Affinage

HDGF

Hepatoma-derived growth factor · UniProt P51858

Length
240 aa
Mass
26.8 kDa
Annotated
2026-04-28
91 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HDGF is a heparin-binding nuclear growth factor that functions both as an intracellular chromatin-associated regulator and as an extracellular signaling molecule, linking transcriptional control, DNA damage repair, and mitogenic signaling to cell proliferation, angiogenesis, and epithelial-mesenchymal transition. Its N-terminal PWWP/HATH domain mediates non-sequence-selective DNA binding, heparin binding (critically dependent on residue K19), RNA association, and protein–protein interactions, while cell-surface heparan sulfates and the receptor nucleolin mediate its internalization via macropinocytosis and activation of MAPK/ERK, PI3K/AKT, and STAT3 signaling cascades (PMID:16384999, PMID:25117899, PMID:20964630, PMID:37827291, PMID:26392778). In the nucleus, HDGF forms complexes with DDX5 and β-catenin to regulate Wnt/β-catenin–c-Myc signaling and miRNA expression, transcriptionally represses targets such as ALCAM to control Rho-GTPase-dependent cytoskeletal remodeling, activates KRAS transcription, and recruits CtIP to H3K36me3-marked loci to facilitate homologous recombination repair (PMID:28751441, PMID:33239755, PMID:40001585, PMID:36574142). HDGF expression is transcriptionally repressed by p53 through HDAC-dependent chromatin remodeling and post-transcriptionally stabilized by m6A methylation readers (IGF2BP2) and RNA-binding proteins (G3BP2), while its protein levels are regulated by USP14-mediated deubiquitination downstream of NAP1L1; HDGF-null mice are viable, indicating functional redundancy during normal development (PMID:22006999, PMID:36265285, PMID:40414865, PMID:18570251).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2004 Medium

    Establishing the baseline expression and subcellular distribution of HDGF across tissues answered where and when this growth factor operates, revealing broad expression with nuclear/cytoplasmic dual localization and developmental regulation in the brain.

    Evidence Immunohistochemistry, immunocytochemistry, Western blotting across mouse tissue panels and developmental time points

    PMID:14572309

    Open questions at the time
    • No functional consequence of developmental regulation demonstrated
    • Mechanism controlling nuclear vs. cytoplasmic partitioning not defined
  2. 2005 High

    Solving the NMR structure of the PWWP domain and demonstrating its non-sequence-selective DNA-binding activity established the molecular basis for HDGF's chromatin association.

    Evidence NMR structure determination, SELEX, and NMR titrations with DNA

    PMID:16384999

    Open questions at the time
    • No specific genomic target sites identified
    • Functional consequence of DNA binding on gene regulation not tested
  3. 2008 High

    Generation of HDGF-knockout mice showed the gene is dispensable for normal development, raising the question of whether its growth-factor activities are redundant with HRP family members or context-dependent.

    Evidence HDGF-null mice (GFP knock-in) with proliferation, cell-cycle, and apoptosis assays on dermal fibroblasts

    PMID:18570251

    Open questions at the time
    • Compensation by HRP-2/HRP-3 not formally tested
    • Stress or disease-specific phenotypes not examined in knockout
  4. 2008 Medium

    Demonstrating caspase-dependent dephosphorylation of HDGF during apoptosis revealed that HDGF is an early target of the apoptotic signaling cascade, though the kinase/phosphatase pair and functional consequence remain unclear.

    Evidence 2D phosphoproteomics, mass spectrometry, GFP-HDGF imaging, caspase inhibitor experiments in endothelial cells

    PMID:18465786

    Open questions at the time
    • Identity of the phosphatase mediating dephosphorylation unknown
    • Functional impact of dephosphorylation on HDGF activity not determined
  5. 2011 High

    Identifying heparan sulfate-dependent macropinocytic internalization and the HATH domain as the entry module resolved how extracellular HDGF re-enters cells and differentially affects MAPK signaling depending on receptor engagement.

    Evidence Internalization assays in HS-deficient cells, macropinocytosis inhibitors, K96A mutant, migration/proliferation assays in NIH 3T3 fibroblasts

    PMID:20964630

    Open questions at the time
    • Identity of the cell-surface receptor mediating HS-independent signaling not defined here
    • Whether macropinocytosis is the sole route of entry in vivo unknown
  6. 2011 Medium

    Tandem affinity purification revealing 106 HATH-domain-dependent interactors, plus RNA co-immunoprecipitation, expanded HDGF from a simple growth factor to a multifunctional hub in ribosome biogenesis, RNA processing, and DNA repair.

    Evidence SBP/Flag tandem affinity purification with LC-MS/MS, Co-IP, RT-PCR SBP-RIP

    PMID:21907836

    Open questions at the time
    • Most interactors not individually validated by reciprocal methods
    • RNA targets not identified at sequence level
  7. 2011 High

    Showing that p53 transcriptionally represses HDGF through HDAC-dependent chromatin remodeling established a direct tumor-suppressor–oncoprotein regulatory axis.

    Evidence p53 overexpression, HDAC chromatin remodeling assay, neutralizing antibody functional studies

    PMID:22006999

    Open questions at the time
    • Specific p53 binding site on HDGF promoter not mapped
    • Whether other p53 family members also repress HDGF untested
  8. 2014 High

    Pinpointing K19 as the critical residue for heparin binding by NMR titration of side-chain resonances provided atomic-level understanding of the HDGF–heparan sulfate interaction.

    Evidence H2CN NMR pulse sequence with site-directed mutagenesis

    PMID:25117899

    Open questions at the time
    • Structural model of full heparin–PWWP complex not determined
    • In vivo relevance of K19 mutation not tested
  9. 2015 Medium

    Demonstrating that HDGF knockdown suppresses VEGF and in vivo angiogenesis in HCC established a mechanistic link between HDGF and tumor vascularization.

    Evidence shRNA knockdown, xenograft models, VEGF mRNA/protein quantification

    PMID:26637859

    Open questions at the time
    • Direct vs. indirect regulation of VEGF transcription by HDGF not resolved
    • Whether HDGF signals through autocrine or paracrine VEGF induction unclear
  10. 2016 Medium

    Identifying HDGF as a passively released alarmin from necrotic/apoptotic cells that activates ERK1/2 and p38 MAPK revealed a damage-associated molecular pattern function distinct from its growth-factor role.

    Evidence ELISA, cell fractionation, necrosis/apoptosis induction, phospho-Western blotting, migration assays in ovarian cancer cells

    PMID:26612514

    Open questions at the time
    • Receptor mediating alarmin signaling not identified in this study
    • Whether alarmin function operates in non-cancer contexts unknown
  11. 2017 High

    Discovery of the HDGF–DDX5–β-catenin complex and its suppression of miR-296-3p to activate PRKCA-FAK-Ras signaling defined a nuclear transcriptional mechanism linking HDGF to Wnt pathway output and EMT.

    Evidence Co-IP with mass spectrometry, GST pull-down, ChIP, EMSA, luciferase reporter assays

    PMID:28751441

    Open questions at the time
    • Stoichiometry and assembly order of the trimeric complex not determined
    • Whether HDGF DNA-binding activity is required for complex function untested
  12. 2017 Medium

    Demonstrating that HDGF isoforms are differentially sorted into or onto exosomes (HDGF-A inside, HDGF-B/C on the surface) revealed an unconventional secretion mechanism with isoform-specific trafficking.

    Evidence Exosome isolation, protease protection assay, conditioned media fractionation

    PMID:27926477

    Open questions at the time
    • Functional consequence of exosomal HDGF delivery on recipient cells not tested
    • Sorting signal beyond N-terminal peptide not fully defined
  13. 2019 High

    Identification of a ZEB1→HDGF→β-catenin/TCF4 positive feedback loop driving endometrial cancer metastasis showed how HDGF integrates EMT transcription factor input with Wnt signaling amplification.

    Evidence Reciprocal Co-IP, ChIP on HDGF promoter, immunofluorescence, in vitro and in vivo functional assays

    PMID:31815037

    Open questions at the time
    • Whether the feedback loop operates in normal tissues unknown
    • Mechanism of HDGF-induced β-catenin nuclear translocation not resolved
  14. 2020 High

    ChIP-seq and functional studies revealing that HDGF transcriptionally represses ALCAM to activate Rac1/Cdc42 and cytoskeletal remodeling defined a nuclear mechanism for HDGF-driven metastasis in Ewing sarcoma.

    Evidence ChIP-seq, gene expression profiling, Rac1/Cdc42 activation assays, orthotopic murine models

    PMID:33239755

    Open questions at the time
    • Whether HDGF directly binds the ALCAM promoter or acts through a co-repressor complex not distinguished
    • Generalizability to non-Ewing sarcoma contexts untested
  15. 2021 Medium

    Linking HDGF to STAT3 pathway activation (Tyr705/Ser727 phosphorylation) in radioresistance, with RXRα acting as a transcriptional repressor of HDGF, added a new signaling axis and therapeutic vulnerability.

    Evidence HDGF knockdown, STAT3 phosphorylation Western blots, RXRα ChIP on HDGF promoter, in vitro/in vivo radioresistance assays

    PMID:34376200

    Open questions at the time
    • Whether HDGF activates STAT3 directly or through an intermediate kinase unresolved
    • TKT's mechanistic role in HDGF–STAT3 signaling incompletely defined
  16. 2022 Medium

    Convergent studies showed NAP1L1 interacts with HDGF to bridge DDX5/β-catenin signaling in colon cancer and c-Jun/CCND1 signaling in glioma, establishing NAP1L1 as a context-dependent upstream scaffold for HDGF oncogenic functions.

    Evidence Co-IP, knockdown/overexpression rescue, xenograft models in colon cancer and glioma cells

    PMID:34959221 PMID:36148951

    Open questions at the time
    • Direct binding interface between NAP1L1 and HDGF not mapped
    • Whether NAP1L1–HDGF interaction is constitutive or signal-regulated unknown
  17. 2022 Medium

    Discovery that m6A modification and RNA-binding proteins (G3BP2, later IGF2BP2) stabilize HDGF mRNA revealed a post-transcriptional regulatory layer controlling HDGF abundance in cancer and macrophage biology.

