A Zbtb7a proto‐oncogene as a novel target for miR‐125a

Abstract

In our previous study, we showed that miR-125a directly targeted a WT1 oncogene, which was overexpressed in leukemia and various kinds of solid tumors including lung, breast, gastric, and colon cancers, and brain tumors and was deeply involved in leukemogenesis and tumorigenesis and that miR-125a knockout mice overexpressed WT1 and developed myeloproliferative disease. It had been also reported that miR-125a is downregulated in leukemia and various types of solid tumors such as lung cancers, suggesting its tumor suppressor function. Therefore, it is important to elucidate what is target(s) of miR-125a for understandings of such functions although few target genes for it are known. In the present study, Zbtb7a oncogene was identified as a potential target for miR-125a by gene expression profiling in miR-125a knockout mice combined with bioinformatics target prediction. EGFP-3'UTR reporter assay showed that miR-125a suppressed Zbtb7a expression through its direct binding to the Zbtb7a-3'UTR. Zbtb7a knockdown by siRNA suppressed cell proliferation and induced G1 cell cycle arrest and apoptosis in lung cancer cells. Furthermore, miR-125a expression showed a negative correlation with Zbtb7a expression in non-small cell lung cancer tissues. The present study showed for the first time that Zbtb7a was a direct target for miR-125a and was involved in cell cycle progression and apoptosis of lung cancer cells. These results also demonstrated that deregulation of miR-125a-Zbtb7a signaling was associated with the development and progression of lung cancer. © 2015 Wiley Periodicals, Inc.

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma

“…The presence of an association between ZBTB7A downregulation and poor patient survival further support for the importance of ZBTB7A alterations in HNSCC. In previous studies, miR-20a, miR-100 and miR-125a have been shown to be suppressor miRNAs that are able to reduce expression of the ZBTB7A proto-oncogene in tumors (26)(27)(28). However, it has been found that miR-106b targeting of ZBTB7A increases the survival of hepatocellular carcinoma cells (25).…”

“…Although the roles of ZBTB7A in carcinogenesis are controversial and the mechanisms by which it acts remain largely obscure, frequent deletion and downregulation of ZBTB7A has been shown to occur in a range of malignancies including OSCC (20,(23)(24)(25). In addition, miR-106b and other miRNAs have been shown to target ZBTB7A in such malignancies (25)(26)(27)(28).…”

Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf

“…In mammalians, miR-125a appears to be expressed in most tissues, mainly targeting membrane receptors or intracellular signal transductors of mitogenic signals, thus limiting cell proliferation. Expression of this miRNA generally increases with cell differentiation whereas it is downregulated in several types of tumors, such as breast [25–27], lung [32, 33], ovarian [40], gastric [41], colon [42], and cervical [43] cancers, neuroblastoma [29], medulloblastoma [30], glioblastoma [31], and retinoblastoma [44]. Limited studies on the expression of miR-125a in HCC have also been performed.…”

“…In particular, 200 ng of RNA were retrotranscribed by Transcriptor High Fidelity cDNASynthesis Sample kit (Roche) using random examer primers; 1 μl of cDNA product was then used to amplify the target sequences along with GAPDH as reference. Primers were: GAPDH, 5′-GAAGGTGAAGGTCGGAGTC-3′ and 5′-GAAGATGGTGATGGGATTT-3′; SIRT7, 5′-GTCTG CATGAGCAGAAGCTG-3′ and 5′-GGAACGCAGGA GGTACAGAC-3′; c-Raf, 5′-GCAATGAAGAGGCTGGT AGC-3′ and 5′- GGAGCAGCTCAATGGAAGAC-3′; Zbtb7a, 5′-ACGAGTGCAACATCTGCAAG-3′ and 5′-GG TCGTAGTTGTGGGCAAAG-3′ [33]; MMP11, 5′-TCC TGACTTCTTTGGCTGTG-3′ and 5′-CCATGGGTCT CTAGCCTGAT-3′ [35]. The expression levels of miR-125a and its targeted transcripts were normalized to their respective reference genes by using the 2 −ΔCt method.…”

“…This finding is consistent with the observed underexpression of miR-125a in human primary neuroblastomas. MiR-125a is also down-regulated in other tumors, such as medulloblastoma [30], glioblastoma [31], and lung cancer [32] where it suppresses cell proliferation by targeting Zbtb7a proto-oncogene [33]. …”