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Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy

Zhou Yang1, Yusheng Chen1, Xiyi Wei2

  • 1Department of General Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, P.R. China.

International Journal of Oncology
|April 3, 2020
PubMed

Insights

Neurotrophin-4 (NTF4) promotes colorectal cancer (CRC) development by suppressing autophagy. Inhibiting NTF4 activates autophagy, hindering tumor growth and improving survival, suggesting NTF4 as a potential CRC biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Autophagy is crucial in colorectal cancer (CRC) progression and treatment resistance.
  • The role of autophagy in CRC is complex, with studies reporting both pro- and anti-tumorigenic functions.
  • Neurotrophin-4 (NTF4) has emerged as a novel oncogene implicated in cancer development.

Purpose of the Study:

  • To investigate the role of neurotrophin-4 (NTF4) in colorectal cancer (CRC) pathogenesis.
  • To elucidate the regulatory mechanism of NTF4 in CRC, focusing on its interaction with autophagy.
  • To evaluate the therapeutic potential of targeting NTF4 in CRC treatment.

Main Methods:

  • Quantitative analysis of NTF4 expression in CRC tumor tissues versus non-tumor mucosa.
  • Genetic knockdown of NTF4 using short hairpin RNA (shRNA) in CRC cell lines.
  • Assessment of epithelial-to-mesenchymal transition (EMT), autophagy markers (Atg5), and cell signaling pathways (MAPK).
  • In vitro assays for cell invasion, migration, proliferation, colony formation, and cell cycle analysis.
  • In vivo studies using subcutaneous xenografts in Balb/c-nu mice.
  • Pharmacological inhibition of autophagy using chloroquine (CQ).

Main Results:

  • NTF4 was significantly overexpressed in CRC tissues and correlated with poor prognosis and advanced TNM stage.
  • NTF4 knockdown in CRC cells suppressed EMT, activated autophagy via Atg5 and MAPK pathways, and inhibited cell invasion, migration, proliferation, and colony formation.
  • NTF4 knockdown also induced cell cycle arrest and reduced tumor growth in xenograft models.
  • Autophagy inhibition with CQ reversed the anti-tumor effects of NTF4 knockdown, restoring invasive and proliferative capabilities.
  • NTF4 promotes tumorigenesis and CRC development through the regulation of autophagy.

Conclusions:

  • NTF4 acts as an oncogene in CRC, promoting tumor development and progression by suppressing autophagy.
  • Targeting NTF4 could be a potential therapeutic strategy for CRC.
  • NTF4 may serve as a valuable diagnostic and prognostic biomarker for CRC patients.
Keywords:
neurotrophin-4colorectal cancerepithelial-to-mesenchymal transitionautophagymitogen-activated protein kinase pathway

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