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Comprehensive Genetic Search to Clarify the Molecular Mechanism of Drug Resistance Identifies ASCL2-LEF1/TSPAN8 Axis in Colorectal Cancer

  • Toshimichi Tanaka
  • Keita Kojima
  • Kazuko Yokota
  • Yoko Tanaka
  • Yosuke Ooizumi
  • Satoru Ishii
  • Nobuyuki Nishizawa
  • Keigo Yokoi
  • Hideki Ushiku
  • Mariko Kikuchi
  • Ken Kojo
  • Naoko Minatani
  • Hiroshi Katoh
  • Takeo Sato
  • Takatoshi Nakamura
  • Masakazu Sawanobori
  • Masahiko Watanabe
  • Keishi YamashitaEmail author
Gastrointestinal Oncology
  • 31 Downloads

Abstract

Background

Treatment-resistance genes limiting anticancer therapy have not been well clarified in colorectal cancer (CRC). We explored gene expression profiles to identify biomarkers for predicting treatment resistance to an anticancer drug in CRC.

Methods

Six CRC cell lines were treated with phenylbutyrate (PB). The gene expression profiles were then compared using microarrays (harboring 54,675 genes), and genes associated with PB resistance were identified. Candidate genes were functionally examined in cell lines and clinically validated for treatment resistance in clinical samples.

Results

Both DLD1 and HCT15 cells were PB resistant, while HCT116 cells were identified as PB sensitive. On microarray analysis, among the PB resistance-related genes, the expression of the genes ASCL2, LEF1, and TSPAN8 was clearly associated with PB resistance. PB-sensitive cells transfected with one of these three genes exhibited significant (P < 0.001) augmentation of PB resistance; ASCL2 induced expression of both LEF1 and TSPAN8, while neither LEF1 nor TSPAN8 induced ASCL2. RNA interference via ASCL2 knockdown made PB-resistant cells sensitive to PB and inhibited both genes. ASCL2 knockdown also played a critical role in sensitivity to treatment by 5-fluorouracil and radiotherapy in addition to PB. Finally, ASCL2 expression was significantly correlated with histological grade of rectal cancer with preoperative chemoradiation therapy.

Conclusions

ASCL2 was identified as a causative gene involved in therapeutic resistance against anticancer treatments in CRC.

Notes

Supplementary material

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Supplementary material 1 (XLSX 11 kb)
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Supplementary material 2 (XLSX 10 kb)
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Supplementary material 3 (XLSX 9 kb)

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Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Toshimichi Tanaka
    • 1
  • Keita Kojima
    • 1
  • Kazuko Yokota
    • 1
  • Yoko Tanaka
    • 1
  • Yosuke Ooizumi
    • 1
  • Satoru Ishii
    • 1
  • Nobuyuki Nishizawa
    • 1
  • Keigo Yokoi
    • 1
  • Hideki Ushiku
    • 1
  • Mariko Kikuchi
    • 1
  • Ken Kojo
    • 1
  • Naoko Minatani
    • 1
  • Hiroshi Katoh
    • 1
  • Takeo Sato
    • 1
  • Takatoshi Nakamura
    • 1
  • Masakazu Sawanobori
    • 2
  • Masahiko Watanabe
    • 1
  • Keishi Yamashita
    • 2
    • 3
    Email author
  1. 1.Department of SurgeryKitasato University School of MedicineSagamiharaJapan
  2. 2.Epigenetic Treatment Research GroupChiyoda-kuJapan
  3. 3.Division of Advanced Surgical Oncology, Department of Research and Development Center for New Medical FrontiersKitasato University School of MedicineSagamiharaJapan

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