Overexpression of forkhead box M1 transcription factor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer

Kaoru Okada, Yoshiyuki Fujiwara, Tsuyoshi Takahashi, Yurika Nakamura, Shuji Takiguchi, Kiyokazu Nakajima, Hiroshi Miyata, Makoto Yamasaki, Yukinori Kurokawa, Masaki Mori, Yuichiro Doki

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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.

Original languageEnglish
Pages (from-to)1035-1043
Number of pages9
JournalAnnals of Surgical Oncology
Volume20
Issue number3
DOIs
Publication statusPublished - Mar 1 2013
Externally publishedYes

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docetaxel
Forkhead Transcription Factors
Stomach Neoplasms
Drug Therapy
Fluorouracil
Cell Line
Excipients
Drug Resistance
Microtubules
Antineoplastic Agents
Small Interfering RNA
Cisplatin
Disease-Free Survival

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

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Overexpression of forkhead box M1 transcription factor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer. / Okada, Kaoru; Fujiwara, Yoshiyuki; Takahashi, Tsuyoshi; Nakamura, Yurika; Takiguchi, Shuji; Nakajima, Kiyokazu; Miyata, Hiroshi; Yamasaki, Makoto; Kurokawa, Yukinori; Mori, Masaki; Doki, Yuichiro.

In: Annals of Surgical Oncology, Vol. 20, No. 3, 01.03.2013, p. 1035-1043.

Research output: Contribution to journalArticle

Okada, K, Fujiwara, Y, Takahashi, T, Nakamura, Y, Takiguchi, S, Nakajima, K, Miyata, H, Yamasaki, M, Kurokawa, Y, Mori, M & Doki, Y 2013, 'Overexpression of forkhead box M1 transcription factor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer', Annals of Surgical Oncology, vol. 20, no. 3, pp. 1035-1043. https://doi.org/10.1245/s10434-012-2680-0
Okada, Kaoru ; Fujiwara, Yoshiyuki ; Takahashi, Tsuyoshi ; Nakamura, Yurika ; Takiguchi, Shuji ; Nakajima, Kiyokazu ; Miyata, Hiroshi ; Yamasaki, Makoto ; Kurokawa, Yukinori ; Mori, Masaki ; Doki, Yuichiro. / Overexpression of forkhead box M1 transcription factor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer. In: Annals of Surgical Oncology. 2013 ; Vol. 20, No. 3. pp. 1035-1043.
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T1 - Overexpression of forkhead box M1 transcription factor (FOXM1) is a potential prognostic marker and enhances chemoresistance for docetaxel in gastric cancer

AU - Okada, Kaoru

AU - Fujiwara, Yoshiyuki

AU - Takahashi, Tsuyoshi

AU - Nakamura, Yurika

AU - Takiguchi, Shuji

AU - Nakajima, Kiyokazu

AU - Miyata, Hiroshi

AU - Yamasaki, Makoto

AU - Kurokawa, Yukinori

AU - Mori, Masaki

AU - Doki, Yuichiro

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N2 - 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.

AB - 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.

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