RRC ID 80037
Author Okada K, Fujiwara Y, Takahashi T, Nakamura Y, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Kurokawa Y, Mori M, Doki Y.
Title Overexpression of forkhead box M1 transcription factor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer.
Journal Ann Surg Oncol
Abstract BACKGROUND:Mammalian forkhead box transcription factor 1 (FoxM1) has been overexpressed and correlated with pathogenesis in a variety of human malignancies. We investigated the expression status and clinical significance of its overexpression in gastric adenocarcinoma. Furthermore, we demonstrated correlations between FoxM1 overexpression and drug resistance to chemotherapeutic agents in gastric cancer cells and gastric cancer patients treated with chemotherapy.
METHODS:Fifty-three (69%) of 77 tumors were diagnosed as positive for FoxM1 by immunohistochemistry. Multivariate analysis identified FoxM1 expression as a significant independent prognostic predictor for overall and disease-free survival in gastric cancer patients (hazard ratio 3.9 and 3.5, respectively). Furthermore, we investigated associations between FoxM1 overexpression and clinical response of chemotherapy for patients with advanced gastric cancer.
RESULTS:Our clinical results showed that FoxM1 overexpression was significantly associated with resistance in chemotherapy of docetaxel in addition to 5-fluorouracil (5-FU) plus S-1 plus cisplatin (CDDP) and was not significant in chemotherapy of 5-FU plus CDDP for patients with advanced gastric cancer. In vitro experiments showed that Mkn7 transfected FoxM1 siRNA significantly reduced chemoresistance to docetaxel over that with parental cell lines and Mkn45 transfected with FoxM1 significantly enhanced chemoresistance to docetaxel over that with parental cell lines.
CONCLUSIONS:Our study showed that FoxM1 was an independent prognostic factor in gastric cancer. Furthermore, we showed that FoxM1 was a critical molecule for chemoresistance to a microtubule-stabilizing anticancer agent, docetaxel. Taken together, those results suggest that inhibition of overexpressed FoxM1 will be a promising therapeutic strategy for advanced gastric cancer.
Volume 20(3)
Pages 1035-43
Published 2013-3-1
DOI 10.1245/s10434-012-2680-0
PMID 23054116
MeSH Adenocarcinoma / drug therapy Adenocarcinoma / metabolism Adenocarcinoma / mortality* Aged Antineoplastic Combined Chemotherapy Protocols / pharmacology* Apoptosis / drug effects Biomarkers, Tumor / genetics Biomarkers, Tumor / metabolism* Blotting, Western Cell Proliferation / drug effects Cisplatin / administration & dosage Docetaxel Drug Resistance, Neoplasm* Female Fluorouracil / administration & dosage Follow-Up Studies Forkhead Box Protein M1 Forkhead Transcription Factors / antagonists & inhibitors Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism* Gastric Mucosa / metabolism* Gene Expression Regulation, Neoplastic Humans Immunoenzyme Techniques Lymphatic Metastasis Male Neoplasm Staging Prognosis RNA, Messenger / genetics RNA, Small Interfering / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Stomach Neoplasms / drug therapy Stomach Neoplasms / metabolism Stomach Neoplasms / mortality* Survival Rate Taxoids / administration & dosage Tumor Cells, Cultured
IF 4.061
Human and Animal Cells MKN7 MKN45(RCB1001)