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ANKRD49 promotes the metastasis of NSCLC via activating JNK-ATF2/c-Jun-MMP-2/9 axis

Jia Sun1,2, Jin-Rui Hu3, Chao-Feng Liu1

  • 1Department of Pulmonary and Critical Care Medicine, Shanxi Province Key Laboratory of Respiratory Disease, the First Hospital, Shanxi Medical University, NHC Key Laboratory of Pneumoconiosis, Taiyuan, Shanxi, 030001, China.

BMC Cancer
|November 14, 2023
PubMed
Abstract

Insights

Ankyrin repeat domain 49 (ANKRD49) promotes non-small cell lung cancer (NSCLC) invasion and metastasis by activating JNK signaling, which upregulates MMP-2/MMP-9 expression through c-Jun and ATF2. This study clarifies ANKRD49

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Ankyrin repeat domain 49 (ANKRD49) is highly expressed in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC).
  • The precise role of ANKRD49 in non-small cell lung cancer (NSCLC) pathogenesis remains unclear.
  • Previous studies suggested ANKRD49 promotes LUAD cell invasion via the p38-ATF-2-MMP2/MMP9 pathway.

Purpose of the Study:

  • To investigate the function and mechanism of ANKRD49 in NSCLC using various cell lines.
  • To elucidate the signaling pathways and molecular targets regulated by ANKRD49 in NSCLC.
  • To validate the role of ANKRD49 in NSCLC tumorigenicity and metastasis in vivo.

Main Methods:

  • Real-time qPCR to assess ANKRD49 expression in NSCLC tissues and adjacent normal tissues.
  • In vitro assays (overexpression, RNA interference, gelatin zymography, CCK-8, colony formation, wound healing, migration, invasion) in NCI-H1299 and NCI-H1703 cells.
  • Immunoprecipitation, chromatin immunoprecipitation, and nude mouse models to analyze molecular interactions, transcriptional regulation, and tumorigenicity.

Main Results:

  • ANKRD49 expression is significantly higher in NSCLC tissues compared to normal tissues.
  • ANKRD49 overexpression enhances migration and invasion in NSCLC cells by increasing MMP-2 and MMP-9 levels.
  • ANKRD49 activates the JNK pathway, leading to c-Jun and ATF2 phosphorylation and subsequent transcriptional activation of MMP-2/MMP-9 promoters.

Conclusions:

  • ANKRD49 promotes NSCLC cell invasion and metastasis through JNK-mediated transcriptional activation of MMP-2/MMP-9 via c-Jun and ATF2.
  • The identified molecular mechanism differs from previously reported pathways in A549 cells, highlighting NSCLC heterogeneity.
  • This study provides a comprehensive understanding of ANKRD49's role in NSCLC progression and metastasis.
Keywords:
ANKRD49ATF2Matrix metalloproteinasesMetastasisc-Jun

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