL-6, and CBS-mediated suppression of PRRX2 reduces IL-6/STAT3 pathway activity, leading to reduced Treg infiltration and increased apoptosis in hepatocellular carcinoma.","method":"HCC cell line overexpression/knockdown, in vivo xenograft and Cbs heterozygous knockout mouse models, signaling pathway analysis","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional experiments in vitro and in vivo with mechanistic pathway placement, single lab","pmids":["34413167"],"is_preprint":false},{"year":2017,"finding":"PRRX2 (Prrx2) is a direct target of miR-212-5p; miR-212-5p suppresses Prrx2 by binding its 3'-UTR, and Prrx2 overexpression partially rescues miR-212-5p-mediated suppression of EMT in triple-negative breast cancer cells.","method":"Luciferase reporter assay targeting 3'-UTR, Western blot, wound healing and Transwell invasion assays, overexpression rescue experiments","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay plus rescue experiment, single lab, two orthogonal methods","pmids":["29216628"],"is_preprint":false},{"year":2017,"finding":"Knockdown of Prrx2 induces mesenchymal-to-epithelial transition in breast cancer cells, prevents nuclear translocation of β-catenin, and inhibits Wnt/β-catenin signaling, suppressing invasion and migration in vitro and tumor growth in vivo.","method":"shRNA knockdown in breast cancer cell lines, Western blot for EMT and Wnt/β-catenin markers, in vitro invasion/migration assays, nude mouse xenograft","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo KD with defined pathway readout, single lab","pmids":["28750408"],"is_preprint":false},{"year":2019,"finding":"PRRX2 knockdown in colon cancer cells inactivates Wnt/β-catenin signaling (reducing p-GSK3βSer9/GSK3β, nuclear/cytoplasmic β-catenin, TCF4, and Vimentin; increasing E-cadherin), suppresses invasion and migration in vitro, and reduces liver metastasis in vivo; the Wnt activator LiCl reverses the inhibitory effect of PRRX2 silencing.","method":"siRNA/shRNA knockdown in CT-26 and CMT93 colon cancer cells, Western blot, Transwell invasion/migration assay, liver-metastatic mouse model, LiCl pathway rescue","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo KD with epistatic rescue by Wnt activator, single lab","pmids":["31471104"],"is_preprint":false},{"year":2022,"finding":"PRRX2 activation in prostate cancer cells promotes enzalutamide resistance through alterations in the CDK4/6/Rb/E2F and BCL2 pathways, identified via a genome-wide CRISPR activation screen.","method":"Genome-wide CRISPRa screen in metastatic castration-sensitive prostate cancer cells, pathway analysis of CDK4/6/Rb/E2F and BCL2, CDK4/6 and BCL2 inhibitor treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPRa screen plus pharmacological pathway validation, single lab","pmids":["35405009"],"is_preprint":false},{"year":2023,"finding":"Myoblast-derived exosomal PRRX2 directly binds to the MIR22HG promoter and promotes its transcription and expression; MIR22HG then sponges miR-128 to enhance YAP nuclear translocation, thereby facilitating osteogenic differentiation of BMSCs.","method":"Dual-luciferase reporter assay, RIP assay, ChIP assay, immunofluorescence for YAP nuclear translocation, exosome isolation and delivery, siRNA knockdown, overexpression rescue in BMSCs, ovariectomy mouse model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, luciferase, IF) in single lab","pmids":["37081396"],"is_preprint":false},{"year":2014,"finding":"KLF6 specifically stimulates Prrx2 expression; KLF6 can bind to the Prrx2 promoter as shown by EMSA, and siRNA-mediated KLF6 knockdown reduces Prrx2 expression in pituitary cells.","method":"Promoter luciferase assay, electrophoretic mobility shift assay (EMSA), siRNA knockdown, immunohistochemistry","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus promoter assay plus siRNA knockdown, single lab","pmids":["24881871"],"is_preprint":false},{"year":2019,"finding":"Attenuation of PRRX2 (together with HEY2) significantly enhances the transdifferentiation of adult human skin fibroblasts to induced neurons when combined with ASCL1 overexpression and p53 knockdown, indicating PRRX2 functions as a barrier in the fibroblast gene regulatory network that suppresses neural fate acquisition.","method":"shRNA knockdown of PRRX2 in human skin fibroblasts, RNAseq comparison of skin vs lung fibroblasts during neuronal conversion, MAP2+ neuron quantification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAseq plus functional shRNA KD with defined neuronal conversion phenotype, single lab","pmids":["31255287"],"is_preprint":false},{"year":2024,"finding":"PRRX2 directly binds to the ATOX1 promoter and positively regulates ATOX1 transcription in hepatocellular carcinoma cells; PRRX2 knockdown inhibits cell proliferation, invasion, and EMT while promoting cuproptosis, effects partially reversed by ATOX1 overexpression.","method":"ChIP assay, dual-luciferase reporter assay, JASPAR-predicted binding site analysis, siRNA knockdown, overexpression rescue in HCC cell lines, xenograft model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase plus rescue experiments, single lab","pmids":["40393577"],"is_preprint":false},{"year":2024,"finding":"PRRX2 directly binds to the Panx3 promoter and positively regulates Panx3 expression in preodontoblasts; PRRX2 knockdown with siRNA inhibits Panx3 expression, and PRRX2 overexpression in HEK293 cells increases luciferase activity from a Panx3 promoter reporter.","method":"Dual-luciferase reporter assay, electrophoretic mobility shift assay (EMSA), siRNA knockdown in dental papilla-derived cells","journal":"Journal of