Affinage

CLDN8

Claudin-8 · UniProt P56748

Length
225 aa
Mass
24.8 kDa
Annotated
2026-06-09
14 papers in source corpus 9 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLDN8 is a tight junction protein that functions as a context-dependent regulator of epithelial barrier integrity and, in cancer settings, of cell proliferation and migration (PMID:28474805, PMID:35124427). In epithelial tissues including intestinal mucosa and skin, CLDN8 supports permeability barrier function: its loss increases epithelial permeability and barrier dysfunction (PMID:32209121, PMID:40160514), and Cldn8 loss in vivo abrogates rescue of intestinal barrier defects, placing CLDN8 as a downstream effector of mucosal barrier maintenance (PMID:35124427). CLDN8 expression is tightly controlled at multiple levels — transcriptionally it is directly activated by androgen receptor through functional androgen-responsive elements in its promoter (PMID:28474805) and directly repressed by SOX9 (PMID:35124427), and post-transcriptionally it is suppressed by several miRNAs that bind its 3'UTR, including miR-361-5p and miR-31-3p (PMID:31161266, PMID:40160514), as well as miR-223 and miR-21 acting downstream of inflammatory and exosomal signals (PMID:29788092, PMID:32209121). Inflammatory cytokine signaling (IL-9 via miR-21; IL-4/IL-13/TNF-α/IFN-γ via JAK) drives CLDN8 downregulation in colitis and skin contexts (PMID:29788092, PMID:40296865). In colorectal cancer, CLDN8 promotes proliferation, migration and invasion by activating MAPK/ERK signaling and upregulating p-ERK and MMP9 (PMID:31118793). CLDN8 also physically associates with IL-22 in colon cancer cells (PMID:31900207).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2017 Medium

    Established that CLDN8 is a direct transcriptional target of androgen receptor and is functionally pro-tumorigenic, defining both an upstream regulator and a cellular role in prostate cancer.

    Evidence Luciferase reporter with androgen-responsive element mutagenesis, ChIP/AR binding mapping, AR inhibitor blockade, plus gain/loss-of-function proliferation, migration and cytoskeletal assays in prostate cancer cells

    PMID:28474805

    Open questions at the time
    • Mechanism by which CLDN8 stabilizes the cytoskeleton not defined
    • Signal transduction pathway downstream of CLDN8 in prostate cancer not identified
  2. 2018 Medium

    Placed CLDN8 downstream of an inflammatory IL-9/miR-21 axis in intestinal barrier regulation, linking cytokine signaling to CLDN8 suppression.

    Evidence Caco-2/NCM460/SW480 cell assays and TNBS colitis mouse model with anti-IL-9 mAb rescue of CLDN8 levels

    PMID:29788092

    Open questions at the time
    • Direct miR-21 binding to CLDN8 3'UTR not shown
    • Whether CLDN8 restoration alone rescues barrier function not isolated
  3. 2019 Medium

    Demonstrated CLDN8 drives colorectal cancer aggressiveness through MAPK/ERK activation, providing a downstream effector pathway for CLDN8's pro-tumor effects.

    Evidence Knockdown/overexpression in SW480/HT-29, western blot for p-ERK/MMP9, PD98059 rescue, and xenograft model

    PMID:31118793

    Open questions at the time
    • How a tight junction protein activates ERK mechanistically not resolved
    • Direct vs indirect regulation of MMP9 unclear
  4. 2019 Medium

    Identified miR-361-5p as a direct 3'UTR-binding suppressor of CLDN8 and showed CLDN8 promotes survival in retinoblastoma, extending CLDN8 regulation to a non-epithelial cancer.

    Evidence 3'UTR luciferase reporter, CLDN8 siRNA, and CCK-8/EdU/flow cytometry proliferation and apoptosis assays

    PMID:31161266

    Open questions at the time
    • Downstream effectors of CLDN8 in retinoblastoma not identified
    • No in vivo confirmation
  5. 2020 Medium

    Showed mast cell exosomal miR-223 directly suppresses CLDN8 to increase epithelial permeability, connecting intercellular exosomal signaling to barrier control.

    Evidence Exosome transfer from HMC-1 to NCM460/HT-29/CaCO2, microarray, miR-223 inhibitor rescue, permeability assay

    PMID:32209121

    Open questions at the time
    • Direct miR-223 binding site on CLDN8 not mapped by mutagenesis
    • In vivo relevance not established
  6. 2020 Low

    Reported a physical CLDN8-IL-22 interaction and a LINC00662/miR-340-5p ceRNA circuit co-regulating both, proposing a non-junctional protein partnership for CLDN8.