    Evidence Mettl3-dependent m6A assays, mRNA stability assays, RIP, macrophage-specific HDGF KO mice in atherosclerosis models; IGF2BP2 RIP and stability assays in ESCC

    PMID:34782720 PMID:36265285 PMID:39206979

    Open questions at the time
    • Specific m6A sites on HDGF mRNA not mapped at nucleotide resolution in all studies
    • Relative contribution of transcriptional vs. post-transcriptional regulation in different cell types unclear
  18. 2023 High

    Identifying nucleolin (NCL) as the surface receptor through which extracellular HDGF stimulates mitochondrial ROS and oxidative phosphorylation, with Ser103 required for activity, resolved a long-standing question about the identity of the HDGF receptor.

    Evidence Recombinant HDGF, Ser103Ala mutagenesis, Seahorse metabolic flux, NCL knockdown, neutralizing antibody, orthotopic hepatoma model

    PMID:37827291

    Open questions at the time
    • Whether NCL is the sole HDGF receptor or acts with co-receptors not excluded
    • Structural basis of HDGF–NCL interaction unknown
  19. 2025 Medium

    Demonstrating that HDGF recruits CtIP to H3K36me3-marked chromatin to facilitate homologous recombination established HDGF as a reader-effector linking active chromatin marks to DNA damage repair.

    Evidence HDGF knockout cells, RNA-seq, Co-IP/interaction assays, drug sensitivity assays in colorectal cancer

    PMID:40001585

    Open questions at the time
    • Whether PWWP domain directly reads H3K36me3 in the context of HR repair not formally shown
    • Structural basis of CtIP recruitment by HDGF not determined
  20. 2025 Medium

    Placing HDGF within the FBXW7→NAP1L1→USP14 deubiquitination axis showed that HDGF protein stability is regulated by ubiquitin-dependent proteostasis, connecting HDGF levels to autophagy and chemosensitivity.

    Evidence Ubiquitination/deubiquitination assays, Co-IP, knockdown/overexpression, in vivo NPC models

    PMID:40414865

    Open questions at the time
    • Specific ubiquitination sites on HDGF not mapped
    • Whether other E3 ligases target HDGF directly unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of full-length HDGF in complex with nucleolin, heparan sulfate, or chromatin substrates is lacking, and the relative contributions of intracellular versus extracellular HDGF pools to its diverse signaling outputs remain mechanistically unresolved.
  • No crystal or cryo-EM structure of full-length HDGF or HDGF–NCL complex
  • Relative physiological importance of intracellular chromatin functions vs. extracellular growth factor signaling undetermined
  • Functional redundancy with HRP-2 and HRP-3 not systematically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0048018 receptor ligand activity 4 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 1 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3 GO:0005576 extracellular region 2 GO:0005694 chromosome 2 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
BLMCTNNB1DDX5HDGFL1NAP1L1NCLRBBP8ZEB1
Complex memberships
HDGF–DDX5–β-cateninHDGF–HRP-2c heteromerNAP1L1–HDGF–USP14

