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Reciprocal expression of trefoil factor-1 and thyroid transcription factor-1 in lung adenocarcinomas

Daisuke Matsubara1,2, Taichiro Yoshimoto1, Manabu Soda3

  • 1Division of Integrative Pathology, Jichi Medical University, Shimotsuke, Japan.

Cancer Science
|April 3, 2020
PubMed

Insights

Trefoil factor-1 (TFF-1) is highly expressed in non-terminal respiratory unit (non-TRU) lung adenocarcinomas, correlating with KRAS mutations and poor prognosis. TFF-1 shows potential as a biomarker and therapeutic target for these lung cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Targeted therapies for EGFR and ALK mutations have benefited lung adenocarcinoma patients.
  • Targetable mutations are primarily found in TTF-1/NKX2-1-positive terminal respiratory unit (TRU) types, not non-TRU types.
  • Understanding non-TRU subtypes is crucial for developing new therapeutic strategies.

Purpose of the Study:

  • To elucidate the molecular characteristics of major non-TRU-type lung adenocarcinoma subtypes.
  • To investigate the role of trefoil factor-1 (TFF-1) in non-TRU lung adenocarcinomas.
  • To assess TFF-1 as a potential biomarker and therapeutic target.

Main Methods:

  • Analyzed 19 lung adenocarcinoma cell lines (11 TRU, 8 non-TRU).
  • Performed immunohistochemical analysis of TFF-1 in 238 primary lung adenocarcinomas.
  • Correlated TFF-1 expression with other markers (HNF4-α, MUC5AC, TTF-1/NKX2-1) and mutations (EGFR, ALK, KRAS).
  • Investigated TFF-1's effect on cell proliferation, colony formation, and apoptosis via knockdown experiments.

Main Results:

  • TFF-1 was strongly expressed in non-TRU-type cell lines and detected in 13% of primary lung adenocarcinomas.
  • TFF-1 expression was frequent in mucinous, enteric, and colloid subtypes, inversely correlated with TTF-1/NKX2-1, and correlated with HNF4-α and MUC5AC.
  • TFF-1-positive cases showed high KRAS mutation frequency, lacked EGFR/ALK mutations, correlated with tumor spread, and indicated poor prognosis in advanced stages.
  • TFF-1 knockdown inhibited proliferation and colony formation, and induced apoptosis in a TFF-1-high, KRAS-mutated cell line.

Conclusions:

  • TFF-1 is characteristically expressed in non-TRU-type lung adenocarcinomas with gastrointestinal features.
  • TFF-1 serves as a potential biomarker for KRAS-mutated lung adenocarcinomas and predicts poor prognosis.
  • TFF-1 represents a potential molecular target for non-TRU-type lung adenocarcinomas.
Keywords:
TFF-1TTF-1lung adenocarcinomamucinous adenocarcinomanon-TRU type

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