    Evidence Co-immunoprecipitation, luciferase reporter, and RNA pulldown in colon cancer cells

    PMID:31900207

    Open questions at the time
    • Single Co-IP without reciprocal validation or binding-domain mapping
    • Functional consequence of the CLDN8-IL-22 interaction not defined
  7. 2022 High

    Defined SOX9 as a direct repressor of CLDN8 and used Cldn8 knockout epistasis to position CLDN8 as the downstream barrier effector of the miR-145-5p/SOX9 axis in Crohn's disease.

    Evidence Dual-luciferase reporter, ChIP, overexpression/RNAi, TNBS colitis model, and miR-145-5p agomir rescue abrogated in Cldn8-/- mice

    PMID:35124427

    Open questions at the time
    • How CLDN8 mechanistically restores barrier integrity at the junction not detailed
    • Relationship of SOX9 repression to other transcriptional regulators of CLDN8 unexplored
  8. 2025 Low

    Extended cytokine-driven CLDN8 suppression to skin, showing JAK-dependent downregulation by inflammatory cytokines in keratinocytes.

    Evidence Cytokine treatment of HaCaT cells with qPCR and JAK inhibitor co-treatment rescue

    PMID:40296865

    Open questions at the time
    • Single qPCR readout without protein or barrier-function confirmation
    • Whether effect is direct or via intermediary miRNAs not addressed
  9. 2025 Medium

    Established miR-31-3p as a direct 3'UTR-targeting suppressor of CLDN8 controlling keratinocyte barrier function, with in vivo psoriasis rescue confirming CLDN8's barrier role in skin.

    Evidence 3'UTR molecular validation, CLDN8 knockdown, miR-31-3p overexpression, antagomir treatment in imiquimod psoriasis mouse model, barrier permeability assay

    PMID:40160514

    Open questions at the time
    • Molecular basis of CLDN8's contribution to keratinocyte permeability barrier not resolved
    • Whether CLDN8 acts alone or with other claudins in skin not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CLDN8 mechanistically transmits signals to the MAPK/ERK pathway and physically organizes tight junctions to control barrier permeability remains unresolved.
  • No structural model of CLDN8
  • No defined junctional binding partners among claudins/occludins
  • Mechanistic link between CLDN8 and ERK activation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
GO:0005198 structural molecule activity 1
Partners
ARIL22

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 CLDN8 transcription is directly activated by androgen receptor (AR): AR binds to the CLDN8 promoter (one binding site identified), two functional androgen-responsive elements were confirmed by reporter assay, and CLDN8 mRNA induction by androgen is blocked by AR inhibitor. Luciferase reporter assay, ChIP/AR binding site mapping, AR inhibitor blockade of CLDN8 induction Cancer science Medium 28474805
2017 CLDN8 overexpression promotes prostate cancer cell proliferation and migration, while knockdown suppresses these processes; CLDN8 also regulates intracellular signal transduction and stabilizes the cytoskeleton. CLDN8 overexpression and siRNA knockdown in prostate cancer cell lines with functional readouts (proliferation, migration, cytoskeletal assays) Cancer science Medium 28474805
2019 CLDN8 promotes colorectal cancer cell proliferation, migration, and invasion by activating the MAPK/ERK signaling pathway, upregulating p-ERK and MMP9; MAPK/ERK inhibitor PD98059 blocks these CLDN8-driven effects. CLDN8 knockdown and overexpression in SW480/HT-29 cells, western blot for p-ERK/MMP9, MAPK inhibitor rescue, in vivo xenograft model Cancer management and research Medium 31118793
2018 IL-9 cytokine signaling downregulates CLDN8 expression via miR-21 as an intermediary; anti-IL-9 treatment restores CLDN8 levels and alleviates colitis, placing CLDN8 downstream of the IL-9/miR-21 axis in intestinal barrier regulation. In vitro cell-based assays (Caco-2, NCM460, SW480), TNBS-induced colitis mouse model, anti-IL-9 mAb treatment with CLDN8 protein/mRNA readout Inflammatory bowel diseases Medium 29788092
2020 Mast cell-derived exosomal miR-223 directly inhibits CLDN8 expression in intestinal epithelial cells, leading to increased epithelial permeability and barrier dysfunction; miR-223 inhibitor reverses the suppression of CLDN8. Exosome transfer from HMC-1 to intestinal epithelial cell lines (NCM460, HT-29, CaCO2), microarray, miR-223 inhibitor rescue, permeability assay Biological research Medium 32209121
2020 CLDN8 directly interacts with IL-22 protein in colon cancer cell lines, as demonstrated by co-immunoprecipitation; both are target genes of miR-340-5p and their co-expression is regulated by LINC00662 acting as a miR-340-5p sponge to activate ERK signaling. Co-immunoprecipitation, luciferase reporter assay, RNA pulldown Journal of experimental & clinical cancer research Low 31900207
2022 SOX9 transcription factor directly represses CLDN8 expression in intestinal epithelial cells; miR-145-5p inhibits SOX9, thereby relieving repression of CLDN8. Promoter hypermethylation of miR-145 in Crohn's disease elevates SOX9 and reduces CLDN8, impairing the intestinal mucosal barrier. miR-145-5p agomir rescue is abrogated in Cldn8-/- mice, confirming epistatic placement of CLDN8 downstream of SOX9. Dual-luciferase reporter assay, chromatin immunoprecipitation, overexpression/RNA interference, TNBS colitis mouse model, Cldn8 knockout genetic epistasis EBioMedicine High 35124427
2019 miR-361-5p directly binds the 3'UTR of CLDN8 mRNA and inhibits CLDN8 expression; CLDN8 knockdown phenocopies miR-361-5p overexpression by inhibiting retinoblastoma cell proliferation and inducing apoptosis. Luciferase reporter assay (3'UTR), CLDN8 siRNA knockdown, cell proliferation and apoptosis assays (CCK-8, EdU, flow cytometry) Child's nervous system Medium 31161266
2025 IL-4, IL-13, TNF-α and IFN-γ downregulate CLDN8 mRNA expression in HaCaT keratinocytes through activation of the JAK signaling pathway; JAK inhibitor treatment blocks this cytokine-mediated CLDN8 suppression. Cytokine treatment of HaCaT cells with qPCR for CLDN8, JAK inhibitor co-treatment rescue Clinical, cosmetic and investigational dermatology Low 40296865
2025 hsa-miR-31-3p directly targets the 3'UTR of CLDN8 mRNA, reducing CLDN8 expression; both CLDN8 knockdown and miR-31-3p overexpression impair keratinocyte permeability barrier, and miR-31-3p antagomir in an imiquimod psoriasis mouse model restores CLDN8 expression and ameliorates barrier damage. 3'UTR targeting (bioinformatics + molecular validation), CLDN8 knockdown, miR-31-3p overexpression, antagomir treatment in mouse model, barrier permeability assay Biochemistry and biophysics reports Medium 40160514

