Research Paper Volume 13, Issue 3 pp 4482—4502
Identification of downstream signaling cascades of ACK1 and prognostic classifiers in non-small cell lung cancer
- 1 Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
- 2 Department of Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
- 3 Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
- 4 Department of Precision Medicine, Harbin Medical University Cancer Hospital, Harbin 150040, Heilongjiang, China
Received: October 5, 2020 Accepted: November 27, 2020 Published: January 20, 2021
https://doi.org/10.18632/aging.202408How to Cite
Copyright: © 2021 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Activated Cdc42-associated kinase 1 (ACK1) is an oncogene in multiple cancers, but the underlying mechanisms of its oncogenic role remain unclear in non-small cell lung cancer (NSCLC). Herein, we comprehensively investigated the ACK1-regulated cell processes and downstream signaling pathways, as well as its prognostic value in NSCLC. We found that ACK1 gene amplification was associated with mRNA levels in The Cancer Genome Atlas (TCGA) lung cancer cohort. The Oncomine databases showed significantly elevated ACK1 levels in lung cancer. In vitro, an ACK1 inhibitor (dasatinib) increased the sensitivity of NSCLC cell lines to AKT or MEK inhibitors. RNA-sequencing results demonstrated that an ACK1 deficiency in A549 cells affected the MAPK, PI3K/AKT, and Wnt pathways. These results were validated by gene set enrichment analysis (GSEA) of data from 188 lung cancer cell lines. Using Cytoscape, we dissected 14 critical ACK1-regulated genes. The signature with the 14 genes and ACK1 could significantly dichotomize the TCGA lung cohort regarding overall survival. The prognostic accuracy of this signature was confirmed in five independent lung cancer cohorts and was further validated by a prognostic nomogram. Our study unveiled several downstream signaling pathways for ACK1, and the proposed signature may be a promising prognostic predictor for NSCLC.
Abbreviations
ACK1: activated Cdc42-associated kinase 1; TNK2: non-receptor tyrosine kinase 2; RTKs: receptor tyrosine kinases; EGF: epidermal growth factor; PDGF: platelet-derived growth factor; EMT: epidermal-mesenchymal transition; Uba: ubiquitin-association; LUAD: Lung adenocarcinoma; LUSC: lung squamous cell carcinoma; DEGs: Differentially expressed genes; GEO: Gene Expression Omnibus; TCGA: The Cancer Genome of Atlas; KEGG: Kyoto Encyclopedia of Genes and Genomes; STRING: Search Tool for the Retrieval of Interacting Genes; GSEA: Gene Set Enrichment Analysis; CCLE: Cancer Cell Line Encyclopedia; qPCR: Quantitative PCR; OS: Overall survival; BiNGO: the Biological Networks Gene Ontology tool; MCODE: Molecular Complex Detection; TNM: Tumor-node-metastasis; CIs: Confidence intervals; KM: Kaplan–Meier; MSigDB: Molecular Signatures Database; cDNA: Complementary DNA; CNV: Copy number variation; c-index: The concordance index; MEFs: mouse embryonic fibroblasts.