title: MicroRNA 96 is a post-transcriptional suppressor of anaplastic lymphoma kinase expression.
abstract: Anaplastic lymphoma kinase (ALK) constitutes a part of the oncogenic fusion proteins nucleophosmin-ALK and echinoderm microtubule-associated protein like 4-ALK, which are aberrantly expressed in a subset of T-cell anaplastic large-cell lymphoma and non-small-cell lung cancer, respectively. The expression of mutated, constitutively active ALK also occurs in a subset of neuroblastoma tumors. ALK is believed to play an important role in promoting tumor survival. Nevertheless, the mechanisms underlying the expression of ALK in cancer cells are not completely known. MicroRNA (miR) has been implicated in the regulation of the expression of both oncogenes and tumor suppressor genes. We tested the hypothesis that the expression of ALK could be regulated by miR. Three Internet-based algorithms identified miR-96 to potentially bind with the ALK 3'-untranslated region. Notably, miR-96 levels were markedly decreased in ALK-expressing cancer cell lines and primary human tumors compared with their normal cellular and tissue counterparts. Transfection of the cell lines with miR-96 decreased levels of the different forms of ALK protein, without significant effects on ALK mRNA. Furthermore, miR-96 decreased the phosphorylation of ALK target proteins, including Akt, STAT3, JNK, and type I insulin-like growth factor receptor, and it down-regulated JunB. These effects were associated with reduced proliferation, colony formation, and migration of ALK-expressing cancer cells. These data provide novel evidence that decreases in miR-96 could represent a mechanism underlying the aberrant expression of ALK in cancer cells.
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Vishwamitra
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Desiree
authors.initials: D
authors.lastname: Wilson
authors.forename: Roxsan
authors.initials: R
authors.lastname: Manshouri
authors.forename: Choladda V
authors.initials: CV
authors.lastname: Curry
authors.forename: Bin
authors.initials: B
authors.lastname: Shi
authors.forename: Xi Ming
authors.initials: XM
authors.lastname: Tang
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Sheehan
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
mesh_terms: D000465:Algorithms; D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002633:Chemotaxis / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D016415:Sequence Alignment; D014162:Transfection
chemical_list: C541492:MIRN96 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases