Histone deacetylase inhibitors inhibit metastasis by restoring a tumor suppressive microRNA-150 in advanced cutaneous T-cell lymphoma
| Autor: | Hiroki Nakanishi, Akihiro Kitadate, Naoto Takahashi, Kazuaki Teshima, Fumito Abe, Sho Ikeda, Junsuke Yamashita, Hiroyuki Tagawa, Makoto Sugaya, Tomomitsu Miyagaki, Chikara Asaka |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Indoles Skin Neoplasms Time Factors Mice SCID Hydroxamic Acids Metastasis chemistry.chemical_compound CTCL Cell Movement Mice Inbred NOD hemic and lymphatic diseases Panobinostat Vorinostat Hematology Histone deacetylase inhibitor Lymphoma T-Cell Cutaneous Gene Expression Regulation Neoplastic Oncology Female medicine.drug Research Paper Signal Transduction Receptors CCR6 medicine.medical_specialty medicine.drug_class HDACI Antineoplastic Agents 03 medical and health sciences miR-150 Internal medicine Cell Line Tumor medicine metastasis Animals Humans Neoplasm Invasiveness business.industry Cutaneous T-cell lymphoma medicine.disease Xenograft Model Antitumor Assays Lymphoma Histone Deacetylase Inhibitors MicroRNAs 030104 developmental biology chemistry Immunology Cancer research business CCR6 |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Fumito Abe 1, * , Akihiro Kitadate 1, * , Sho Ikeda 1 , Junsuke Yamashita 2 , Hiroki Nakanishi 3 , Naoto Takahashi 1 , Chikara Asaka 4 , Kazuaki Teshima 5 , Tomomitsu Miyagaki 6 , Makoto Sugaya 6 , Hiroyuki Tagawa 1 1 Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan 2 Division of Bioscience Center, Radioisotope, Akita University, Akita, Japan 3 Research Center for Biosignal, Akita University, Akita, Japan 4 Department of Otolaryngology, Noshiro Kousei Medical Center, Noshiro, Japan 5 Department of Hematology, Hiraka General Hospital, Yokote, Japan 6 Department of Dermatology, University of Tokyo, Tokyo, Japan * These authors share first authorship Correspondence to: Hiroyuki Tagawa, email: htagawa0279jp@yahoo.co.jp Keywords: HDACI, miR-150, CCR6, CTCL, metastasis Received: September 24, 2016 Accepted: November 24, 2016 Published: December 07, 2016 ABSTRACT Tumor suppressive microRNA (miR)-150 inhibits metastasis by combining with the C-C chemokine receptor 6 (CCR6) “seed sequence” mRNA of the 3′-untranslated region (3′-UTR) in advanced cutaneous T-cell lymphoma (CTCL). Because the histone deacetylase inhibitor (HDACI) vorinostat showed excellent outcomes for treating advanced CTCL, HDACIs may reduce the metastasis of CTCL by targeting miR-150 and/ or CCR6. To examine whether these candidate molecules are essential HDACI targets in advanced CTCL, we used the My-La, HH, and HUT78 CTCL cell lines for functional analysis because we previously demonstrated that their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) induced multiple metastases. We found that pan- HDACIs (vorinostat and panobinostat) inhibited the migration of CTCL cells and downregulated CCR6. The miRNA microarray analysis against CTCL cell lines demonstrated that these pan-HDACIs commonly upregulated 161 miRNAs, including 34 known tumor suppressive miRNAs such as miR-150. Although 35 miRNAs possessing the CCR6 “seed sequence” were included in these 161 miRNAs, miR-150 and miR-185-5p were downregulated in CTCL cells compared to in normal CD4+ T-cells. The transduction of 12 candidate miRNAs against CTCL cells revealed that miR-150 most efficiently inhibited their migration capabilities and downregulated CCR6. Quantitative reverse transcriptase-polymerase chain reaction demonstrated that miR-150 was downregulated in advanced but not early CTCL primary cases. Finally, we injected miR-150 or siCCR6 into CTCL mice and found that mouse survival was significantly prolonged. These results indicate that miR-150 and its target, CCR6, are essential therapeutic targets of pan-HDACIs in advanced CTCL with metastatic potential. |
| Databáze: | OpenAIRE |
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