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 LncRNA LINC00662 promotes colon cancer tumor growth and metastasis by competitively binding with miR-340-5p to regulate CLDN8/IL22 co-expression and activating ERK signaling pathway. Journal of experimental & clinical cancer research : CR 99 31900207
2020 Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells. Biological research 73 32209121
2017 CLDN8, an androgen-regulated gene, promotes prostate cancer cell proliferation and migration. Cancer science 36 28474805
2019 CLDN8 promotes colorectal cancer cell proliferation, migration, and invasion by activating MAPK/ERK signaling. Cancer management and research 30 31118793
2018 Cytokine IL9 Triggers the Pathogenesis of Inflammatory Bowel Disease Through the miR21-CLDN8 Pathway. Inflammatory bowel diseases 22 29788092
2022 Hypermethylation of miR-145 promoter-mediated SOX9-CLDN8 pathway regulates intestinal mucosal barrier in Crohn's disease. EBioMedicine 18 35124427
2019 MiR-361-5p inhibits cell proliferation and induces cell apoptosis in retinoblastoma by negatively regulating CLDN8. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 12 31161266
2017 Missense mutation at CLDN8 associated with a high plasma interferon gamma-inducible protein 10 level in methadone-maintained patients with urine test positive for morphine. PloS one 4 29145422
2024 Significance and Possible Biological Mechanism for CLDN8 Downregulation in Kidney Renal Clear Cell Carcinoma Tissues. World journal of oncology 2 38993257
2025 Hsa-miR-31-3p targets CLDN8 to compromise skin barrier integrity in psoriasis. Biochemistry and biophysics reports 1 40160514
2025 IL-4, IL-13, TNF-α and IFN-γ Downregulate CLDN8 Expression Through Activating JAK Signaling Pathway in HaCaT Cells. Clinical, cosmetic and investigational dermatology 1 40296865
2025 Knockdown of Claudin-8 (CLDN8) Indicates a Link Between Breast Cancer Cell Sensitivity to Chemotherapeutics and Reveals a Potential Use of CLDN8 as a Molecular Diagnostic and Target for Therapy. International journal of molecular sciences 1 40508219
2024 CircSCNN1A inhibits the proliferation, migration and invasion of renal cell carcinoma cells by decreasing CLDN8 expression through miR-590-5p. Genesis (New York, N.Y. : 2000) 1 38764323
2026 Intestinal barrier dysfunction and differential CLDN8 and MUC1 expression in vedolizumab responsiveness among inflammatory bowel disease patients: a proof-of-concept study. The Malaysian journal of pathology 0 42059166

Missed literature

Know a paper Affinage missed for CLDN8? Flag it for the maintainers and the community.

No submissions yet.