Abstract
In multiple types of tumors, fibrotic collagen is regarded as the 'highway' for cancer cell migration, which is mainly modified by lysyl hydroxylase 2 (PLOD2). The previous findings have demonstrated that the expression of PLOD2 was regulated by multiple factors, including HIF-1α, TGF-β and microRNA-26a/b. Although PLOD2 was confirmed to be related to poor prognosis in lung adenocarcinoma, the regulatory mechanism and function of PLOD2 in human lung adenocarcinoma is poorly understood. On the other hand, upregulation or hyperactivation of epidermal growth factor receptor is considered as a prognostic marker in many cancers, especially in non-small-cell lung cancer (NSCLC). In this study, we found that PLOD2 was elevated in NSCLC specimens and positively links to NSCLC poor prognosis. Gain- and loss-of-function studies and orthotopic implantation metastasis model pinpointed that PLOD2 promotes NSCLC metastasis directly by enhancing migration and indirectly by inducing collagen reorganization. In addition, we revealed that PLOD2 was regulated by PI3K/AKT-FOXA1 axis. The transcription factor FOXA1 directly bound to the PLOD2 promoter, and turned on PLOD2 transcription. In summary, our findings revealed a regulatory mechanism of NSCLC metastasis through EGFR-PI3K/AKT-FOXA1-PLOD2 pathway, and provided PLOD2 as a therapeutic target for NSCLC treatment.
Highlights
Nowadays, the survival of patients with malignant tumors has improved owing to the development of advanced treatment options
The coexpression analysis suggested that phosphorylation of EGFR (P-EGFR) and PLOD2 were simultaneously expressed in adenocarcinoma tissues and tissue microarray (Supplementary Figures S1g and 1h), which were consistent with the results shown in NSCLC cell lines (Supplementary Figures S1c–e)
Collagen deposition and fibril organization were detected by picrosirius red staining, which showed that collagen deposition was increased and the degree of fibrillar organization was enhanced in human lung adenocarcinoma tissues (Figures 1i and j)
Summary
The survival of patients with malignant tumors has improved owing to the development of advanced treatment options. The extracellular matrix (ECM), as the chief component of the TME, has important roles in multiple stages during tumor progression, including adhesion, migration, proliferation, differentiation and survival, especially in tumor metastasis.[5] Recently, many therapeutic strategies have been designed to target both TME and tumor cells.[6,7,8]. Results from multiple types of human cancers suggest that the accumulation of stabilized collagen is enhanced by different covalent intra- and intermolecular crosslinks.[10,11,12,13] The different types of collagen organization are determined after crosslink formation by the hydroxylation of collagen telopeptidyl and helical Lys residues.[13,14]. It is well known that the EGFR inhibitors widely face primary resistance (~60%)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
