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

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.

• Authors: 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 Yamashita
• Journal: Annals of surgical oncology (Ann Surg Oncol) Vol. 26 Issue 13 Pg. 4814-4825 (Dec 2019) ISSN: 1534-4681 [Electronic] United States
• PMID: 31529309 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Genetic Markers
• Peptides, Cyclic
• SOX2 protein, human
• SOXB1 Transcription Factors
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• YM753 compound

Topics

• Aged
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Biomarkers, Tumor (genetics)
• Cell Proliferation
• Drug Resistance, Neoplasm (genetics)
• Esophageal Neoplasms (drug therapy, genetics, pathology)
• Esophageal Squamous Cell Carcinoma (drug therapy, genetics, pathology)
• Female
• Follow-Up Studies
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Genetic Markers
• Humans
• Male
• Peptides, Cyclic (pharmacology)
• Prognosis
• SOXB1 Transcription Factors (genetics)
• Survival Rate
• Transcription Factors (genetics)
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (genetics)