title: Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells.
abstract: Breast cancer stem cells (BCSCs) have the greatest potential to maintain tumorigenesis in all subtypes of tumor cells and were regarded as the key drivers of tumor. Recent evidence has demonstrated that BCSCs contributed to a high degree of resistance to therapy. However, how BCSCs self renewal and tumorigenicity are maintained remains obscure. Herein, our study illustrated that overexpression of let-7a reduced cell proliferation and mammosphere formation ability of breast cancer stem cells(BCSCs) in a KRas-dependent manner through different pathways in vitro and in vivo. To be specific, we provided the evidence that let-7a was decreased, and reversely the expression of KRas was increased with moderate expression in early stages (I/II) and high expression in advanced stages (III/IV) in breast cancer specimens. In addition, the negative correlation between let-7a and KRas was clearly observed. In vitro, we found that let-7a inhibited mammosphere-forming efficiency and the mammosphere-size via NF-κB and MAPK/ERK pathway, respectively. The inhibitory effect of let-7a on mammosphere formation efficiency and the size of mammospheres was abolished after the depletion of KRas. On the contrary, enforced expression of KRas rescued the effect of let-7a. In vivo, let-7a inhibited the growth of tumors, whereas the negative effect of let-7a was rescued after overexpressing KRas. Taken together, our findings suggested that let-7a played a tumor suppressive role in a KRas-dependent manner.
authors.affiliation: a Second Department of Thoracic Surgery; First Affiliated Hospital; Medical College of Xi'an Jiaotong University ; Xi'an , Shaanxi ; PR China.
authors.forename: Chongwen
authors.initials: C
authors.lastname: Xu
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Sida
authors.initials: S
authors.lastname: Qin
authors.forename: Huangzhen
authors.initials: H
authors.lastname: Wang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Zheng
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Du
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dapeng
authors.initials: D
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D035683:MicroRNAs; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; C487931:mirnlet7 microRNA, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: BCSCs, breast cancer stem cells; MAPK/ERK; MFE, mammosphere-forming efficiency; NF-κB; breast cancer stem cells, KRas, let-7a; mammosphere formation capacity