title: Loss of Mel-18 enhances breast cancer stem cell activity and tumorigenicity through activating Notch signaling mediated by the Wnt/TCF pathway.
abstract: Mel-18 has been proposed as a negative regulator of Bmi-1, a cancer stem cell (CSC) marker, but it is still unclear whether Mel-18 is involved in CSC regulation. Here, we examined the effect of Mel-18 on the stemness of human breast CSCs. In Mel-18 small hairpin RNA (shRNA)-transduced MCF-7 cells, side population (SP) cells and breast CSC surface marker (CD44(+)/CD24(-)/ESA(+))-expressing cells, which imply a CSC population, were enriched. Moreover, the self-renewal of CSCs was enhanced by Mel-18 knockdown, as measured by the ability for tumorsphere formation in vitro and tumor-initiating capacity in vivo. Similarly, Mel-18 overexpression inhibited the number and self-renewal activity of breast CSCs in SK-BR-3 cells. Furthermore, our data showed that Mel-18 blockade up-regulated the expression of the Wnt/TCF target Jagged-1, a Notch ligand, and consequently activated the Notch pathway. Pharmacologic inhibition of the Notch and Wnt pathways abrogated Mel-18 knockdown-mediated tumorsphere formation ability. Taken together, our findings suggest that Mel-18 is a novel negative regulator of breast CSCs that inhibits the stem cell population and in vitro and in vivo self-renewal through the inactivation of Wnt-mediated Notch signaling.
authors.affiliation: Dept. of Pathology, College of Medicine, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul, 133-791, Republic of Korea.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Won
authors.forename: Jeong-Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Dong-Hui
authors.initials: DH
authors.lastname: Shin
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Park
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
authors.forename: Hyoung-Chin
authors.initials: HC
authors.lastname: Kim
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008957:Models, Genetic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058985:Side-Population Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051820:TCF Transcription Factors / Q000235:genetics*; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C489348:PCGF2 protein, human; D051881:Receptor, Notch1; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D063150:Polycomb Repressive Complex 1