Abstract
Despite the importance of AKT overactivation in tumor progression, results from clinical trials of various AKT inhibitors remain suboptimal, suggesting that AKT-driven tumor metastasis needs to be further understood. Herein, based on long non-coding RNA (lncRNA) profiling induced by active AKT, we identify that VAL (Vimentin associated lncRNA, LINC01546), which is directly induced by AKT/STAT3 signaling, functions as a potent pro-metastatic molecule and is essential for active AKT-induced tumor invasion, metastasis and anoikis resistance in lung adenocarcinoma (LAD). Impressively, chemosynthetic siRNAs against VAL shows great therapeutic potential in AKT overactivation-driven metastasis. Interestingly, similar to activated AKT in LAD cells, although unable to induce epithelial-mesenchymal transition (EMT), VAL exerts potent pro-invasive and pro-metastatic effects through directly binding to Vimentin and competitively abrogating Trim16-depedent Vimentin polyubiquitination and degradation. Taken together, our study provides an interesting demonstration of a lncRNA-mediated mechanism for active AKT-driven EMT-independent LAD metastasis and indicates the great potential of targeting VAL or Vimentin stability as a therapeutic approach.
Highlights
Lung cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related death worldwide[1]
We further demonstrate that this long non-coding RNA (lncRNA) is essential for lung adenocarcinoma (LAD) metastasis driven by AKT overactivation
AKT/STAT3-induced VAL correlates with poor prognosis of LAD
Summary
Lung cancer is the most commonly diagnosed cancer type and the leading cause of cancer-related death worldwide[1]. Fischer et al recently showed that using an EMT lineage-tracing system in spontaneous breast-to-lung metastasis model, a small proportion of tumor cells within primary breast tumors undergo EMT, spontaneous lung metastases mainly consist of non-EMT tumor cells with epithelial phenotype[8] These studies have highlighted the fact that the mechanisms underlying tumor metastasis are far more complex than what has been understood. The roles of the large majority of lncRNAs in AKT-driven tumor development and progression remain unclear In this current study, we profile global lncRNA expression in activated AKT-overexpressing LAD cell lines with significantly potentiated metastatic abilities irrelevant to EMT process and identify an intergenic cytoplasmic lncRNA VAL (LINC01546, ENSG00000228459), which is induced by activated AKT via STAT3 transcriptional activity and correlates with disease progression and poor outcomes of LAD, as a potent pro-metastatic molecule. These results should provide insights into the metastatic process of LAD and opportunities for LAD diagnosis and treatment
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