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 The HDGF PWWP domain adopts a defined NMR structure and functions as a nonspecific DNA-binding domain, with the C-terminal region differing from a previously determined structure; NMR titrations with DNA propose interaction via the minor groove. NMR structure determination (NOEs, J-couplings, dipolar couplings), SELEX (selected and amplified binding assay), NMR titrations with DNA Protein science High 16384999
2011 The HATH domain of HDGF is essential for both protein-protein and protein-RNA interactions; tandem affinity purification identified 106 HDGF-interacting proteins involved in ribosome biogenesis, RNA processing, DNA damage repair, and transcriptional regulation; HDGF also associates with RNAs. SBP/Flag-tag tandem affinity purification coupled with LC-MS/MS, Co-IP, RT-PCR RNA co-immunoprecipitation (SBP-RIP) Journal of proteomics Medium 21907836
2011 Cell surface heparan sulfates (HS) are required for HDGF internalization; the HATH/PWWP domain binds HS and enters cells via macropinocytosis; HS-mediated internalization of a receptor-binding-deficient HATH mutant (K96A) inhibits cell migration and proliferation through differential effects on MAPK signaling and matrix metalloprotease expression in NIH 3T3 fibroblasts. Cell-based internalization assays with HS-deficient cells, macropinocytosis inhibitor studies, migration/proliferation assays, Western blotting for MAPK pathway The Biochemical journal High 20964630
2011 p53 transcriptionally represses HDGF by altering HDAC-dependent chromatin remodeling; wild-type p53 introduction decreases endogenous HDGF expression and neutralizing HDGF antibodies block cell growth, migration, and invasion. p53 overexpression, HDAC-dependent chromatin remodeling assay, neutralizing antibody treatment, cell growth/migration/invasion assays Cancer research High 22006999
2012 HDGF forms heteromers with HRP-2 isoform c (which has a 53-amino acid deletion in its HATH region); this specific heteromer binds chromatin similarly to LEDGF and is displaced from condensed mitotic metaphase chromatin, unlike other HRP-2 isoforms. Co-immunoprecipitation, chromatin binding assays, identification of novel splice variant The FEBS journal Medium 22212508
2008 HDGF is dephosphorylated during the early steps of TNF+cycloheximide-induced apoptosis in endothelial cells in a caspase-dependent manner, occurring before mitochondrial membrane permeabilization; this dephosphorylation does not affect nuclear localization of HDGF. 2D gel of 32P-labeled samples, mass spectrometry, Western blot, GFP-HDGF live imaging, caspase inhibitor (zVADfmk) experiments Journal of cellular biochemistry Medium 18465786
2008 HDGF-deficient (knockout) mice are viable with no apparent morphological abnormalities; HDGF-deficient dermal fibroblasts show unaltered proliferation rates, cell-cycle distributions, and apoptotic rates, demonstrating that HDGF is dispensable for normal mouse development. Knockout mouse generation (GFP knock-in), cell proliferation assay, cell-cycle analysis, TNFα-induced apoptosis assay Developmental dynamics High 18570251
2004 HDGF protein is expressed broadly across tissues (highest in brain, testis, lung, and spleen) and localizes to both nucleus and cytoplasm; in cultured neocortical neurons, HDGF is restricted to the soma while the related HRP-3 is also found in neurites; expression is regulated during brain development with peak levels around birth. Immunohistochemistry, immunocytochemistry with specific antisera, in situ hybridization, Western blot of tissue panels The Biochemical journal Medium 14572309
2017 HDGF forms a complex with DDX5 and β-catenin; DDX5 directly interacts with HDGF and induces β-catenin-c-Myc signaling, which suppresses miR-296-3p and activates PRKCA-FAK-Ras signaling, cell cycle, and EMT; this was demonstrated by CoIP combined with mass spectrometry and GST pull-down. Co-immunoprecipitation with mass spectrometry, GST pull-down, ChIP, EMSA, luciferase reporter assays Clinical cancer research High 28751441
2019 ZEB1 interacts with HDGF protein and co-localizes with it in the nucleus; ZEB1 binds to the HDGF promoter as a transcription factor to stimulate HDGF transcription; HDGF in turn promotes β-catenin nuclear translocation and TCF4 interaction, creating a positive feedback loop (ZEB1/HDGF/β-catenin/TCF4) driving endometrial cancer metastasis. Co-immunoprecipitation, immunofluorescence co-localization, ChIP on HDGF promoter, Western blotting, in vitro/in vivo functional assays American journal of cancer research High 31815037
2020 HDGF drives Ewing sarcoma metastasis by transcriptionally repressing ALCAM (activated leukocyte cell adhesion molecule), leading to expression and activation of Rho-GTPases Rac1 and Cdc42, actin cytoskeleton remodeling, and increased cell-matrix adhesion; ChIP-seq and gene expression profiling defined the HDGF/ALCAM/GTPase axis. ChIP-seq, gene expression profiling, functional invasion/migration assays, Rac1/Cdc42 activation assays, in vivo orthotopic murine models, human cohort analysis Oncogene High 33239755
2021 NAP1L1 interacts with HDGF at the protein level (co-localizing in the cytoplasm); HDGF in turn interacts with c-Jun, leading to induction of CCND1/CDK4/CDK6 expression; this NAP1L1-HDGF-c-Jun-CCND1/CDK4/CDK6 axis promotes glioma proliferation and cisplatin resistance. Co-immunoprecipitation, immunofluorescence, knockdown/overexpression experiments, Western blotting, in vivo xenograft Aging Medium 34959221
2022 NAP1L1 interacts with HDGF and recruits DDX5, inducing β-catenin/CCND1 signaling to promote colon cancer cell proliferation; restoration of HDGF or DDX5 rescues growth in NAP1L1-knockdown cells. Co-immunoprecipitation, knockdown/overexpression rescue experiments, MTT, colony formation, EdU incorporation, in vivo xenograft Acta biochimica et biophysica Sinica Medium 36148951
2022 G3BP2 binds to HDGF mRNA transcript to stabilize it, thereby enhancing HDGF expression and promoting esophageal squamous cell carcinoma cell migration and invasion; LINC01554 maintains G3BP2 expression by protecting it from ubiquitination-dependent degradation. RNA-seq, RNA immunoprecipitation, co-immunoprecipitation, knockdown/overexpression functional assays, in vivo models Oncogene Medium 34782720
