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Annals of Surgical Oncology

, Volume 26, Issue 13, pp 4814–4825 | Cite as

Comprehensive Exploration to Identify Predictive DNA Markers of ΔNp63/SOX2 in Drug Resistance in Human Esophageal Squamous Cell Carcinoma

  • Yosuke Ooizumi
  • Keita Kojima
  • Kazuharu Igarashi
  • Yoko Tanaka
  • Hiroki Harada
  • Kazuko Yokota
  • Takeshi Kaida
  • Satoru Ishii
  • Toshimichi Tanaka
  • Keigo Yokoi
  • Nobuyuki Nishizawa
  • Marie Washio
  • Hideki Ushiku
  • Hiroshi Katoh
  • Yoshimasa Kosaka
  • Hiroaki Mieno
  • Kei Hosoda
  • Masahiko Watanabe
  • Chikatoshi Katada
  • Naoki Hiki
  • Keishi YamashitaEmail author
Translational Research and Biomarkers
  • 109 Downloads

Abstract

Background

OBP-801 is a novel histone deacetylase inhibitor being developed as an anticancer drug. In this study, we explored genes to predict drug resistance in human cancer.

Methods

OBP-801 resistance was assessed in 37 strains of human cancer cell lines. Expression microarrays harboring 54,675 genes were used to focus on candidate genes, which were validated for both functional and clinical relevance in esophageal squamous cell carcinoma (ESCC).

Results

OBP-801 is sensitive to esophageal, gastric, and thyroid cancer, and resistant to some esophageal and colorectal cancers. We therefore used ESCC to explore genes. Comprehensive exploration focused on ΔNp63/SOX2, which were both genetically and epigenetically overexpressed in ESCC. Genomic amplifications of ΔNp63/SOX2 were tightly correlated each other (r = 0.81). Importantly, genomic amplification of ΔNp63/SOX2 in the resected tumors after neoadjuvant chemotherapy was significantly associated with histological grade of response (G1). Forced expression of either of these two genes did not induce each other, suggesting that their functional relevances were independent and showed robust drug resistance in OBP-801, as well as 5-fluorouracil. Furthermore, ΔNp63 could exert a potent oncogenic potential. RNA interference of ΔNp63 supported its oncological properties, as well as drug resistance.

Conclusion

Comprehensive exploration of genes involved in anticancer drug residence could identify critical oncogenes of ΔNp63/SOX2 that would predict chemotherapy response in ESCC.

Notes

Disclosures

This work received a research grant from Oncolys BioPharma Inc., Tokyo, Japan.

Supplementary material

10434_2019_7795_MOESM1_ESM.xlsx (20 kb)
Supplementary material 1 (XLSX 19 kb)
10434_2019_7795_MOESM2_ESM.xlsx (11 kb)
Supplementary material 2 (XLSX 10 kb)
10434_2019_7795_MOESM3_ESM.pptx (72 kb)
Supplementary Fig. S1 OBP-801 sensitivity according to four types of cancer cells. Viable cancer cell counts s after 72 h of OBP-801 administration (5–100 nM) compared with control cells. Error bar represents the standard error. Experiments were performed for a single time only (PPTX 72 kb)
10434_2019_7795_MOESM4_ESM.pptx (480 kb)
Supplementary Fig. S2 Identification and confirmation of expression profiles of OBP-801 resistance-related and sensitivity-related genes. (a) Schematic representations of p63 structures and primer designs (blue: TAp63-specific; red: ΔNp63-specific; and black: common p63). Gene expression was also shown for both TAp63-specific and ΔNp63-specific PCR primers. (b) OBP-801 did not alter expressions of ΔNp63 and SOX2 in esophageal squamous cell carcinoma cell lines (PPTX 480 kb)

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Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Yosuke Ooizumi
    • 1
  • Keita Kojima
    • 1
  • Kazuharu Igarashi
    • 1
  • Yoko Tanaka
    • 1
  • Hiroki Harada
    • 1
  • Kazuko Yokota
    • 1
  • Takeshi Kaida
    • 1
  • Satoru Ishii
    • 1
  • Toshimichi Tanaka
    • 1
  • Keigo Yokoi
    • 1
  • Nobuyuki Nishizawa
    • 1
  • Marie Washio
    • 1
  • Hideki Ushiku
    • 1
  • Hiroshi Katoh
    • 1
  • Yoshimasa Kosaka
    • 1
  • Hiroaki Mieno
    • 1
  • Kei Hosoda
    • 1
  • Masahiko Watanabe
    • 1
  • Chikatoshi Katada
    • 2
  • Naoki Hiki
    • 1
  • Keishi Yamashita
    • 1
    • 3
    Email author
  1. 1.Department of SurgeryKitasato University School of MedicineSagamiharaJapan
  2. 2.Department of GastroenterologyKitasato University School of MedicineSagamiharaJapan
  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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