oral biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus luciferase reporter plus siRNA KD, single lab","pmids":["39733924"],"is_preprint":false},{"year":2025,"finding":"PRRX2 directly enhances transcription of GLI2, activating the Hedgehog pathway; this inhibits tumor cell senescence and promotes proliferation, invasion, and metastasis in pancreatic cancer; Hedgehog pathway inhibitors or GLI2 silencing partially reverse PRRX2's oncogenic effects.","method":"ChIP/luciferase (implied by 'directly enhanced transcription'), shRNA knockdown and overexpression in pancreatic cancer cells, senescence assays, Hedgehog pathway inhibitor treatment, GLI2 silencing rescue","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional KD/OE with pathway pharmacological rescue, but transcriptional activation of GLI2 mechanism inferred from abstract without explicit Tier 1 method described","pmids":["40619170"],"is_preprint":false},{"year":2025,"finding":"PRRX2 binds to the CNTN3 promoter and transcriptionally activates CNTN3 in colorectal cancer; PRRX2 knockdown reduces CNTN3 expression, reverses EMT markers, and suppresses metastatic phenotypes; rescue with CNTN3 overexpression restores these effects.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, shRNA knockdown and rescue overexpression in CRC cell lines, xenograft model","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase plus knockdown/rescue, single lab","pmids":["41882765"],"is_preprint":false},{"year":2025,"finding":"PRRX2 amplifies TGF-β signaling through transcriptional activation of TGFB1 and activates Fibronectin 1 to remodel the ECM in pancreatic ductal adenocarcinoma; PRRX2 knockdown reduces tumor cell migration in vitro.","method":"Single-cell RNA-seq and spatial transcriptomics, cell-to-cell communication network analysis, shRNA knockdown in PDAC cell lines, multicolor immunofluorescence staining","journal":"Chinese medical journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — primarily bioinformatics with limited experimental validation (single migration assay), single lab","pmids":["41456929"],"is_preprint":false},{"year":2020,"finding":"Silencing Prrx2 in breast cancer cells inhibits nuclear β-catenin expression and downregulates Wnt/β-catenin signaling activity, suppressing cell proliferation in vitro and tumor growth in vivo.","method":"shRNA knockdown in MDA-MB-231 and MCF-7 cells, MTT proliferation assay, nude mouse xenograft, Western blot for β-catenin","journal":"Zhonghua yi xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method per endpoint, largely recapitulates prior findings","pmids":["32234171"],"is_preprint":false},{"year":2024,"finding":"Silencing of Marveld3 leads to upregulation of PRRX2, which subsequently reduces intracellular Fe2+ and ROS levels and suppresses lipid peroxidation, thereby attenuating radiation-induced ferroptosis in skin cells.","method":"siRNA silencing of Marveld3, PRRX2 overexpression/siRNA in HaCaT and WS1 cells, MDA/Fe2+/ROS assays, BODIPY staining, RNA sequencing","journal":"Molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cell assays but mechanism linking PRRX2 to ferroptosis suppression is incompletely characterized at molecular level, single lab","pmids":["39434056"],"is_preprint":false}],"current_model":"PRRX2 is a paired-related homeobox transcription factor that directly binds the promoters of target genes (including GCH1, IL-6, ATOX1, Panx3, GLI2, CNTN3, TGFB1, and MIR22HG) to transcriptionally activate them; it promotes EMT, invasion, and metastasis in multiple cancer types via Wnt/β-catenin, TGF-β, and Hedgehog signaling, drives enzalutamide resistance through CDK4/6/Rb/E2F and BCL2 pathways in prostate cancer, suppresses ferroptosis through GCH1/BH4 upregulation, and can be post-translationally degraded via ubiquitin-mediated proteasomal pathway upon binding of circLRFN5; in normal physiology, it acts as a mesenchymal/stem-progenitor cell regulator in pituitary development and osteogenesis, and functions as a barrier to neural fate in fibroblasts."},"narrative":{"mechanistic_narrative":"PRRX2 is a paired-related homeobox transcription factor that drives mesenchymal programs by directly binding target gene promoters and activating their transcription, functioning as a pro-EMT, pro-invasive, and pro-metastatic regulator across multiple cancers [PMID:28750408, PMID:40393577, PMID:41882765]. Its oncogenic output converges on several developmental signaling axes: it sustains Wnt/β-catenin signaling by promoting nuclear β-catenin accumulation in breast and colon cancer, where Wnt-activator rescue restores invasion after PRRX2 loss [PMID:28750408, PMID:31471104]; it amplifies Hedgehog signaling through direct transcriptional activation of GLI2 to suppress senescence and promote pancreatic cancer growth [PMID:40619170]; and it transcriptionally activates downstream effectors including IL-6 (feeding IL-6/STAT3 and Treg-mediated immune modulation in hepatocellular carcinoma), ATOX1 (limiting cuproptosis), CNTN3, and GCH1 [PMID:34413167, PMID:40393577, PMID:41882765, PMID:36266731]. Through GCH1-driven BH4 antioxidant production, PRRX2 suppresses ferroptosis in glioma stem cells, and its protein level is constrained by circLRFN5-directed ubiquitin-proteasomal degradation [PMID:36266731]. PRRX2 expression is itself controlled upstream by KLF6, which binds the Prrx2 promoter in pituitary cells, and by miR-212-5p, which represses Prrx2 via its 3'-UTR [PMID:24881871, PMID:29216628]. In normal physiology PRRX2 acts as a mesenchymal/progenitor regulator: myoblast exosome-delivered PRRX2 activates the MIR22HG promoter to drive YAP-dependent