Tumoral expression of TXR1 and TSP1 predicts overall survival of patients with lung adenocarcinoma treated with first-line docetaxel-gemcitabine regimen.
OBJECTIVE
In vitro data suggest that down-regulation of thrombospondin 1 (TSP1) expression from TXR1 is associated with resistance to taxane-based chemotherapy. The prognostic and predictive value of tumoral expression of both genes was evaluated in patients with lung adenocarcinoma treated with first-line docetaxel and gemcitabine.


METHODS
Tumor samples from 96 patients, with stage IIIB (with pleural effusion) or IV lung adenocarcinomas, were analyzed for TXR1 and TSP1 mRNA levels by quantitative real-time PCR, from microdissected cells derived from patients' primary tumors.


RESULTS
The mRNA levels of the two genes were inversely correlated (Spearman's test = -0.49; P < 0.0001). Patients with low TXR1 mRNA levels experienced a longer median time to tumor progression (TTP; P < 0.0001) and median overall survival (mOS; P = 0.001) when compared with patients with high TXR1 expression. Patients with high TSP1 expression presented longer TTP (P = 0.002) and mOS (P < 0.0001) when compared with patients with low TSP1 expression. Moreover, patients with high TSP1 and low TXR1 expression (n = 36) presented higher prolonged TTP (P = 0.009) and mOS (P < 0.0001) compared with patients with high TXR1 and low TSP1 expression. Multivariate analysis showed that high TXR1/low TSP1 expression was an independent prognostic factor for decreased TTP (hazard ratio, 1.7; 95% confidence interval, 1.1-3.27; P = 0.016) and mOS (hazard ratio, 2.55; 95% confidence interval, 1.57-4.15; P < 0.0001).


CONCLUSIONS
These data confirm the in vitro model of TSP1 and TXR1 effect on taxane resistance in lung adenocarcinomas and merit further evaluation.
Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Crete, Greece.
Chara
C
Papadaki
Dimitris
D
Mavroudis
Maria
M
Trypaki
Anastasios
A
Koutsopoulos
Efstathios
E
Stathopoulos
Dora
D
Hatzidaki
Eleftheria
E
Tsakalaki
Vassilis
V
Georgoulias
John
J
Souglakos
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D000093542:Gemcitabine
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C513606:PRR13 protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; C481348:SPZ1 protein, human; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D000093542:Gemcitabine