Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer
| Autor: | Frederic J. Kaye, Zirong Chen, Xin Zhou, Lizi Wu, Wei Ni, Steven W. Li, Jianrong Lu, Rongqiang Yang, DongTao Fu |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Cancer Research Tumor suppressor gene Protein Serine-Threonine Kinases Biology Disease-Free Survival Small hairpin RNA Mice 03 medical and health sciences 0302 clinical medicine AMP-Activated Protein Kinase Kinases Carcinoma Non-Small-Cell Lung Gene expression medicine Animals Humans Cyclic AMP Response Element-Binding Protein Lung cancer Autocrine signalling Cell Proliferation Gene knockdown Articles Cell cycle medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Gene expression profiling Autocrine Communication Oncology A549 Cells 030220 oncology & carcinogenesis Cancer research Intercellular Signaling Peptides and Proteins Female Transcriptome Signal Transduction Transcription Factors |
| Zdroj: | JNCI: Journal of the National Cancer Institute. 111:664-674 |
| ISSN: | 1460-2105 0027-8874 |
| DOI: | 10.1093/jnci/djy166 |
| Popis: | Background The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P Conclusions LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers. |
| Databáze: | OpenAIRE |
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