title: Regulation of multidrug resistance 1 expression by CDX2 in ovarian mucinous adenocarcinoma.
abstract: Epithelial ovarian cancer is an aggressive gynecological malignancy with a high mortality rate. Resistance against chemotherapeutic agents often develops in ovarian cancer patients, contributing to high recurrence rates. The multidrug resistance 1 (MDR1/ABCB1) gene encodes P-glycoprotein, which affects the pharmacokinetic properties of anticancer agents. We previously reported that the Caudal-related homeobox transcription factor CDX2 transcriptionally regulates MDR1 expression in colorectal cancer. CDX2 is a factor that influences cancer cell differentiation, malignancy, and cancer progression. We hypothesized that profiling of CDX2 and MDR1 expression could be an effective strategy for predicting anticancer drug resistance. We studied the expression of these factors in clinical samples from ovarian cancer patients. We found that endogenous MDR1 expression was positively associated with CDX2 expression in ovarian mucinous adenocarcinoma. Using ovarian mucinous adenocarcinoma cell lines, we also observed decreased MDR1 expression following inhibition of CDX2 by RNA interference. In addition, CDX2 overexpression in MN-1 cells, which display low endogenous CDX2, resulted in upregulation of MDR1 expression. CDX2 induced MDR1-dependent resistance to vincristine and paclitaxel, which was reversed by treatment with the MDR1-specific inhibitor verapamil. Our findings show that CDX2 promotes upregulation of MDR1 expression, leading to drug resistance in ovarian mucinous adenocarcinoma. Therefore, our study demonstrates the potential of novel chemotherapy regimens based on CDX2 status and MDR1 expression in ovarian mucinous adenocarcinoma.
authors.affiliation: Program for Applied Biomedicine, Division of Clinical Medical Science, Department of Obstetrics and Gynecology, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Iemasa
authors.initials: I
authors.lastname: Koh
authors.affiliation: Program for Biomedical Research, Division of Frontier Medical Science, Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hinoi
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sentani
authors.affiliation: Program for Applied Biomedicine, Division of Clinical Medical Science, Department of Obstetrics and Gynecology, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Hirata
authors.affiliation: Program for Applied Biomedicine, Division of Clinical Medical Science, Department of Obstetrics and Gynecology, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Nosaka
authors.affiliation: Program for Biomedical Research, Division of Frontier Medical Science, Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niitsu
authors.affiliation: Program for Biomedical Research, Division of Frontier Medical Science, Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Miguchi
authors.affiliation: Program for Biomedical Research, Division of Frontier Medical Science, Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Department of Molecular Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.affiliation: Program for Biomedical Research, Division of Frontier Medical Science, Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.affiliation: Program for Applied Biomedicine, Division of Clinical Medical Science, Department of Obstetrics and Gynecology, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, 734-8551, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kudo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000071616:CDX2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000071616:CDX2 Transcription Factor
keywords: CDX2; MDR1; chemotherapy; mucinous adenocarcinoma; ovarian cancer