2022 Mettl3-mediated N6-methyladenosine (m6A) RNA methylation enhances HDGF mRNA stability and protein expression in M1 macrophages; elevated HDGF in macrophages drives M1 polarization through energy metabolism reprogramming, promoting atherosclerosis. m6A methylation assays, mRNA stability assays, macrophage-specific HDGF knockout mice, in vivo atherosclerosis model (ApoeKO mice), metabolic analysis Biochemical and biophysical research communications Medium 36265285
2023 HDGF stimulates mitochondrial ROS generation and bioenergetics (basal and maximal oxygen consumption, oxidative phosphorylation) in hepatoma cells in a dose-dependent manner via the HDGF receptor nucleolin (NCL); an inactive Ser103Ala mutant fails to promote ROS generation or oncogenic behaviors; knockdown of NCL or antibody neutralization of surface NCL abolishes HDGF-induced ROS and mitochondrial energetics. Recombinant HDGF treatment, active-site mutagenesis (Ser103Ala), Seahorse metabolic flux assay, flow cytometry (ROS detection), NCL knockdown, neutralizing antibody, antioxidant rescue experiments, in vivo orthotopic hepatoma model The Journal of biological chemistry High 37827291
2025 HDGF modulates DNA damage response in colorectal cancer by recruiting CtIP (C-terminal binding protein-interacting protein) to facilitate homologous recombination repair; HDGF also serves as a recognition protein for H3K36me3, participating in repair of damaged transcriptionally active genes to maintain genomic stability. HDGF knockout cells, RNA-seq, Co-IP/interaction assays, drug sensitivity assays Biomolecules Medium 40001585
2016 In ovarian cancer cells, HDGF is predominantly nuclear and passively released by necrotic and late apoptotic cells (functioning as an alarmin); extracellular HDGF stimulates phosphorylation of ERK1/2 and p38 MAPK in both non-cancer and ovarian cancer cells, and enhances cellular migration. Immunofluorescence imaging, cell fractionation, ELISA (secretion measurement), necrosis/apoptosis induction, ERK/p38 phosphorylation Western blot, migration assays Apoptosis Medium 26612514
2014 The K19 residue in HDGF is crucial for heparin binding; H2CN NMR titrations of side-chain resonances (Hε-Cε-Nζ of Lys, Hδ-Cδ-Nε of Arg) revealed that K19 shows the most significant perturbation upon heparin binding, correlated with free energy changes in mutants. H2CN NMR pulse sequence, site-directed mutagenesis, NMR titration experiments Biochimica et biophysica acta High 25117899
2015 Extracellular/recombinant HDGF activates AKT and MAPK signaling pathways in osteosarcoma cells to stimulate proliferation; intrinsic (intracellular) HDGF is also required for osteosarcoma cell proliferation. Recombinant HDGF stimulation, Western blotting for AKT/MAPK phosphorylation, siRNA knockdown, MTT proliferation assay OncoTargets and therapy Medium 26392778
2021 HDGF activates the STAT3 signaling pathway (specifically STAT3-Tyr705 and STAT3-Ser727 phosphorylation and STAT3 transcriptional activity) to drive radioresistance in breast cancer; RXRα binding to the HDGF promoter blocks HDGF transcriptional activity; TKT was implicated in HDGF-enhanced STAT3 activity. HDGF knockdown, Western blotting for STAT3 phosphorylation, RXRα ChIP on HDGF promoter, in vitro and in vivo radioresistance assays Journal of translational medicine Medium 34376200
2019 HDGF induces macrophage polarization toward M2 type through the IL-4/JAK1/STAT3 signaling pathway; HDGF dose-dependently promotes IL-4 expression in NSCLC cells, which in turn drives M2 polarization. Western blotting, qRT-PCR, ELISA, flow cytometry, HDGF overexpression, RNA-seq, in vivo tumor model Journal of ethnopharmacology Medium 35973634
2017 HDGF-A isoform is located inside exosomes, whereas HDGF-B and HDGF-C isoforms are found exclusively on the outer surface of exosomes; HDGF-A is also found as unbound protein in conditioned media; the N-terminal peptide of HDGF-A determines intra-exosomal localization. Exosome isolation, protease protection assay, Western blotting, fractionation of conditioned media Biological chemistry Medium 27926477
2025 FBXW7 (E3 ubiquitin ligase) directly ubiquitinates NAP1L1, promoting its degradation; reduced NAP1L1 impairs recruitment of USP14, decreasing USP14-mediated deubiquitination of HDGF and reducing HDGF protein levels; reduced HDGF in turn suppresses USP14-mediated p62 deubiquitination, promoting autophagy and cisplatin sensitivity in nasopharyngeal carcinoma. Co-immunoprecipitation, ubiquitination assays, deubiquitination assays, knockdown/overexpression experiments, in vivo NPC models Molecular cancer Medium 40414865
2024 IGF2BP2 (m6A reader) binds to and stabilizes HDGF mRNA transcripts in an m6A-dependent manner, promoting HDGF protein expression and ESCC progression. RNA immunoprecipitation, mRNA stability assays, IGF2BP2 overexpression/knockdown, transcriptome sequencing Journal of cancer research and therapeutics Medium 39206979
2025 HDGF protects retinal pigment epithelium from ferroptosis via a dual mechanism: activating p38 MAPK/AKT and SIRT1/PGC-1α axes to restore mitochondrial biogenesis, while enhancing the glutathione/GPX4 antioxidant system via the PGC-1α/Nrf2 pathway. Exogenous HDGF treatment, Western blotting, ROS/lipid peroxidation assays, mitochondrial function assays, pathway inhibitor studies Antioxidants Medium 41462634
2022 BLM directly interacts with HDGF; HDGF activates KRAS transcription and suppresses RhoA transcription, activating the MAPK/ERK pathway; BLM and HDGF knockdown has synergistic effects on suppressing prostate cancer proliferation and invasion. Co-immunoprecipitation, ChIP-seq, dual-luciferase reporter assay, Western blotting, in vivo xenograft Journal of cell communication and signaling Medium 36574142
2015 HDGF knockdown in HCC cells suppresses VEGF expression and reduces in vivo angiogenesis of developed tumors; the anti-tumor effects of HDGF suppression in vivo exceeded the effect predicted from in vitro data alone, implicating angiogenesis as a key effector mechanism. HDGF shRNA stable knockdown, xenograft murine model, real-time PCR and immunostaining for VEGF and angiogenesis markers Anticancer research Medium 26637859