osteogenic differentiation of BMSCs, it activates Panx3 transcription in preodontoblasts, and it serves as a barrier to neural fate in fibroblasts whose attenuation enhances induced-neuron conversion [PMID:37081396, PMID:39733924, PMID:31255287].","teleology":[{"year":2014,"claim":"Established an upstream transcriptional regulator of PRRX2, placing it within a defined pituitary gene network rather than treating it as an orphan factor.","evidence":"Promoter luciferase, EMSA, and siRNA knockdown of KLF6 in pituitary cells","pmids":["24881871"],"confidence":"Medium","gaps":["Does not identify PRRX2's own direct target genes in pituitary","Physiological consequence of KLF6→PRRX2 axis in vivo not established"]},{"year":2017,"claim":"Defined PRRX2 as a pro-EMT effector controlled by miR-212-5p and acting through Wnt/β-catenin, providing the first mechanistic link between PRRX2 and metastatic phenotypes.","evidence":"3'-UTR luciferase reporter, shRNA knockdown, invasion/migration assays, and xenografts in breast cancer cells","pmids":["29216628","28750408"],"confidence":"Medium","gaps":["Direct promoter targets mediating Wnt activation not identified","Mechanism by which PRRX2 controls β-catenin nuclear translocation unresolved"]},{"year":2019,"claim":"Generalized the PRRX2–Wnt/β-catenin invasion axis to colon cancer with epistatic rescue, and separately revealed a normal role as a barrier to neural reprogramming in fibroblasts.","evidence":"Knockdown plus LiCl Wnt-rescue and liver-metastasis model in colon cancer cells; shRNA knockdown plus RNAseq during fibroblast-to-neuron conversion","pmids":["31471104","31255287"],"confidence":"Medium","gaps":["Direct Wnt-pathway target genes still inferred from markers, not ChIP","Fibroblast gene-regulatory targets of PRRX2 not mapped"]},{"year":2021,"claim":"Identified PRRX2 as a direct transcriptional activator of IL-6, linking it to IL-6/STAT3 signaling and immune modulation in hepatocellular carcinoma.","evidence":"Overexpression/knockdown in HCC lines with xenograft and Cbs heterozygous knockout mouse models","pmids":["34413167"],"confidence":"Medium","gaps":["Direct promoter occupancy at IL-6 not shown by ChIP in this entry","Whether CBS regulates PRRX2 directly or indirectly unresolved"]},{"year":2022,"claim":"Connected PRRX2 to redox/ferroptosis control and post-translational regulation, showing it activates GCH1/BH4 to suppress ferroptosis while being degraded via circLRFN5-directed ubiquitination.","evidence":"RIP, RNA pull-down, ubiquitination assay, ChIP, and luciferase in glioma stem cells","pmids":["36266731"],"confidence":"Medium","gaps":["The E3 ligase mediating circLRFN5-dependent degradation not identified","Ubiquitination sites on PRRX2 unmapped"]},{"year":2022,"claim":"Implicated PRRX2 in therapy resistance, showing its activation confers enzalutamide resistance through CDK4/6/Rb/E2F and BCL2 pathways in prostate cancer.","evidence":"Genome-wide CRISPRa screen with CDK4/6 and BCL2 inhibitor validation in prostate cancer cells","pmids":["35405009"],"confidence":"Medium","gaps":["Whether PRRX2 directly transactivates CDK4/6 or BCL2 genes not determined","Direct target promoters in prostate cancer not defined"]},{"year":2023,"claim":"Defined a physiological gain-of-function role: exosome-delivered PRRX2 directly activates MIR22HG transcription to drive YAP-dependent osteogenic differentiation.","evidence":"ChIP, RIP, luciferase, immunofluorescence, exosome delivery, and ovariectomy mouse model in BMSCs","pmids":["37081396"],"confidence":"Medium","gaps":["How PRRX2 is loaded into myoblast exosomes unknown","Generality of PRRX2-MIR22HG-YAP axis beyond osteogenesis untested"]},{"year":2024,"claim":"Expanded the direct PRRX2 target repertoire to ATOX1 (cuproptosis suppression in HCC) and Panx3 (preodontoblast regulation), reinforcing its role as a sequence-specific promoter-binding activator.","evidence":"ChIP, luciferase, EMSA, JASPAR site analysis, siRNA knockdown, and rescue in HCC and dental papilla-derived cells","pmids":["40393577","39733924"],"confidence":"Medium","gaps":["Consensus PRRX2 binding motif not derived across targets","Tissue-specificity of target selection not explained"]},{"year":2024,"claim":"Linked PRRX2 to radiation-induced ferroptosis resistance in skin cells downstream of Marveld3 silencing.","evidence":"siRNA/overexpression with Fe2+/ROS/lipid-peroxidation assays and RNAseq in HaCaT and WS1 cells","pmids":["39434056"],"confidence":"Low","gaps":["Molecular mechanism linking PRRX2 to ferroptosis suppression in skin incompletely characterized","Direct PRRX2 targets controlling Fe2+/ROS not identified"]},{"year":2025,"claim":"Broadened the oncogenic signaling output of PRRX2 to Hedgehog (via GLI2), CNTN3-driven CRC metastasis, and TGF-β/Fibronectin-mediated ECM remodeling in pancreatic cancer.","evidence":"ChIP/luciferase and knockdown/rescue in pancreatic and colorectal cancer cells; single-cell/spatial transcriptomics with knockdown migration assay in PDAC","pmids":["40619170","41882765","41456929"],"confidence":"Medium","gaps":["GLI2 and TGFB1 direct binding inferred without explicit Tier 1 confirmation in two entries","Integration of Wnt, Hedgehog, and TGF-β outputs by PRRX2 not mechanistically unified"]},{"year":null,"claim":"How PRRX2 selects context-specific promoter targets and integrates its convergence on Wnt, Hedgehog, and TGF-β signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined consensus DNA-binding motif or genome-wide occupancy map","Cofactors directing tissue-specific target selection unknown","No structural model of PRRX2-DNA or PRRX2-cofactor complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6,9,10,11,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,6,9,10,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,9,12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,6,9,10,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,11,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7,8,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,9,15]}],"complexes":[],"partners":["CIRCLRFN5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99811","full_name":"Paired mesoderm homeobox protein 2","aliases":["Paired-related homeobox protein 2","PRX-2"],"length_aa":253,"mass_kda":27.1,"function":"May play a role in the scarless healing of cutaneous wounds during the first two trimesters of development","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q99811/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRRX2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRRX2","total_profiled":1310},"omim":[{"mim_id":"604675","title":"PAIRED-RELATED HOMEOBOX GENE 2; PRRX2","url":"https://www.omim.org/entry/604675"},{"mim_id":"167420","title":"PAIRED-RELATED HOMEOBOX GENE 1; PRRX1","url":"https://www.omim.org/entry/167420"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":52.0}],"url":"https://www.proteinatlas.org/search/PRRX2"},"hgnc":{"alias_symbol":["PRX2","PMX2"],"prev_symbol":[]},"alphafold":{"accession":"Q99811","domains":[{"cath_id":"1.10.10.60","chopping":"111-180","consensus_level":"medium","plddt":90.4911,"start":111,"end":180}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99811","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99811-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99811-F1-predicted_aligned_error_v6.png","plddt_mean":66.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRRX2","jax_strain_url":"https://www.jax.org/strain/search?query=PRRX2"},"sequence":{"accession":"Q99811","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99811.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99811/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99811"}},"corpus_meta":[{"pmid":"36266731","id":"PMC_36266731","title":"CircLRFN5 inhibits the progression of glioblastoma via PRRX2/GCH1 mediated ferroptosis.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36266731","citation_count":133,"is_preprint":false},{"pmid":"34413167","id":"PMC_34413167","title":"Cystathionine β-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis.","date":"2021","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34413167","citation_count":52,"is_preprint":false},{"pmid":"29216628","id":"PMC_29216628","title":"MiR-212-5p Suppresses the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer by Targeting Prrx2.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29216628","citation_count":49,"is_preprint":false},{"pmid":"24770895","id":"PMC_24770895","title":"PRRX1 and PRRX2 distinctively participate in pituitary organogenesis and a cell-supply system.","date":"2014","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/24770895","citation_count":45,"is_preprint":false},{"pmid":"11063257","id":"PMC_11063257","title":"Human PRRX1 and PRRX2 genes: cloning, expression, genomic localization, and exclusion as disease genes for Nager syndrome.","date":"2000","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/11063257","citation_count":42,"is_preprint":false},{"pmid":"37081396","id":"PMC_37081396","title":"Myoblast-derived exosomal Prrx2 attenuates osteoporosis via transcriptional regulation of lncRNA-MIR22HG to activate Hippo pathway.","date":"2023","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/37081396","citation_count":38,"is_preprint":false},{"pmid":"25795141","id":"PMC_25795141","title":"PRRX1- and PRRX2-positive mesenchymal stem/progenitor cells are involved in vasculogenesis during rat embryonic pituitary development.","date":"2015","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/25795141","citation_count":35,"is_preprint":false},{"pmid":"35405009","id":"PMC_35405009","title":"A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer.","date":"2022","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35405009","citation_count":30,"is_preprint":false},{"pmid":"31471104","id":"PMC_31471104","title":"Inhibition of PRRX2 suppressed colon cancer liver metastasis via inactivation of Wnt/β-catenin signaling pathway.","date":"2019","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/31471104","citation_count":18,"is_preprint":false},{"pmid":"31255287","id":"PMC_31255287","title":"Attenuation of PRRX2 and HEY2 enables efficient conversion of adult human skin fibroblasts to neurons.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31255287","citation_count":17,"is_preprint":false},{"pmid":"24881871","id":"PMC_24881871","title":"Expression of Krüppel-like factor 6, KLF6, in rat pituitary stem/progenitor cells and its regulation of the PRRX2 gene.","date":"2014","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/24881871","citation_count":13,"is_preprint":false},{"pmid":"28750408","id":"PMC_28750408","title":"Silencing of Prrx2 Inhibits the Invasion and Metastasis of Breast Cancer both In Vitro and In Vivo by Reversing Epithelial-Mesenchymal Transition.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28750408","citation_count":12,"is_preprint":false},{"pmid":"39434056","id":"PMC_39434056","title":"Upregulation of PRRX2 by silencing Marveld3 as a protective mechanism against radiation-induced ferroptosis in skin cells.","date":"2024","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/39434056","citation_count":5,"is_preprint":false},{"pmid":"40393577","id":"PMC_40393577","title":"Transcriptional regulation of ATOX1 by PRRX2 impacts the progression and cuproptosis of hepatocellular carcinoma.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40393577","citation_count":3,"is_preprint":false},{"pmid":"41089673","id":"PMC_41089673","title":"Single-cell and bulk RNA-sequencing reveal PRRX2-driven cancer-associated fibroblast-mediated perineural invasion for predicting the immunotherapy outcome in colorectal cancer.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41089673","citation_count":2,"is_preprint":false},{"pmid":"40619170","id":"PMC_40619170","title":"PRRX2 Regulates GLI2 to Promote Proliferation, Invasion, and Metastasis by Inhibiting Senescence via Hedgehog Signaling.","date":"2025","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/40619170","citation_count":1,"is_preprint":false},{"pmid":"39733924","id":"PMC_39733924","title":"Prrx2, the paired-related homeobox transcription factor, functions as a potential regulator of pannexin 3 expression in odontoblast differentiation.","date":"2024","source":"Journal of oral biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/39733924","citation_count":1,"is_preprint":false},{"pmid":"41456929","id":"PMC_41456929","title":"Single-cell and spatial transcriptomics reveal the interaction between PRRX2-driven epithelial cells and SPP1+ macrophages in mediating gemcitabine resistance in pancreatic ductal adenocarcinoma.","date":"2025","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41456929","citation_count":0,"is_preprint":false},{"pmid":"32234171","id":"PMC_32234171","title":"[Effects of Prrx2 gene silencing on the proliferation of breast cancer and its molecular mechanisms].","date":"2020","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/32234171","citation_count":0,"is_preprint":false},{"pmid":"41882765","id":"PMC_41882765","title":"PRRX2-CNTN3 axis promotes epithelial-to-mesenchymal transition and metastasis in colorectal cancer.","date":"2026","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/41882765","citation_count":0,"is_preprint":false},{"pmid":"41684173","id":"PMC_41684173","title":"Clinicopathological Characteristics of PRRX1 and PRRX2 Genes Expressions in Colorectal Cancer Patients.","date":"2026","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/41684173","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.11.681802","title":"Single-cell lineage trajectory defines CDK inhibitor-sensitive cells-of-origin in esophageal squamous cell cancer","date":"2025-10-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.11.681802","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.13.618070","title":"From Transcriptomic Signatures to Active-Site Docking and ADMET Properties Prediction: Bioinformatics-Guided Exploration of Binding Mechanisms of Cardioprotective Phytoconstituents Against Dysregulated Targets in Hypertrophic Cardiomyopathy","date":"2024-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.13.618070","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.15.608116","title":"The Identification of Key Genes and Biological Pathways in Cardiac Arrest by Integrated Bioinformatics and Next Generation Sequencing Data Analysis","date":"2024-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.15.608116","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16248,"output_tokens":3936,"usd":0.053892,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11739,"output_tokens":3757,"usd":0.07631,"stage2_stop_reason":"end_turn"},"total_usd":0.130202,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"CircLRFN5 binds directly to PRRX2 protein and promotes its degradation via a ubiquitin-mediated proteasomal pathway; PRRX2 transcriptionally upregulates GCH1 expression in glioma stem cells, suppressing ferroptosis by generating the antioxidant tetrahydrobiopterin (BH4).\",\n      \"method\": \"RNA immunoprecipitation, RNA pull-down assay, ubiquitination assay, dual-luciferase reporter assay, chromatin immunoprecipitation assay, shRNA knockdown/overexpression in glioma stem cells\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, pulldown, ChIP, ubiquitination assay) in a single lab\",\n      \"pmids\": [\"36266731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRRX2 functions as a transcription factor for IL-6, and CBS-mediated suppression of PRRX2 reduces IL-6/STAT3 pathway activity, leading to reduced Treg infiltration and increased apoptosis in hepatocellular carcinoma.\",\n      \"method\": \"HCC cell line overexpression/knockdown, in vivo xenograft and Cbs heterozygous knockout mouse models, signaling pathway analysis\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional experiments in vitro and in vivo with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"34413167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRRX2 (Prrx2) is a direct target of miR-212-5p; miR-212-5p suppresses Prrx2 by binding its 3'-UTR, and Prrx2 overexpression partially rescues miR-212-5p-mediated suppression of EMT in triple-negative breast cancer cells.\",\n      \"method\": \"Luciferase reporter assay targeting 3'-UTR, Western blot, wound healing and Transwell invasion assays, overexpression rescue experiments\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay plus rescue experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"29216628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of Prrx2 induces mesenchymal-to-epithelial transition in breast cancer cells, prevents nuclear translocation of β-catenin, and inhibits Wnt/β-catenin signaling, suppressing invasion and migration in vitro and tumor growth in vivo.