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|Public on Jun 21, 2017
|TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [pts]
|Expression profiling by array
|Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.
|Microarray analysis using a SurePrint G3 Human GE 8 x 60K ver 2 Microarray G4851B (Agilent) was conducted.
Tumors of 75 lung adenocarcinoma patients which successfully underwent potential curative resection at Aichi Cancer Center, Nagoya, Japan, were investigated.
|Griesing S, Kajino T, Tai MC, Liu Z, Nakatochi M, Shimada Y, Suzuki M, Takahashi T
|Jun 29, 2016
|Last update date
|Jan 09, 2018
|Aichi Cancer Center
|1-1 Kanokoden, Chikusa-ku
|Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Probe Name version)
|This SubSeries is part of SuperSeries:
|TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma
|TAR (of TXT)