TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.
BACKGROUND
About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor β activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma.


METHODS
TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT-PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma.


RESULTS
In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandard's tumour regression grade classifications, respectively).


CONCLUSIONS
The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy.
Digestive Molecular Clinical Oncology Research Unit, Università degli studi di Verona, Verona, Italy.|Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Piro
Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|General and Upper G.I. Surgery Division, Department of Surgery, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Giacopuzzi
Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|General and Upper G.I. Surgery Division, Department of Surgery, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Bencivenga
Digestive Molecular Clinical Oncology Research Unit, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Carbone
Section of Epidemiology and Medical Statistics, Department of Public Health and Community Medicine, Università degli studi di Verona, Verona, Italy.
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Verlato
Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Frizziero
Digestive Molecular Clinical Oncology Research Unit, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Zanotto
Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Mina
Digestive Molecular Clinical Oncology Research Unit, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|Section of Epidemiology and Medical Statistics, Department of Public Health and Community Medicine, Università degli studi di Verona, Verona, Italy.
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Merz
Digestive Molecular Clinical Oncology Research Unit, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Santoro
Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|General and Upper G.I. Surgery Division, Department of Surgery, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Zanoni
Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|General and Upper G.I. Surgery Division, Department of Surgery, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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De Manzoni
Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Tortora
Digestive Molecular Clinical Oncology Research Unit, Università degli studi di Verona, Verona, Italy.|Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.|Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
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Melisi
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012372:ROC Curve; D011836:Radiation Tolerance; D043823:Taxoids / Q000008:administration & dosage; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000008:administration & dosage; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002945:Cisplatin; D000077143:Docetaxel; D005472:Fluorouracil; D051034:Inhibitor of Apoptosis Proteins; D020930:MAP Kinase Kinase Kinases; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D043823:Taxoids; D044767:Ubiquitin-Protein Ligases; D015025:Zearalenone; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C494832:BIRC3 protein, human