\",\n      \"method\": \"shRNA knockdown in breast cancer cell lines, Western blot for EMT and Wnt/β-catenin markers, in vitro invasion/migration assays, nude mouse xenograft\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo KD with defined pathway readout, single lab\",\n      \"pmids\": [\"28750408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRRX2 knockdown in colon cancer cells inactivates Wnt/β-catenin signaling (reducing p-GSK3βSer9/GSK3β, nuclear/cytoplasmic β-catenin, TCF4, and Vimentin; increasing E-cadherin), suppresses invasion and migration in vitro, and reduces liver metastasis in vivo; the Wnt activator LiCl reverses the inhibitory effect of PRRX2 silencing.\",\n      \"method\": \"siRNA/shRNA knockdown in CT-26 and CMT93 colon cancer cells, Western blot, Transwell invasion/migration assay, liver-metastatic mouse model, LiCl pathway rescue\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo KD with epistatic rescue by Wnt activator, single lab\",\n      \"pmids\": [\"31471104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRRX2 activation in prostate cancer cells promotes enzalutamide resistance through alterations in the CDK4/6/Rb/E2F and BCL2 pathways, identified via a genome-wide CRISPR activation screen.\",\n      \"method\": \"Genome-wide CRISPRa screen in metastatic castration-sensitive prostate cancer cells, pathway analysis of CDK4/6/Rb/E2F and BCL2, CDK4/6 and BCL2 inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPRa screen plus pharmacological pathway validation, single lab\",\n      \"pmids\": [\"35405009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Myoblast-derived exosomal PRRX2 directly binds to the MIR22HG promoter and promotes its transcription and expression; MIR22HG then sponges miR-128 to enhance YAP nuclear translocation, thereby facilitating osteogenic differentiation of BMSCs.\",\n      \"method\": \"Dual-luciferase reporter assay, RIP assay, ChIP assay, immunofluorescence for YAP nuclear translocation, exosome isolation and delivery, siRNA knockdown, overexpression rescue in BMSCs, ovariectomy mouse model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, luciferase, IF) in single lab\",\n      \"pmids\": [\"37081396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF6 specifically stimulates Prrx2 expression; KLF6 can bind to the Prrx2 promoter as shown by EMSA, and siRNA-mediated KLF6 knockdown reduces Prrx2 expression in pituitary cells.\",\n      \"method\": \"Promoter luciferase assay, electrophoretic mobility shift assay (EMSA), siRNA knockdown, immunohistochemistry\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus promoter assay plus siRNA knockdown, single lab\",\n      \"pmids\": [\"24881871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Attenuation of PRRX2 (together with HEY2) significantly enhances the transdifferentiation of adult human skin fibroblasts to induced neurons when combined with ASCL1 overexpression and p53 knockdown, indicating PRRX2 functions as a barrier in the fibroblast gene regulatory network that suppresses neural fate acquisition.\",\n      \"method\": \"shRNA knockdown of PRRX2 in human skin fibroblasts, RNAseq comparison of skin vs lung fibroblasts during neuronal conversion, MAP2+ neuron quantification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAseq plus functional shRNA KD with defined neuronal conversion phenotype, single lab\",\n      \"pmids\": [\"31255287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRRX2 directly binds to the ATOX1 promoter and positively regulates ATOX1 transcription in hepatocellular carcinoma cells; PRRX2 knockdown inhibits cell proliferation, invasion, and EMT while promoting cuproptosis, effects partially reversed by ATOX1 overexpression.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, JASPAR-predicted binding site analysis, siRNA knockdown, overexpression rescue in HCC cell lines, xenograft model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase plus rescue experiments, single lab\",\n      \"pmids\": [\"40393577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRRX2 directly binds to the Panx3 promoter and positively regulates Panx3 expression in preodontoblasts; PRRX2 knockdown with siRNA inhibits Panx3 expression, and PRRX2 overexpression in HEK293 cells increases luciferase activity from a Panx3 promoter reporter.\",\n      \"method\": \"Dual-luciferase reporter assay, electrophoretic mobility shift assay (EMSA), siRNA knockdown in dental papilla-derived cells\",\n      \"journal\": \"Journal of oral biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus luciferase reporter plus siRNA KD, single lab\",\n      \"pmids\": [\"39733924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRRX2 directly enhances transcription of GLI2, activating the Hedgehog pathway; this inhibits tumor cell senescence and promotes proliferation, invasion, and metastasis in pancreatic cancer; Hedgehog pathway inhibitors or GLI2 silencing partially reverse PRRX2's oncogenic effects.\",\n      \"method\": \"ChIP/luciferase (implied by 'directly enhanced transcription'), shRNA knockdown and overexpression in pancreatic cancer cells, senescence assays, Hedgehog pathway inhibitor treatment, GLI2 silencing rescue\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional KD/OE with pathway pharmacological rescue, but transcriptional activation of GLI2 mechanism inferred from abstract without explicit Tier 1 method described\",\n      \"pmids\": [\"40619170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRRX2 binds to the CNTN3 promoter and transcriptionally activates CNTN3 in colorectal cancer; PRRX2 knockdown reduces CNTN3 expression, reverses EMT markers, and suppresses metastatic phenotypes; rescue with CNTN3 overexpression restores these effects.