ABSTRACT
Small cell lung cancer (SCLC) continues to cause poor clinical outcomes due to limited advances in sustained treatments for rapid cancer cell proliferation and progression. The transcriptional factor Forkhead Box M1 (FOXM1) regulates cell proliferation, tumor initiation, and progression in multiple cancer types. However, its biological function and clinical significance in SCLC remain unestablished. Analysis of the Cancer Cell Line Encyclopedia and SCLC datasets in the present study disclosed significant upregulation of FOXM1 mRNA in SCLC cell lines and tissues. Gene set enrichment analysis (GSEA) revealed that FOXM1 is positively correlated with pathways regulating cell proliferation and DNA damage repair, as evident from sensitization of FOXM1-depleted SCLC cells to chemotherapy. Furthermore, Foxm1 knockout inhibited SCLC formation in the Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) mouse model associated with increased levels of neuroendocrine markers, Ascl1 and Cgrp, and decrease in Yap1. Consistently, FOXM1 depletion in NCI-H1688 SCLC cells reduced migration and enhanced apoptosis and sensitivity to cisplatin and etoposide. SCLC with high FOXM1 expression (N = 30, 57.7%) was significantly correlated with advanced clinical stage, extrathoracic metastases, and decrease in overall survival (OS), compared with the low-FOXM1 group (7.90 vs. 12.46 months). Moreover, the high-FOXM1 group showed shorter progression-free survival after standard chemotherapy, compared with the low-FOXM1 group (3.90 vs. 8.69 months). Our collective findings support the utility of FOXM1 as a prognostic biomarker and potential molecular target for SCLC.
Subject(s)
Biomarkers, Tumor , Forkhead Box Protein M1/genetics , Lung Neoplasms/etiology , Lung Neoplasms/mortality , Small Cell Lung Carcinoma/etiology , Small Cell Lung Carcinoma/mortality , Adult , Aged , Aged, 80 and over , Animals , Cell Line, Tumor , Cell Proliferation , Disease Models, Animal , Female , Forkhead Box Protein M1/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lung Neoplasms/diagnosis , Male , Mice , Mice, Transgenic , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Small Cell Lung Carcinoma/diagnosis , X-Ray Microtomography , Xenograft Model Antitumor AssaysABSTRACT
The purpose of this study was to examine the effects of age on active leg stiffness adjustment, electromyogram (EMG) activities and energy stored during eccentric and concentric phases in performing a maximal functional task involving stretch-shorten cycle. Ten young (24.3+/-2 years) and 10 old (68.6+/-5 years) healthy male subjects were filmed during maximal performance of counter movement jump (CMJ) and squat jump (SJ) on force plate. Integrated EMG (IEMG), ground reaction force (GRF), active leg stiffness, energy stored/returned and active work done by the muscles were compared between two groups on eccentric (ECC) and concentric (CON) phases of CMJ. The GRF, leg stiffness and energy stored in ECC and GRF, IEMG, energy returned and active work in CON were less in the elderly (p<0.05). These results demonstrate that the neuromuscular function of adjusting active stiffness, storing elastic energy and optimizing the performance may decrease with age during CMJ.
