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Epigenetic inactivation of COL4A4 orchestrates JAK2/STAT3-driven progression and microenvironment reprogramming in

Hanxi Zhou1, Xiong Tian1, Zhenyu Yang1

  • 1Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, China.

International Immunopharmacology
|August 18, 2026
PubMed
Abstract

Insights

Collagen type IV alpha 4 (COL4A4) acts as a tumor suppressor in renal cell carcinoma (RCC). Its downregulation, due to DNA methylation, impacts the tumor microenvironment and offers a potential epigenetic therapeutic target for RCC.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Renal cell carcinoma (RCC) lacks effective early detection biomarkers.
  • Epigenetic silencing via DNA methylation is prevalent in RCC.
  • The role of COL4A4 in RCC pathogenesis and its regulation are not well understood.

Purpose of the Study:

  • To investigate the expression, epigenetic regulation, and clinical significance of COL4A4 in RCC.
  • To elucidate the functional role of COL4A4 in RCC progression and its association with the tumor microenvironment (TME).
  • To explore COL4A4 as a potential therapeutic target in RCC.

Main Methods:

  • Integrated analysis of bulk and single-cell RNA sequencing (scRNA-seq), DNA methylation data, and clinical cohorts.
  • In vitro functional assays and in vivo xenograft models to assess COL4A4's biological functions.
  • Mechanistic studies involving demethylation treatment and pathway inhibition (JAK2/STAT3).

Main Results:

  • COL4A4 expression is downregulated in RCC, linked to promoter hypermethylation, and serves as an independent prognostic factor.
  • COL4A4 suppresses RCC cell proliferation, migration, invasion, and tumor growth by negatively modulating the JAK2/STAT3 pathway.
  • Low COL4A4 expression correlates with altered extracellular matrix-receptor interactions and an immunosuppressive TME.

Conclusions:

  • COL4A4 functions as a methylation-silenced tumor suppressor in RCC.
  • COL4A4 negatively regulates JAK2/STAT3 signaling and influences TME characteristics.
  • COL4A4 represents a promising epigenetic therapeutic target for renal cell carcinoma.
Keywords:
COL4A4DNA methylationJAK2/STAT3Renal cell carcinomaTumor microenvironment

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