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

Abstract

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.

MicroRNAs as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes

“…For the first time, we demonstrated that DOX caused a higher expression of miR-187-3p in human cardiomyocytes. Notably, miR-187-3p overexpressing T-lymphoma cells show resistance to DNA damaging agents such as DOX, cisplatin and cyclophosphamide (Yan et al 2014). Thus, we may assume that miR-187-3p overexpression in cardiomyocytes is the result of DOX-induced DNA damage.…”

The RHOA G17V gene mutation occurs frequently in peripheral T-cell lymphoma and is associated with a characteristic molecular signature

“…However, explanations involving other biological mechanisms cannot be ruled out. 7 Although standard prognostic indices for this series (International Prognostic Index and Prognostic Index for PTCL-u) identified prognostic subgroup of patients (both indices, P , .001), the mutational status of the RHOA gene did not, either in the total group of all patients or after histologic subclassification (AITL vs PTCL-NOS) ( Table 1 and supplemental Tables 2-3 available on the Blood Web site. ).…”

C-MYC is related to GATA3 expression and associated with poor prognosis in nodal peripheral T-cell lymphomas

“…MYC is known to be activated by the loss of SNF5 (SMARCB1), 2 overexpression of microRNA187, 5 and by its own gene amplification or translocation, thereby favoring the rapid appearance of T-cell neoplasms in humans.…”