MicroRNA187 overexpression is related to tumor progression and determines sensitivity to bortezomib in peripheral T-cell lymphoma

• Published in: Leukemia Vol. 28; no. 4; pp. 880 - 887
• Main Authors: Yan, Z-X, Wu, L-L, Xue, K, Zhang, Q-L, Guo, Y, Romero, M, Leboeuf, C, Janin, A, Chen, S-J, Wang, L, Zhao, W-L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2014; Nature Publishing Group
• Subjects: 631/337/384/331; 692/420/755; 692/699/67/1059/2326; 692/699/67/1990/291/1621/1916; Adapter proteins; AKT protein; Animals; Antineoplastic Agents - therapeutic use; Boronic Acids - therapeutic use; Bortezomib; Cancer Research; Cell growth; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Cisplatin; Critical Care Medicine; Cyclophosphamide; Dehydrogenases; Development and progression; Disease Progression; Doxorubicin; Ectopic expression; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Gemcitabine; Genes; Genomics; Grb2 protein; Hematology; Homology; Hospitals; Humans; Intensive; Internal Medicine; Kinases; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Leukemia; Leukemia research; Lymphocytes T; Lymphoma; Lymphoma, T-Cell, Peripheral - drug therapy; Lymphoma, T-Cell, Peripheral - genetics; Lymphoma, T-Cell, Peripheral - pathology; Medicine; Medicine & Public Health; Mice; MicroRNA; MicroRNAs; MicroRNAs - physiology; miRNA; Myc protein; Oncology; original-article; Phosphorylation; Physiological aspects; Proteasome inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - physiology; Pyrazines - therapeutic use; Ras protein; Sensitivity; T cell lymphoma; Tumor cell lines; Tumor suppressor genes; Tumorigenesis; Tumors; Xenografts; Xenotransplantation; United States > US; China; Germany; microRNA187; peripheral T-cell lymphoma; chemoresistance; tumor progression; bortezomib; MYC
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.291

MicroRNAs (miRs) are involved in tumorigenesis by regulating tumor suppressor genes and/or oncogenes. MiR187 was overexpressed in peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and associated with high Ki67 expression, elevated lactate dehydrogenase, advanced International Prognostic Index and poor prognosis of patients.
In vitro
, ectopic expression of miR187 in T-lymphoma cell lines accelerated tumor cell proliferation, whereas treatment with miR187 inhibitor reduced cell growth. MiR187 downregulated tumor suppressor gene disabled homolog-2 (Dab2), decreased the interaction of Dab2 with adapter protein Grb2, resulting in Ras activation, phosphorylation/activation of extracellular signal-regulated kinase (ERK) and AKT, and subsequent stabilization of MYC oncoprotein. MiR187-overexpressing cells were resistant to chemotherapeutic agents like doxorubicin, cyclophosphamide, cisplatin and gemcitabine, but sensitive to the proteasome inhibitor bortezomib. Bortezomib inhibited T-lymphoma cell proliferation by downregulating miR187, dephosphorylating ERK and AKT and degrading MYC. In a murine xenograft model established with subcutaneous injection of Jurkat cells, bortezomib particularly retarded the growth of miR187-overexpressing tumors, consistent with the downregulation of miR187, Ki67 and MYC expression. Collectively, these findings indicated that miR187 was related to tumor progression in PTCL-NOS through modulating Ras-mediated ERK/AKT/MYC axis. Although potentially oncogenic, miR187 indicated the sensitivity of T-lymphoma cells to bortezomib. Cooperatively targeting ERK and AKT could be a promising clinical strategy in treating MYC-driven lymphoid malignancies.