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Updated: Aug 5, 2026

Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
07:50

Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer

Published on: September 18, 2020

Hypomethylation of GNA15 Promotes Pancreatic Ductal Adenocarcinoma Progression and Macrophage M2 Polarization via

Weihui Guo1, Zhenyuan Qian1, Lei Wang1

  • 1Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 30, 2026
PubMed

Insights

Pancreatic cancer (PDAC) progression involves GNA15, which promotes M2 macrophage polarization via the STAT3-CXCL8 pathway. Targeting this axis offers a new strategy for PDAC treatment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) presents complex progression challenges and limited immunotherapy options.
  • G protein alpha subunit 15 (GNA15) upregulation in PDAC correlates with poor patient prognosis.

Purpose of the Study:

  • To elucidate the role of GNA15 in PDAC progression and immune modulation.
  • To identify GNA15 as a potential therapeutic target for PDAC.

Main Methods:

  • Investigated TET3-mediated GNA15 regulation via demethylation in pancreatic cancer cells (PCs).
  • Analyzed GNA15-induced STAT3 phosphorylation and CXCL8 expression through the GP130-JAK pathway.
  • Examined CXCL8's role in macrophage M2 polarization via CXCR1/CXCR2.
  • Assessed GNA15 expression's association with Gemcitabine resistance and combination therapy efficacy.

Main Results:

  • TET3 upregulates GNA15 expression in PCs via demethylation.
  • GNA15 activates STAT3 phosphorylation, promoting CXCL8 release.
  • CXCL8 drives M2 polarization in macrophages.
  • High GNA15 expression is linked to Gemcitabine resistance.
  • Combination of Reparixin and Gemcitabine showed antitumor efficacy.

Conclusions:

  • GNA15 drives PDAC progression and M2 macrophage polarization through the STAT3-CXCL8 axis.
  • Targeting the GNA15-STAT3-CXCL8 pathway represents a novel therapeutic strategy for PDAC.
Keywords:
CXCL8GNA15STAT3chemoresistancemacrophage polarizationpancreatic cancer

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