ArticleJournal of the National Cancer Institute2019
Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer.
Article in Journal of the National Cancer Institute, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 32 citations in OpenAlex.
- Targeting LKB1-inactivated lung cancers with a stapled peptide inhibitor of the CRTC-CREB pathway.Molecular therapy. Oncology · 2026Article
- The subtype identification of colorectal cancer and construction of the risk model based on cholesterol synthesis-related genes to predict prognosis and guide immunotherapy.International journal of colorectal disease · 2026Article
- Construction of a lung adenocarcinoma prognostic model based on KEAP1/NRF2/HO‑1 mutation‑mediated upregulated genes and bioinformatic analysis.Oncology letters · 2025Article
- LKB1 Mutations Enhance Radiosensitivity in Non-Small Cell Lung Cancer Cells by Inducing G2/M Cell Cycle Phase Arrest.Current molecular medicine · 2025Article
- The YAP1-MAML2 fusion drives tumorigenesis and sustains tumor growth.Molecular therapy. Oncology · 2024Article
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- The diverse influences of relaxin-like peptide family on tumor progression: Potential opportunities and emerging challenges.Heliyon · 2024Review
- Metabolic barriers in non-small cell lung cancer withFrontiers in oncology · 2023Review
- Comprehensive Analysis of a Novel Immune-Related Gene Signature in Lung Adenocarcinoma.Journal of clinical medicine · 2022Article
- Dissecting the ferroptosis-related prognostic biomarker and immune microenvironment of driver gene-negative lung cancer.Experimental biology and medicine (Maywood, N.J.) · 2022Article
- LKB1: Can We Target an Hidden Target? Focus on NSCLC.Frontiers in oncology · 2022Review
- Exploration of the prognostic signature reflecting tumor microenvironment of lung adenocarcinoma based on immunologically relevant genes.Bioengineered · 2021Article
- Relevant and Non-Redundant Feature Selection for Cancer Classification and Subtype Detection.Cancers · 2021Article
- Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation.eLife · 2021Article
- Targeting Notch and EGFR signaling in human mucoepidermoid carcinoma.Signal transduction and targeted therapy · 2021Article
- Article
- INSL4 as prognostic marker for proliferation and invasiveness in Non-Small-Cell Lung Cancer.Journal of Cancer · 2021Article
- Article
- Identification of a Novel Tumor Microenvironment-Associated Eight-Gene Signature for Prognosis Prediction in Lung Adenocarcinoma.Frontiers in molecular biosciences · 2020Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundThe 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.
methodsINSL4 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.
resultsINSL4 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 < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival.
conclusionsLKB1 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.
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