A novel exon 15-deleted, splicing variant of Slit2 shows potential for growth inhibition in addition to invasion inhibition in lung cancer

Yu Ying Lin, Chun Hung Yang, Gwo Tarng Sheu, Chi Ying F Huang, Yu Chung Wu, Shu Ming Chuang, Ming Ji Fann, Han Chang, Huei Lee, Jinghua Tsai Chang

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Abstract

BACKGROUND: The axon guidance cue molecule Slit2 has been shown to suppress cancer cell invasion. However, the role of Slit2 in growth inhibition is still controversial. The authors identified a novel exon 15 (AKEQYFIP)-deleted slit2, located at the end of the second leucine-rich repeat (LRR2). Because LRR2 interacts with Robo1 receptor to inhibit invasion, they hypothesized that exon 15 plays an important role in modulating Slit2 function. METHODS: Slit2 expression was assessed via microarray analysis in 27 lung adenocarcinomas. Exon 15-deleted slit2 (slit2-ΔE15) and exon 15-containing slit2 (slit2-WT) were cloned and expressed in the CL1-5 lung cancer cell line. The effect of exon 15 on Slit2-mediated cell growth was evaluated by a xenografted model and in vitro cell growth assays. The effect of exon 15 on Slit2-mediated invasion was analyzed with a modified Boyden chamber in vitro. RESULTS: Tumor growth from CL1-5/Slit2-WT cells was comparable to that from CL1-5 cells bearing empty vector. However, tumor size from CL1-5/Slit2-ΔE15 cells was much smaller than that from Slit2-WT cells or vector control cells in the xenografted model. In vitro analyses demonstrated that Slit2-WT inhibits invasion of CL1-5 cells. In addition to inhibiting invasion, Slit2-ΔE15 greatly suppresses cell growth. CONCLUSIONS: The data demonstrated that exon 15 modulates Slit2 function in growth inhibition of lung cancer cells. Because slit2-ΔE15 splice variant is present in low invasive cancer cells and nontumor lung tissues, loss of this splice variant is an important event in tumor progression and invasion.

Original languageEnglish
Pages (from-to)3404-3415
Number of pages12
JournalCancer
Volume117
Issue number15
DOIs
Publication statusPublished - Aug 1 2011
Externally publishedYes

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Keywords

  • cell growth
  • cell invasion
  • lung cancer
  • Slit2
  • splice variants

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lin, Y. Y., Yang, C. H., Sheu, G. T., Huang, C. Y. F., Wu, Y. C., Chuang, S. M., Fann, M. J., Chang, H., Lee, H., & Chang, J. T. (2011). A novel exon 15-deleted, splicing variant of Slit2 shows potential for growth inhibition in addition to invasion inhibition in lung cancer. Cancer, 117(15), 3404-3415. https://doi.org/10.1002/cncr.25890