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 miRomics and Proteomics Reveal a miR-296-3p/PRKCA/FAK/Ras/c-Myc Feedback Loop Modulated by HDGF/DDX5/β-catenin Complex in Lung Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 86 28751441
2013 Downregulation of miR-16 promotes growth and motility by targeting HDGF in non-small cell lung cancer cells. FEBS letters 84 23954293
2013 Downregulation of miR-497 promotes tumor growth and angiogenesis by targeting HDGF in non-small cell lung cancer. Biochemical and biophysical research communications 83 23673296
2014 HDGF: a novel jack-of-all-trades in cancer. Future oncology (London, England) 75 25236340
2012 Differential proteomic analysis of human glioblastoma and neural stem cells reveals HDGF as a novel angiogenic secreted factor. Stem cells (Dayton, Ohio) 70 22331796
2019 Long Noncoding RNA HCP5 Regulates Pancreatic Cancer Gemcitabine (GEM) Resistance By Sponging Hsa-miR-214-3p To Target HDGF. OncoTargets and therapy 57 31632071
2005 High resolution structure of the HDGF PWWP domain: a potential DNA binding domain. Protein science : a publication of the Protein Society 56 16384999
2019 Long non-coding RNA AGAP2-AS1 promotes the proliferation of glioma cells by sponging miR-15a/b-5p to upregulate the expression of HDGF and activating Wnt/β-catenin signaling pathway. International journal of biological macromolecules 55 30684575
2013 Anti-HDGF targets cancer and cancer stromal stem cells resistant to chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 51 23695169
2004 Expression patterns and different subcellular localization of the growth factors HDGF (hepatoma-derived growth factor) and HRP-3 (HDGF-related protein-3) suggest functions in addition to their mitogenic activity. The Biochemical journal 51 14572309
2014 MiR-195 targets HDGF to inhibit proliferation and invasion of NSCLC cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 47 24891187
2013 miR-141 suppresses proliferation and motility of gastric cancer cells by targeting HDGF. Molecular and cellular biochemistry 45 24276755
2020 HDGF enhances VEGF‑dependent angiogenesis and FGF‑2 is a VEGF‑independent angiogenic factor in non‑small cell lung cancer. Oncology reports 44 32319650
2002 Antisense oligonucleotides of hepatoma-derived growth factor (HDGF) suppress the proliferation of hepatoma cells. Hepato-gastroenterology 43 12397753
2013 Downregulated expression of hepatoma-derived growth factor (HDGF) reduces gallbladder cancer cell proliferation and invasion. Medical oncology (Northwood, London, England) 34 23609195
2017 MicroRNA-195 inhibits the behavior of cervical cancer tumors by directly targeting HDGF. Oncology letters 33 28693232
2012 HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas. Gut 33 22490522
2019 ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription. American journal of cancer research 32 31815037
2015 Differential proteomic analysis reveals that EGCG inhibits HDGF and activates apoptosis to increase the sensitivity of non-small cells lung cancer to chemotherapy. Proteomics. Clinical applications 30 26175166
2011 Interactome study suggests multiple cellular functions of hepatoma-derived growth factor (HDGF). Journal of proteomics 28 21907836
2020 Circular RNA circMAGI3 accelerates the glycolysis of non-small cell lung cancer through miR-515-5p/HDGF. American journal of translational research 27 32774748
2020 Hsa_circ_0079480 promotes tumor progression in acute myeloid leukemia via miR-654-3p/HDGF axis. Aging 27 33290265
2021 NAP1L1 promotes proliferation and chemoresistance in glioma by inducing CCND1/CDK4/CDK6 expression through its interaction with HDGF and activation of c-Jun. Aging 26 34959221
2011 p53 negatively regulates the hepatoma growth factor HDGF. Cancer research 26 22006999
2020 MicroRNA-139-5p inhibits cell viability, migration and invasion and suppresses tumor growth by targeting HDGF in non-small cell lung cancer. Oncology letters 25 32194674
2020 A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway. Oncogene 25 33239755
2016 Hepatoma derived growth factor (HDGF) dynamics in ovarian cancer cells. Apoptosis : an international journal on programmed cell death 25 26612514
2011 Cell surface heparan sulfates mediate internalization of the PWWP/HATH domain of HDGF via macropinocytosis to fine-tune cell signalling processes involved in fibroblast cell migration. The Biochemical journal 25 20964630
2022 Marsdenia tenacissima extract disturbs the interaction between tumor-associated macrophages and non-small cell lung cancer cells by targeting HDGF. Journal of ethnopharmacology 24 35973634
2014 A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma. Journal of neuro-oncology 24 24986090
