title: CD24 suppresses malignant phenotype by downregulation of SHH transcription through STAT1 inhibition in breast cancer cells.
abstract: Hedgehog (Hh) signaling has been found to be activated in breast cancer stem cells (BCSCs). However, the precise role of the BCSCs marker, CD24, remains unclear. Here, we describe a relationship between CD24 and Sonic Hedgehog (SHH), and reveal a role for this relationship in the induction of a malignant phenotype of breast cancer. CD24 siRNA-transfected breast cancer cells (BCCs) demonstrated higher expression of SHH and GLI1, increased anchorage-independent proliferation, and enhanced invasiveness and superior tumorigenicity compared with control. Conversely, CD24 forced-expressing BCCs possessed decreased SHH and GLI1 expression, anchorage-independent proliferation, and invasiveness. Suppression of SHH decreased invasiveness through inhibition of matrix metalloproteinase (MMP)-2 expression, GLI1 expression, anchorage-independent proliferation, tumorigenicity, and tumor volume in vivo in CD24 siRNA transfected BCCs. DNA microarray analysis identified STAT1 as a relationship between CD24 and SHH. CD24 siRNA-transfected BCCs with concurrent STAT1 inhibition exhibited decreased SHH expression, invasiveness, anchorage-independent proliferation, tumorigenicity, and tumor volume in vivo. These results suggest that CD24 suppresses development of a malignant phenotype by down-regulating SHH transcription through STAT1 inhibition. CD24 gene transfer or STAT1 inhibition may represent new effective therapeutic strategies to target refractory breast cancer.
authors.affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Suyama
authors.affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: ohnishi@surg1.med.kyushu-u.ac.jp.
authors.forename: Hideya
authors.initials: H
authors.lastname: Onishi
authors.affiliation: Shukoukai Inc., Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Imaizumi
authors.affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shinkai
authors.affiliation: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Umebayashi
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizuuchi
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Katano
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051927:CD24 Antigen / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; D053823:Hedgehog Proteins; D034741:RNA, Small Interfering; C509239:SHH protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human
keywords: Breast cancer; CD24; Cancer stem cell; STAT1; Sonic hedgehog