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, shRNA knockdown and rescue overexpression in CRC cell lines, xenograft model\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase plus knockdown/rescue, single lab\",\n      \"pmids\": [\"41882765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRRX2 amplifies TGF-β signaling through transcriptional activation of TGFB1 and activates Fibronectin 1 to remodel the ECM in pancreatic ductal adenocarcinoma; PRRX2 knockdown reduces tumor cell migration in vitro.\",\n      \"method\": \"Single-cell RNA-seq and spatial transcriptomics, cell-to-cell communication network analysis, shRNA knockdown in PDAC cell lines, multicolor immunofluorescence staining\",\n      \"journal\": \"Chinese medical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — primarily bioinformatics with limited experimental validation (single migration assay), single lab\",\n      \"pmids\": [\"41456929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Silencing Prrx2 in breast cancer cells inhibits nuclear β-catenin expression and downregulates Wnt/β-catenin signaling activity, suppressing cell proliferation in vitro and tumor growth in vivo.\",\n      \"method\": \"shRNA knockdown in MDA-MB-231 and MCF-7 cells, MTT proliferation assay, nude mouse xenograft, Western blot for β-catenin\",\n      \"journal\": \"Zhonghua yi xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per endpoint, largely recapitulates prior findings\",\n      \"pmids\": [\"32234171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Silencing of Marveld3 leads to upregulation of PRRX2, which subsequently reduces intracellular Fe2+ and ROS levels and suppresses lipid peroxidation, thereby attenuating radiation-induced ferroptosis in skin cells.\",\n      \"method\": \"siRNA silencing of Marveld3, PRRX2 overexpression/siRNA in HaCaT and WS1 cells, MDA/Fe2+/ROS assays, BODIPY staining, RNA sequencing\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell assays but mechanism linking PRRX2 to ferroptosis suppression is incompletely characterized at molecular level, single lab\",\n      \"pmids\": [\"39434056\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRRX2 is a paired-related homeobox transcription factor that directly binds the promoters of target genes (including GCH1, IL-6, ATOX1, Panx3, GLI2, CNTN3, TGFB1, and MIR22HG) to transcriptionally activate them; it promotes EMT, invasion, and metastasis in multiple cancer types via Wnt/β-catenin, TGF-β, and Hedgehog signaling, drives enzalutamide resistance through CDK4/6/Rb/E2F and BCL2 pathways in prostate cancer, suppresses ferroptosis through GCH1/BH4 upregulation, and can be post-translationally degraded via ubiquitin-mediated proteasomal pathway upon binding of circLRFN5; in normal physiology, it acts as a mesenchymal/stem-progenitor cell regulator in pituitary development and osteogenesis, and functions as a barrier to neural fate in fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRRX2 is a paired-related homeobox transcription factor that drives mesenchymal programs by directly binding target gene promoters and activating their transcription, functioning as a pro-EMT, pro-invasive, and pro-metastatic regulator across multiple cancers [#3, #9, #12]. Its oncogenic output converges on several developmental signaling axes: it sustains Wnt/\\u03b2-catenin signaling by promoting nuclear \\u03b2-catenin accumulation in breast and colon cancer, where Wnt-activator rescue restores invasion after PRRX2 loss [#3, #4]; it amplifies Hedgehog signaling through direct transcriptional activation of GLI2 to suppress senescence and promote pancreatic cancer growth [#11]; and it transcriptionally activates downstream effectors including IL-6 (feeding IL-6/STAT3 and Treg-mediated immune modulation in hepatocellular carcinoma), ATOX1 (limiting cuproptosis), CNTN3, and GCH1 [#1, #9, #12, #0]. Through GCH1-driven BH4 antioxidant production, PRRX2 suppresses ferroptosis in glioma stem cells, and its protein level is constrained by circLRFN5-directed ubiquitin-proteasomal degradation [#0]. PRRX2 expression is itself controlled upstream by KLF6, which binds the Prrx2 promoter in pituitary cells, and by miR-212-5p, which represses Prrx2 via its 3'-UTR [#7, #2]. In normal physiology PRRX2 acts as a mesenchymal/progenitor regulator: myoblast exosome-delivered PRRX2 activates the MIR22HG promoter to drive YAP-dependent osteogenic differentiation of BMSCs, it activates Panx3 transcription in preodontoblasts, and it serves as a barrier to neural fate in fibroblasts whose attenuation enhances induced-neuron conversion [#6, #10, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established an upstream transcriptional regulator of PRRX2, placing it within a defined pituitary gene network rather than treating it as an orphan factor.\",\n      \"evidence\": \"Promoter luciferase, EMSA, and siRNA knockdown of KLF6 in pituitary cells\",\n      \"pmids\": [\"24881871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify PRRX2's own direct target genes in pituitary\", \"Physiological consequence of KLF6\\u2192PRRX2 axis in vivo not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PRRX2 as a pro-EMT effector controlled by miR-212-5p and acting through Wnt/\\u03b2-catenin, providing the first mechanistic link between PRRX2 and metastatic phenotypes.