2022 G3BP2 regulated by the lncRNA LINC01554 facilitates esophageal squamous cell carcinoma metastasis through stabilizing HDGF transcript. Oncogene 23 34782720
2022 NAP1L1 promotes tumor proliferation through HDGF/C-JUN signaling in ovarian cancer. BMC cancer 23 35351053
2022 RNA-m6A modification of HDGF mediated by Mettl3 aggravates the progression of atherosclerosis by regulating macrophages polarization via energy metabolism reprogramming. Biochemical and biophysical research communications 22 36265285
2019 Downregulation of HDGF inhibits the tumorigenesis of bladder cancer cells by inactivating the PI3K-AKT signaling pathway. Cancer management and research 22 31692549
2008 Hepatoma-derived growth factor (HDGF) is dispensable for normal mouse development. Developmental dynamics : an official publication of the American Association of Anatomists 21 18570251
2021 Heparin-binding growth factor (HDGF) drives radioresistance in breast cancer by activating the STAT3 signaling pathway. Journal of translational medicine 20 34376200
2020 Exosomal lncRNA HEIH promotes cisplatin resistance in tongue squamous cell carcinoma via targeting miR-3619-5p/HDGF axis. Acta histochemica 20 33130420
2015 Irradiated fibroblasts promote epithelial-mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma. Biochemical and biophysical research communications 20 25677618
2015 HDGF-related protein-2 (HRP-2) acts as an oncogene to promote cell growth in hepatocellular carcinoma. Biochemical and biophysical research communications 20 25689719
2010 shRNA targeting HDGF suppressed cell growth and invasion of squamous cell lung cancer. Acta biochimica et biophysica Sinica 20 20043047
2019 Long noncoding RNA LINC00342 promotes growth of infantile hemangioma by sponging miR-3619-5p from HDGF. American journal of physiology. Heart and circulatory physiology 19 31469292
2023 HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer. Cell death discovery 18 37301856
2021 Crystal structure of the BRPF2 PWWP domain in complex with DNA reveals a different binding mode than the HDGF family of PWWP domains. Biochimica et biophysica acta. Gene regulatory mechanisms 18 33556623
2019 LncRNA TDRG1 promotes the aggressiveness of gastric carcinoma through regulating miR-873-5p/HDGF axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 18 31726370
2015 Down-regulation of HDGF Inhibits the Growth of Hepatocellular Carcinoma Cells In Vitro and In Vivo. Anticancer research 18 26637859
2020 MicroRNA-95-3p inhibits cell proliferation and metastasis in colorectal carcinoma by HDGF. Biomedical journal 17 32418767
2019 Upregulation of miR‑95-3p inhibits growth of osteosarcoma by targeting HDGF. Pathology, research and practice 14 31257090
2022 NAP1L1 promotes the growth of colon cancer by activating HDGF/DDX5. Acta biochimica et biophysica Sinica 13 36148951
2021 miR-1254 induced by NESG1 inactivates HDGF/DDX5-stimulated nuclear translocation of β-catenin and suppresses NPC metastasis. Molecular therapy. Methods & clinical development 13 33718512
2020 Long non-coding RNA SNHG3 accelerates progression in glioma by modulating miR-384/HDGF axis. Open life sciences 13 33817254
2015 Hepatocarcinoma cell-derived hepatoma-derived growth factor (HDGF) induces regulatory T cells. Cytokine 13 25569374
2020 Long Non-Coding RNA ASB16-AS1 Functions as a miR-760 Sponge to Facilitate the Malignant Phenotype of Osteosarcoma by Increasing HDGF Expression. OncoTargets and therapy 11 32214826
2019 [Curcumin suppresses invasiveness and migration of human glioma cells in vitro by inhibiting HDGF/β-catenin complex]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 11 31511210
2017 MicroRNA‑139 suppressed tumor cell proliferation, migration and invasion by directly targeting HDGF in epithelial ovarian cancer. Molecular medicine reports 11 28713954
2020 MicroRNA-939 Directly Targets HDGF to Inhibit the Aggressiveness of Prostate Cancer via Deactivation of the WNT/β-Catenin Pathway. OncoTargets and therapy 10 32547060
2015 The expression and clinical significance of HDGF in osteosarcoma. OncoTargets and therapy 10 26392778
2014 NMR characterization of the electrostatic interaction of the basic residues in HDGF and FGF2 during heparin binding. Biochimica et biophysica acta 10 25117899
2022 lncRNA DLG1-AS1 promotes cervical cancer cell gemcitabine resistance by regulating miR-16-5p/HDGF. The journal of obstetrics and gynaecology research 9 35388952
2022 MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF. Cancer cell international 9 35578240
2022 BLM promotes malignancy in PCa by inducing KRAS expression and RhoA suppression via its interaction with HDGF and activation of MAPK/ERK pathway. Journal of cell communication and signaling 9 36574142
