Abstract
Lung cancer is the leading cause of tumor-related death worldwide and more efforts are needed to elucidate lung carcinogenesis. Here we investigated the expression of 641 miRNAs in lung tumorigenesis in a K-Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model and 113 human tumors. The conserved miRNA cluster on chromosome 12qF1 was significantly and progressively upregulated during murine lung carcinogenesis. In particular, miR-494-3p expression was correlated with lung cancer progression in mice and with worse survival in lung cancer patients. Mechanistically ectopic expression of miR-494-3p in A549 lung cancer cells boosted the tumor-initiating population enhanced cancer cell motility, and increased the expression of stem cell-related genes. Importantly, miR-494-3p improved the ability of A549 cells to grow and metastasize in vivo, modulating NOTCH1 and PTEN/PI3K/AKT signaling.Overall, these data identify miR-494-3p as a key factor in lung cancer onset and progression and possible therapeutic target.
Highlights
Despite an improved understanding of lung carcinogenesis, lung cancer is still a major cause of cancerrelated death worldwide with increasing incidence in nonsmoker subjects
The 12qF1 miRNAs upregulation in lung tissues from the K-Ras(+/LSLG12Vgeo);RERTn(ert/ert) mouse model is correlated with lung carcinogenesis
To begin to test a role of this association in disease dissemination [14], we examined the expression of 14q32 miRNAs in 16 cases of non-small cell lung cancer (NSCLC) where tumor bulk and the tumor invasive front were isolated by laserassisted microdissection. miR-494-3p expression was significantly higher in the invasive front than in tumor bulk specimens (p = 0.03; Figure 2E)
Summary
Despite an improved understanding of lung carcinogenesis, lung cancer is still a major cause of cancerrelated death worldwide with increasing incidence in nonsmoker subjects. Engineered mouse models may uncover pre-neoplastic precursor lesions, which are often absent in human samples. In this investigation, we studied the conditional knock-in K-Ras(+/LSLG12Vgeo);RERTn(ert/ ert) mouse model of lung cancer [3] and systematically profiled microRNA (miRNA) contents from histologically defined normal, hyperplastic, adenomatous and tumor lung specimens. In this model, lung carcinogenesis is driven by oncogenic K-RasG12V induction by 4-hydroxitamoxifen (4-OHT) administration [4]. Lung adenocarcinoma arises with complete penetrance, evolving from normal to hyperplasia, adenoma and cancer [3, 5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