\",\n      \"evidence\": \"3'-UTR luciferase reporter, shRNA knockdown, invasion/migration assays, and xenografts in breast cancer cells\",\n      \"pmids\": [\"29216628\", \"28750408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter targets mediating Wnt activation not identified\", \"Mechanism by which PRRX2 controls \\u03b2-catenin nuclear translocation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the PRRX2\\u2013Wnt/\\u03b2-catenin invasion axis to colon cancer with epistatic rescue, and separately revealed a normal role as a barrier to neural reprogramming in fibroblasts.\",\n      \"evidence\": \"Knockdown plus LiCl Wnt-rescue and liver-metastasis model in colon cancer cells; shRNA knockdown plus RNAseq during fibroblast-to-neuron conversion\",\n      \"pmids\": [\"31471104\", \"31255287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Wnt-pathway target genes still inferred from markers, not ChIP\", \"Fibroblast gene-regulatory targets of PRRX2 not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified PRRX2 as a direct transcriptional activator of IL-6, linking it to IL-6/STAT3 signaling and immune modulation in hepatocellular carcinoma.\",\n      \"evidence\": \"Overexpression/knockdown in HCC lines with xenograft and Cbs heterozygous knockout mouse models\",\n      \"pmids\": [\"34413167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy at IL-6 not shown by ChIP in this entry\", \"Whether CBS regulates PRRX2 directly or indirectly unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PRRX2 to redox/ferroptosis control and post-translational regulation, showing it activates GCH1/BH4 to suppress ferroptosis while being degraded via circLRFN5-directed ubiquitination.\",\n      \"evidence\": \"RIP, RNA pull-down, ubiquitination assay, ChIP, and luciferase in glioma stem cells\",\n      \"pmids\": [\"36266731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase mediating circLRFN5-dependent degradation not identified\", \"Ubiquitination sites on PRRX2 unmapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated PRRX2 in therapy resistance, showing its activation confers enzalutamide resistance through CDK4/6/Rb/E2F and BCL2 pathways in prostate cancer.\",\n      \"evidence\": \"Genome-wide CRISPRa screen with CDK4/6 and BCL2 inhibitor validation in prostate cancer cells\",\n      \"pmids\": [\"35405009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PRRX2 directly transactivates CDK4/6 or BCL2 genes not determined\", \"Direct target promoters in prostate cancer not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a physiological gain-of-function role: exosome-delivered PRRX2 directly activates MIR22HG transcription to drive YAP-dependent osteogenic differentiation.\",\n      \"evidence\": \"ChIP, RIP, luciferase, immunofluorescence, exosome delivery, and ovariectomy mouse model in BMSCs\",\n      \"pmids\": [\"37081396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PRRX2 is loaded into myoblast exosomes unknown\", \"Generality of PRRX2-MIR22HG-YAP axis beyond osteogenesis untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the direct PRRX2 target repertoire to ATOX1 (cuproptosis suppression in HCC) and Panx3 (preodontoblast regulation), reinforcing its role as a sequence-specific promoter-binding activator.\",\n      \"evidence\": \"ChIP, luciferase, EMSA, JASPAR site analysis, siRNA knockdown, and rescue in HCC and dental papilla-derived cells\",\n      \"pmids\": [\"40393577\", \"39733924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Consensus PRRX2 binding motif not derived across targets\", \"Tissue-specificity of target selection not explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked PRRX2 to radiation-induced ferroptosis resistance in skin cells downstream of Marveld3 silencing.\",\n      \"evidence\": \"siRNA/overexpression with Fe2+/ROS/lipid-peroxidation assays and RNAseq in HaCaT and WS1 cells\",\n      \"pmids\": [\"39434056\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Molecular mechanism linking PRRX2 to ferroptosis suppression in skin incompletely characterized\", \"Direct PRRX2 targets controlling Fe2+/ROS not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the oncogenic signaling output of PRRX2 to Hedgehog (via GLI2), CNTN3-driven CRC metastasis, and TGF-\\u03b2/Fibronectin-mediated ECM remodeling in pancreatic cancer.\",\n      \"evidence\": \"ChIP/luciferase and knockdown/rescue in pancreatic and colorectal cancer cells; single-cell/spatial transcriptomics with knockdown migration assay in PDAC\",\n      \"pmids\": [\"40619170\", \"41882765\", \"41456929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GLI2 and TGFB1 direct binding inferred without explicit Tier 1 confirmation in two entries\", \"Integration of Wnt, Hedgehog, and TGF-\\u03b2 outputs by PRRX2 not mechanistically unified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRRX2 selects context-specific promoter targets and integrates its convergence on Wnt, Hedgehog, and TGF-\\u03b2 signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined consensus DNA-binding motif or genome-wide occupancy map\", \"Cofactors directing tissue-specific target selection unknown\", \"No structural model of PRRX2-DNA or PRRX2-cofactor complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6, 9, 10, 11, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 6, 9, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 9, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 6, 9, 10, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 11, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7, 8, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 9, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"circLRFN5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}