2021 CCNI2 promotes the progression of human gastric cancer through HDGF. Cancer cell international 9 34895232
2012 Interaction of HRP-2 isoforms with HDGF: chromatin binding of a specific heteromer. The FEBS journal 9 22212508
2023 HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria. The Journal of biological chemistry 8 37827291
2008 HDGF is dephosphorylated during the early steps of endothelial cell apoptosis in a caspase-dependent way. Journal of cellular biochemistry 8 18465786
2004 Circulating auto-antibody against hepatoma-derived growth factor (HDGF) in patients with ulcerative colitis. Hepato-gastroenterology 8 15086185
2021 miR-4323 targets hepatoma-derived growth factor (HDGF) to suppress colorectal cancer cell proliferation. Pathology, research and practice 7 34314948
2021 MiR-769-5p, Which Targets HDGF, Inhibits Cell Proliferation and Invasion in Nonsmall Cell Lung Cancer. Cancer biotherapy & radiopharmaceuticals 6 34978893
2025 HDGF Knockout Suppresses Colorectal Cancer Progression and Drug Resistance by Modulating the DNA Damage Response. Biomolecules 5 40001585
2024 The m6A reader IGF2BP2 promotes ESCC progression by stabilizing HDGF mRNA. Journal of cancer research and therapeutics 4 39206979
2022 Long noncoding RNA LINC00649 functions as a microRNA‑432‑5p sponge to facilitate tumourigenesis in colorectal cancer by upregulating HDGF. Molecular medicine reports 4 35088877
2022 Extracellular vesicle proteomic analysis leads to the discovery of HDGF as a new factor in multiple myeloma biology. Blood advances 4 35395072
2021 The Inhibitory Effect of miR-345 on Glioma Progression Is Closely Related to circRNA-hsa_circ_0073237 and HDGF. Cells, tissues, organs 4 34348265
2015 Downregulation of the expression of HDGF attenuates malignant biological behaviors of hilar cholangiocarcinoma cells. Molecular medicine reports 4 26081074
2023 circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway. Open medicine (Warsaw, Poland) 3 36694627
2017 Intra- or extra-exosomal secretion of HDGF isoforms: the extraordinary function of the HDGF-A N-terminal peptide. Biological chemistry 3 27926477
2007 [Expression of HDGF and its implication in stage I non-small cell lung cancer]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 3 18478933
2025 NAP1L1 degradation by FBXW7 reduces the deubiquitination of HDGF-p62 signaling to stimulate autophagy and induce primary cisplatin chemosensitivity in nasopharyngeal carcinoma. Molecular cancer 2 40414865
2024 Anti-HDGF Antibody Targets EGFR Tyrosine Kinase Inhibitor-Tolerant Cells in NSCLC Patient-Derived Xenografts. Cancer research communications 2 39041204
2025 Targeting the HNRNPA2B1/HDGF/PTN Axis to Overcome Radioresistance in Non-Small Cell Lung Cancer. Antioxidants & redox signaling 1 40643435
2023 Decreased acetylation of HDGF improves oviduct production in Rana dybowskii, Rana amurensis, and Rana huanrenensis. Comparative biochemistry and physiology. Part D, Genomics & proteomics 1 37384958
2023 [Retracted] MicroRNA‑139‑5p inhibits cell viability, migration and invasion and suppresses tumor growth by targeting HDGF in non‑small cell lung cancer. Oncology letters 1 37920439
2020 Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination. The Journal of biological chemistry 1 32647008
2026 Multi-Omics Analysis Reveals That the MAZ/HDGF Regulatory Axis Drives High-Grade Serous Ovarian Cancer Progression by Modulating Glycolysis and M2 Macrophage Polarization. IUBMB life 0 41467359
2025 HDGF derived from Müller cells enhances the activation of microglia in diabetic retinopathy. Journal of biomedical research 0 40770862
2025 [CircRAD18 Regulates Daunorubicin Resistance in Acute Myeloid Leukemia Cells through MiR-185-5p/HDGF Axis]. Zhongguo shi yan xue ye xue za zhi 0 41234080
2025 Downregulation of HDGF inhibits tumorigenic phenotypes of hypopharyngeal squamous cell carcinoma by suppressing the AKT/mTOR/VEGF pathway. Frontiers in oncology 0 41278276
2025 A KAT7-lncPVT1 positive feedback loop promotes lung cancer carcinogenesis and therapy resistance via H3K14ac/HDGF/PI3K/AKT Axis. International journal of biological macromolecules 0 41418975
2025 HDGF Protects Retinal Pigment Epithelium from Glyoxal-Induced Ferroptosis via SIRT1/PGC-1α/Nrf2 Pathway. Antioxidants (Basel, Switzerland) 0 41462634
2021 Long Non-Coding RNA ASB16-AS1 Functions as a miR-760 Sponge to Facilitate the Malignant Phenotype of Osteosarcoma by Increasing HDGF Expression [Retraction]. OncoTargets and therapy 0 34526780
2021 MicroRNA-939 Directly Targets HDGF to Inhibit the Aggressiveness of Prostate Cancer via Deactivation of the WNT/β-Catenin Pathway [Retraction]. OncoTargets and therapy 0 34675543
2020 Correction to: A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma. Journal of neuro-oncology 0 33030654