cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth
Zirong Chen, … , Frederic J. Kaye, Lizi Wu
Zirong Chen, … , Frederic J. Kaye, Lizi Wu
Published May 3, 2016
Citation Information: J Clin Invest. 2016;126(6):2267-2279. https://doi.org/10.1172/JCI85250.
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Research Article Oncology

cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

Abstract

The LKB1 tumor suppressor gene is frequently mutated and inactivated in non–small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP–responsive element–binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC.

Authors

Zirong Chen, Jian-Liang Li, Shuibin Lin, Chunxia Cao, Nicholas T. Gimbrone, Rongqiang Yang, Dongtao A. Fu, Miranda B. Carper, Eric B. Haura, Matthew B. Schabath, Jianrong Lu, Antonio L. Amelio, W. Douglas Cress, Frederic J. Kaye, Lizi Wu

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Figure 2

Enhanced LINC00473 expression is highly correlated with human lung adenocarcinoma with LKB1 mutational status and is associated with poor survival.

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Enhanced LINC00473 expression is highly correlated with human lung adeno...
(A) A heatmap shows gene expression levels in RNA samples isolated from 5 LKB1-WT and 5 LKB1-mutant FFPE LUAD samples in NanoString assays. (B) Expression of LINC00473 tv1, but not tv2, was significantly different between LKB1-WT and -mutant groups. (C and D) Representative images for tumors with LINC00473-positive (C) and -negative (D) signals based on RNAscope detection on FFPE LUAD sections. RNA ISH of the housekeeping gene PPIB was performed for sample RNA quality control. Scale bars: 100 μm (left panels), 25 μm (right panels). (E) A survey of human LUAD arrays indicated that 0% of normal lung tissues (n = 38), 10.11% of NSCLC tumors with annotated WT LKB1 (n = 89), and 55.54% of NSCLC tumors with annotated LKB1 mutations (n = 22) were positive for LINC00473 expression. Only those tissues positive for the housekeeping gene PPIB expression were included in this analysis. LINC00473 expression was positively correlated with LKB1 mutations based on Fisher’s exact test (P = 1.93 × 10–5). (F) TCGA-LUAD dataset showed outlier LINC00473 expression in matched tumor (T) (n = 57) compared with adjacent normal tissues (N) (n = 57) as well as unpaired tumor (UT) (n = 454). (G) Kaplan-Meier survival analysis of high LINC00473 expression (n = 48) and low LINC00473 expression (n = 421) in lung cancer patients (P < 0.001). See also Supplemental Figures 4–8 and Supplemental Table 7.