Thyroid transcription factor‐1‐regulated microRNA‐532‐5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma cells. Issue 7 (10th June 2017)

• Record Type: Journal Article
• Authors: Griesing, Sebastian; Kajino, Taisuke; Tai, Mei Chee; Liu, Zhuoran; Nakatochi, Masahiro; Shimada, Yukako; Suzuki, Motoshi; Takahashi, Takashi
• Is Part Of: Cancer science. Volume 108:Issue 7(2017)
• Page Start: 1394
• Page End: 1404
• Publication Date: 2017-06-10
• Subjects: Characteristics and pathology of human cancer -- microRNA/non‐coding RNA respiratory organ -- oncogenes and tumor‐suppressor genes; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13271
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : Thyroid transcription factor‐1 (TTF‐1), also known as NKX2‐1, plays a role as a lineage‐survival oncogene in lung adenocarcinoma that possesses double‐edged sword characteristics. Although evidence from previous studies has steadily accumulated regarding the roles of TTF‐1 in transcriptional regulation of protein‐coding genes, little is known about its regulatory relationship with microRNAs. Here, we utilized an integrative approach designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF‐1‐inducible cell lines in vitro, which identified microRNA (miR)‐532‐5p as a novel transcriptional target of TTF‐1. We found that miR‐532‐5p is directly regulated by TTF‐1 through its binding to a genomic region located 8 kb upstream of miR‐532‐5p, which appears to impose transcriptional regulation independent of that of CLCN5, a protein‐coding gene harboring miR‐532‐5p in its intron 3. Furthermore, our results 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 wild‐type lung adenocarcinoma cell lines. Interestingly, miR‐532‐5p showed effects on MEK‐ERK pathway signaling, specifically in cell lines sensitive to siKRAS treatment, whereas those miR‐532‐5p ‐mediated effects were clearly rendered as phenocopies by repressing expression or inhibiting the function of MKL2 regardless of KRAS mutation status. In summary, our findings show that miR‐532‐5p is a novel transcriptional target of TTF‐1 that plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Abstract : By applying an integrative approach combining in vitro with in vivo data, we identified miR‐532‐5p as a novel transcriptional target of TTF‐1/NKX2‐1, which regulates miR‐532‐5p independent of its host gene CLCN5 . Furthermore, we showed that miR‐532‐5p directly represses oncogenic KRAS and MKL2 and causes apoptosis in lung adenocarcinoma cells.