title: DICER1 regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1.
abstract: Let-7 miRNAs act as tumour suppressors by directly binding to the 3'UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback relationship is Dicer, a central regulator of miRNA expression through sequence-specific silencing. We first identified that DICER1 is the key downstream gene for cyclin D1-induced let-7 expression. In addition, we found that let-7 miRNAs expression decreased because of the p53-induced cell death response, with deregulated cyclin D1. Our results also showed that cyclin D1 is required for Nutlin-3 and TAX-induced let-7 expression in cancer repression and the cell death response. For the first time, we provide evidence that let-7 and cyclin D1 form a feedback loop in regulating therapy response of cancer cells and cancer stem cells, and importantly, that alteration of let-7 expression, mainly caused by cyclin D1, is a sensitive indicator for better chemotherapies response.
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Georgia Regents University Cancer Center, Augusta, GA, USA.|Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Shou-Ching
authors.initials: SC
authors.lastname: Tang
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Chongwen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute of Radiation Medicine, The Chinese Academy of Medical Sciences, Nankai District, Tianjin, China.|Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Sida
authors.initials: S
authors.lastname: Qin
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Du
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Breast Oncology, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Radioation Oncology, Fudan University, Shanghai Cancer Center, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D008856:Microscopy, Fluorescence; D010879:Piperazines / Q000494:pharmacology; D034622:RNA Interference; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C530104:CCND1 protein, human; D007093:Imidazoles; D035683:MicroRNAs; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C487931:mirnlet7 microRNA, human; D019938:Cyclin D1; C482205:nutlin 3; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: DICER1; cancer stem cells; cell apoptosis; cyclin D1; let-7; regulatory loop