title: The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2.
abstract: Pancreatic cancer is one of the life-threatening cancers due to the difficulty in the curative surgery and resistance against conventional therapeutic strategies. Recent studies indicated that cancer stem cells, which exist as a small number of cells within the entire cancer tissue, contribute to the disease progression. Cancer stem cells reveal resistance against conventional chemotherapy, which is derived from the high-expression of multiple transporter genes. Our previous study demonstrated the aggravating role of the homeobox gene MSX2 as an inducer of epithelial-mesenchymal transition, and MSX2 turned out to correlate with the chemoresistance in the current study. Comprehensive analysis of the MSX2-target gene has identified ABCG2 as the responsible gene. Since previous studies reported the pivotal role of ABCG2 as a determining factor of cancer stem cells, the detailed regulatory mechanism of ABCG2 expression by MSX2 was investigated. As a result, the MSX2 expression level in each cell line well correlated with the ABCG2 expression level, and alteration of the MSX2 expression level by over-expression or siRNA-based knockdown affected the ABCG2 expression accordingly. Finally, we identified the functional cooperation of MSX2 and SP1 in the transcriptional regulation of ABCG2 via the SP1 binding elements within the ABCG2 promoter. These findings clarified the intriguing regulatory mechanism of the cancer stem cell-related gene, and will delineate a novel therapeutic target in pancreatic cancer.
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai City, Miyagi, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Hamada
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.forename: Morihisa
authors.initials: M
authors.lastname: Hirota
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kanno
authors.forename: Jun
authors.initials: J
authors.lastname: Umino
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ito
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kume
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D021381:Protein Transport; D014158:Transcription, Genetic
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; C084119:MSX2 protein; D009363:Neoplasm Proteins