Oncogene database

442891

MIR135B

microRNA 135b;MIR135B;microRNA 135b

hsa-mir-135b

1q32.1

ncRNA

Many transformed lymphoma cells show immune-phenotypes resembling the corresponding normal lymphocytes; thus, they provide a guide for proper diagnosis and present promising routes to improve their pathophysiologic understanding and to identify novel therapeutic targets. However, the underlying molecular mechanism(s) of these aberrant immune-phenotypes is largely unknown. Here, we report that microRNA-135b (miR-135b) mediates nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-driven oncogenicity and empowers IL-17-producing immunophenotype in anaplastic large cell lymphoma (ALCL). NPM-ALK oncogene strongly promoted the expression of miR-135b and its host gene LEMD1 through activation of signal transducer and activator of transcription (STAT) 3. In turn, elevated miR-135b targeted FOXO1 in ALCL cells. miR-135b introduction also decreased chemosensitivity in Jurkat cells, suggesting its contribution to oncogenic activities of NPM-ALK. Interestingly, miR-135b suppressed T-helper (Th) 2 master regulators STAT6 and GATA3, and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells, indicating that miR-135b-mediated Th2 suppression may lead to the skewing to ALCL immunophenotype overlapping with Th17 cells. Furthermore, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, demonstrating significance of this "Th17 mimic" pathway as a therapeutic target. These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment.

The high mortality rate of hepatocellular carcinoma (HCC) is associated with its fast-growing malignancy. In tumor microenvironments, certain GPCRs are coupled to Galpha12 for signal transduction. Given the role of forkhead box O1 (FOXO1) in the inhibition of various tumors, this study investigated whether increase of Galpha12 in HCC causes FOXO1 repression, and if so, whether this event occurs through microRNA dysregulation. Overexpression of an active mutant of Galpha12 (Galpha12QL) decreased FOXO1 levels, whereas knockdown of Galpha12 had the opposite effect. Of the microRNAs targeting FOXO1, miR-135b levels were markedly increased by Galpha12 signaling, which led to FOXO1 repression as shown by the experiments using mimic, antisense oligonucleotide or siRNA. Galpha12QL increased the primary form of miR-135b by activating JunB (or c-Jun)/AP-1. Consistently, knockdown of JunB (or c-Jun) decreased miR-135b levels, thereby increasing FOXO1. Moreover, Galpha12QL induced MDM2, the deficiency of which facilitated FOXO1 accumulation. In addition, Galpha12QL repressed miR-194 cluster gene products (194/192/215), which contributed to MDM2-mediated FOXO1 repression. In functional assays, Galpha12QL facilitated tumor cell growth with alterations in cell cycle-associated protein levels, which was antagonized by enforced expression of FOXO1. In human HCCs, FOXO1 levels were decreased as compared with the surrounding liver tissue. Moreover, decrease of FOXO1 or miR-194 was statistically significant between stages T1 and T2, whereas increase of miR-135b discriminated tumor stage T3a versus T1/T2. In conclusion, Galpha12gep oncogene inhibits FOXO1, which may result from the inhibition of FOXO1 de novo synthesis by miR-135b in conjunction with MDM2-mediated destabilization of FOXO1.