title: Genomic DNA copy-number alterations of the let-7 family in human cancers.
abstract: In human cancer, expression of the let-7 family is significantly reduced, and this is associated with shorter survival times in patients. However, the mechanisms leading to let-7 downregulation in cancer are still largely unclear. Since an alteration in copy-number is one of the causes of gene deregulation in cancer, we examined copy number alterations of the let-7 family in 2,969 cancer specimens from a high-resolution SNP array dataset. We found that there was a reduction in the copy number of let-7 genes in a cancer-type specific manner. Importantly, focal deletion of four let-7 family members was found in three cancer types: medulloblastoma (let-7a-2 and let-7e), breast cancer (let-7a-2), and ovarian cancer (let-7a-3/let-7b). For example, the genomic locus harboring let-7a-3/let-7b was deleted in 44% of the specimens from ovarian cancer patients. We also found a positive correlation between the copy number of let-7b and mature let-7b expression in ovarian cancer. Finally, we showed that restoration of let-7b expression dramatically reduced ovarian tumor growth in vitro and in vivo. Our results indicate that copy number deletion is an important mechanism leading to the downregulation of expression of specific let-7 family members in medulloblastoma, breast, and ovarian cancers. Restoration of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of cancer.
authors.affiliation: Department of Obstetrics and Gynecology; University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Hu
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yang
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Shao
authors.forename: Shun
authors.initials: S
authors.lastname: Liang
authors.forename: Janos L
authors.initials: JL
authors.lastname: Tanyi
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056915:DNA Copy Number Variations / Q000235:genetics*; D030541:Databases, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D017384:Sequence Deletion
chemical_list: D035683:MicroRNAs; C487931:mirnlet7 microRNA, human