Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer

Yu Hsuan Chen, Shiow Lin Pan, Jing Chi Wang, Sung Hsin Kuo, Jason Chia Hsien Cheng, Che Ming Teng

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Background: The present study was undertaken to investigate whether radiation induces the expression of vascular endothelial growth factor C (VEGF-C) through activation of the PI3K/Akt/mTOR pathway,subsequently affecting endothelial cells.

Materials and methods: Radiotherapy-induced tumor micro-lymphatic vessel density (MLVD) was determined in a lung cancer xenograft model established in SCID mice. The protein expression and phosphorylation of members of the PI3K/Akt/mTOR pathway and VEGF-C secretion and mRNA expression in irradiated lung cancer cells were assessed by Western blot analysis, enzyme-linked immunosorbent assays (ELISAs), and reverse transcriptase–polymerase chain reaction (RT-PCR). Moreover, specific chemical inhibitors were used to evaluate the role of the PI3K/Akt/mTOR signaling pathway. Conditioned medium (CM) from irradiated control-siRNA or VEGF-C-siRNA-expressing A549 cells was used to evaluate the proliferation of endothelial cells by the MTT assay.

Results: Radiation increased VEGF-C expression in a dose-dependent manner over time at the protein but not at the mRNA level. Radiation also up-regulated the phosphorylation of Akt, mTOR, 4EBP, and eIF4E, but not of p70S6K. Radiation-induced VEGF-C expression was down-regulated by LY294002 and rapamycin (both p <0.05). Furthermore, CM from irradiated A549 cells enhanced human umbilical vein endothelial cell (HUVEC) and lymphatic endothelial cell (LEC) proliferation, which was not observed with CM from irradiated VEGF-C-siRNA-expressing A549 cells.

Conclusions: Radiation-induced activation of the PI3K/Akt/mTOR signaling pathway increases VEGF-C expression in lung cancer cells, thereby promoting endothelial cell proliferation.

Original languageEnglish
Pages (from-to)1154-1162
Number of pages9
JournalStrahlentherapie und Onkologie
Volume190
Issue number12
DOIs
Publication statusPublished - Nov 22 2014
Externally publishedYes

Keywords

  • Endothelial cells
  • Lung cancer cells
  • PI3K/Akt/mTOR signaling pathway
  • Radiation
  • Vascular endothelial growth factor C

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Oncology

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