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N6-methyladenosine Reader IGF2BP2-modified HMMR Promotes Non-small Cell Lung Cancer Metastasis via Interaction with

Jiansheng Zhang1,2,3, Mengzhu Zhang1,3, Aimin Qiu2

  • 1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.

International Journal of Biological Sciences
|February 24, 2025
PubMed

Insights

Hyaluronan mediated motility receptor (HMMR) drives non-small cell lung cancer (NSCLC) metastasis by activating the MAP4K4/JNK pathway. Targeting HMMR or MAP4K4 shows promise for treating advanced lung cancer and preventing metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality globally, with metastasis significantly reducing survival rates.
  • Hyaluronan mediated motility receptor (HMMR) is implicated as an oncogene in NSCLC, but its precise role in metastasis requires elucidation.

Purpose of the Study:

  • To investigate the role and mechanisms of HMMR in NSCLC progression and metastasis.
  • To identify potential therapeutic targets for advanced NSCLC.

Main Methods:

  • Analysis of HMMR expression in NSCLC tumors versus normal tissues.
  • Assessment of HMMR's impact on cell migration and invasion via knockdown and overexpression studies.
  • Investigation of the downstream signaling pathways involving MAP4K4, JNK, and MMP1.
  • Evaluation of IGF2BP2's role in HMMR mRNA stability.
  • Validation in a mouse model using a MAP4K4 inhibitor.

Main Results:

  • Elevated HMMR expression in NSCLC correlates with poorer prognosis and is an independent prognostic factor.
  • HMMR promotes NSCLC cell migration and invasion by activating the MAP4K4/JNK/MMP1 cascade.
  • IGF2BP2 enhances HMMR mRNA stability and expression.
  • MAP4K4 inhibition (GNE-495) effectively suppressed lung metastasis in vivo.

Conclusions:

  • HMMR is a key driver of NSCLC metastasis through the MAP4K4/JNK signaling pathway.
  • HMMR represents a potential therapeutic target for managing NSCLC metastasis.
  • IGF2BP2-mediated regulation of HMMR offers another avenue for therapeutic intervention.
Keywords:
HMMRIGF2BP2MAP4K4N6-methyladenosinenon-small cell lung cancer

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