Researchers at Boston University School of Medicine recently identified new players in the network of genes know to regulate epithelial lung cells, which might also be associated with the development of tumors and other lung disorders. The study was published in the journal Respiratory Research and is entitled “Transcription factor and microRNA interactions in lung cells: an inhibitory link between NK2 homeobox 1, miR-200c and the developmental and oncogenic factors Nfib and Myb.”
The transcription factor NK2 homeobox 1 (Nkx2-1) corresponds to a protein that controls the expression of genes that are specific to the thyroid and the lungs. It plays a vital role in lung formation and in normal respiratory functions after birth, regulating epithelial lung cells’ proliferation and differentiation. Disturbance on Nkx2-1 gene expression can result in medical conditions such as post-natal respiratory distress, lung interstitial disease and lung cancer.
Nkx2-1 is a critical lung factor known to regulate several genes, although its involvement with microRNAs (miRNAs) is not clear. MicroRNAs are small non-coding RNA molecules that also play essential roles in the regulation of gene expression.
In this study, researchers performed miRNA array analyses of lung epithelial cell lines of a mouse model that had reduced levels of Nkx2-1 and found that several miRNAs have an altered expression: 29 miRNAs were negatively regulated, including miR-200c, while 39 other miRNAs were positively regulated by Nkx2-1. Similar results were obtained with an experimental model lacking a functional Nkx2-1 expression, where miRNA-200c had an increased expression in the absence of Nkx2-1.
“We found that Nkx2-1 protein binds to regulatory regions of these miRNAs. In vitro studies indicated that miR-200c is inhibited by Nkx2-1, while miR-200c inhibits its predicted targets Nfib and Myb,” explained the study’s first author Dr. Jean-Bosco Tagne in a news release. Previous evidence has suggested that members of the miRNA-200 family, which are highly enriched in epithelial tissues, are involved in suppressing cancer development and metastasis formation.
Apart from Nkx2-1, the transcription factors Nfib and Myb are also known to play an important role in the regulation of lung cell proliferation and development. All three factors are considered oncogenes that can contribute to tumorigenesis. “The novel link we identified between NKX2-1, miR-200c and NFIB or MYB may participate in propagating fluctuations in the levels of Nkx2-1 in human lung tumors, adding substantial information to understanding lung tumorigenesis, for improvement of its prognosis, diagnosis and treatment,” said Dr. Tagne.
The research team concluded that Nkx2-1 can control the expression of specific miRNAs in lung epithelial cells and that the new players of the regulatory network in lung cells found may interfere with the balance between Nkx2-1, the tumor suppressor miR-200c and the oncogenes Nfib and Myb. “This study adds new players to the regulatory mechanisms driven by Nkx2-1 in lung epithelial cells that may have implications in lung development and tumorigenesis,” concluded Dr. Tagne. The authors believe that their findings could be helpful in the control of lung cell proliferation, cancer formation and progression.