A novel noncoding RNA and human lung cancers with inactivated LKB1 signaling

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 DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths in both men and women in the United States and worldwide. The tumor suppressor LKB1 gene - a gene encoding a serine/threonine kinase that is critical for cellular metabolism, polarity and growth control - is somatically inactivated in approximately 30% of non small cell lung cancer (NSCLC) cases, ranking it as the third most frequently mutated gene in NSCLC. The loss of LKB1 in the context of KRAS mutations promotes lung cancer metastasis in mouse models, and is associated with poor prognosis. The LKB1 status is linked with cancer responsiveness to several targeted agents and chemotherapy in mouse tumor models. LKB1 is thus implicated as diagnostic, prognostic and predictive biomarkers in human lung cancer. However, before clinical benefits that exploit LKB1 deficiency can be achieved, we need to have reliable assays to score tumors with LKB1 functional loss and to further understand the molecular basis for LKB1 tumor suppressor function and its clinical implications. Long noncoding RNAs (lncRNAs) have emerged as a novel class of gene regulators in recent years and are implicated in oncogenesis. We have observed a tight correlation between up-regulated expression of a lncRNA (LINC00473) and LKB1 inactivation in a panel of human NSCLC cell lines. Moreover, overexpression of LKB1 decreased LINC00473 expression, while LKB1 depletion enhanced it. Importantly, our pilot study revealed high LINC00473 expression in human primary lung tumors with downregulated LKB1 protein. Functionally, LINC00473 depletion reduced lung cancer cell proliferation and survival. Our overall preliminary data led us to hypothesize that LKB1 inactivation mediates LINC00473 transcriptional up-regulation and that the induced LINC00473 up-regulation contributes to lung tumorigenesis. This hypothesis will be addressed by two specific aims. Aim 1 will investigate molecular mechanisms underlying LKB1 regulation of LINC00473 expression and assess LINC00473 up-regulation as a biomarker for LKB1-inactivated lung cancers. Aim 2 will determine the role and mechanisms of LINC00473 in regulating lung cancer. The successful completion of these aims will provide significant insights into the roles and mechanisms of LINC00473 in lung tumorigenesis and has the potential to reveal novel biomarkers and potential therapeutic targets for lung cancer.