title: Differentially expressed miRNAs in cancer-stem-like cells: markers for tumor cell aggressiveness of pancreatic cancer.
abstract: Pancreatic cancer (PC) is one of the most deadly cancers. The higher mortality is in part due to treatment resistance and early onset of metastasis. The existence of cancer-stem-like cells (CSLCs) has been widely accepted to be responsible for tumor aggressiveness in PC. Emerging evidence suggests that CSLCs have the capacity for increased cell growth, cell migration/invasion, metastasis, and treatment resistance, which leads to poor clinical outcome. However, the molecular role of CSLCs in tumor development and progression is poorly understood. Therefore, mechanistic understanding, and targeted killing of CSLCs may provide a newer therapeutic strategy for the treatment of PC. It has been well accepted that microRNAs (miRNAs) play critical roles during tumor development and progression through deregulation of multiple genes. Moreover, deregulated expression of miRNAs may also play a key role in the regulation of CSLC characteristics and functions. Here we show that isolated CD44(+)/CD133(+)/EpCAM(+) cells (triple-marker-positive cells) from human PC cell lines, MiaPaCa-2 and L3.6pl cells, display aggressive characteristics, such as increased cell growth, clonogenicity, cell migration, and self-renewal capacity, which is consistent with overexpression of CSLC signatures/markers. We also found deregulated expression of over 400 miRNAs, including let-7, miR-30, miR-125b, and miR-335, in CSLCs. As a proof-of-concept, knockdown of miR-125b resulted in the inhibition of tumor cell aggressiveness of CSLCs (triple-marker-positive cells), consistent with the downregulation of CD44, EpCAM, EZH2, and snail. These results clearly suggest the importance of miRNAs in the regulation of CSLC characteristics, and may serve as novel targets for therapy.
authors.affiliation: 1 Department of Pathology, Karmanos Cancer Institute, Wayne State University , Detroit, Michigan.
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.forename: Ramzi
authors.initials: R
authors.lastname: Mohammad
authors.forename: Eric
authors.initials: E
authors.lastname: Van Buren
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D015870:Gene Expression; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs