title: Txr1: an important factor in oxaliplatin resistance in gastric cancer.
abstract: Oxaliplatin-based chemotherapy is the main treatment regimen for gastric cancer (GC), but can fail because of drug resistance. We investigated the role of a recently identified drug-resistance gene, taxol-resistant gene 1 (Txr1), in oxaliplatin resistance. A retrospective study based on banked tissue was carried out. We collected clinical data from 95 patients with stage II-III GC who were treated with radical D2 surgery and standardized first-line chemotherapy with oxaliplatin; paraffin blocks of their tumor specimens were prepared for a tissue microarray in which Txr1 expression was analyzed immunohistochemically and compared with their clinical data and their 3-year disease-free survival (DFS) rate. The human GC cell line, SGC7901, was developed into the oxaliplatin-resistant cell line, SGC7901/L-OHP, using slowly increased oxaliplatin concentrations over 6 months. The relationship between Txr1 expression and drug-resistance of oxaliplatin in GC was studied with drug intervention, gene silencing technology, real-time PCR and Western blot analysis. Of the 95 patients with GC, those with TXR1(-) GC had longer postoperative 3-year DFS (77.8 %) than those with TXR1(+) GC (52.9 %). In oxaliplatin-resistant SGC7901/L-OHP cells, the main expression location of Txr1 shifted from the nucleus to cytoplasm, and both the mRNA and protein expression of Txr1 were higher than that of the parental cells, whereas expression of thrombospondin-1 (TSP1) decreased. When the Txr1 gene was silenced, TSP1 expression increased and the oxaliplatin resistance was significantly reduced in SGC7901/L-OHP cells. Changed Txr1 expression in GC affects the efficacy of oxaliplatin-based chemotherapy. Increased Txr1 expression decreases TSP1 expression and inhibits apoptosis. Txr1 could be a target in reversing oxaliplatin resistance in GC.
authors.affiliation: Department of General Surgery, Beijing Jishuitan Hospital, The Fourth Medical College of Peking University, Beijing, China, frankbjt@126.com.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Bi
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Bai
authors.forename: Xuemei
authors.initials: X
authors.lastname: Ma
authors.forename: Jianning
authors.initials: J
authors.lastname: Song
authors.forename: Yantong
authors.initials: Y
authors.lastname: Guo
authors.forename: Jingming
authors.initials: J
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.forename: Shiwei
authors.initials: S
authors.lastname: Han
authors.forename: Zhongtao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D000077022:Survivin; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D009944:Organoplatinum Compounds; C513606:PRR13 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C481348:SPZ1 protein, human; D000077022:Survivin; D000077150:Oxaliplatin