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The X-Linked Tumor Suppressor TSPX Regulates Genes Involved in the EGFR Signaling Pathway and Cell Viability to
Tatsuo Kido1, Hui Kong1, Yun-Fai Chris Lau1
1Division of Cell and Developmental Genetics, Department of Medicine, Veterans Affairs Medical Center, and the Institute for Human Genetics, University of California, San Francisco, CA 94121, USA.
Abstract:
Background: TSPX is an X-linked tumor suppressor that was initially identified in non-small cell lung cancer (NSCLC) cell lines. However, its expression patterns and downstream mechanisms in NSCLC remain unclear. This study aims to investigate the functions of TSPX in NSCLC by identifying its potential downstream targets and their correlation with clinical outcomes. Methods: RNA-seq transcriptome and pathway enrichment analyses were conducted on the TSPX-overexpressing NSCLC cell lines, A549 and SK-MES-1, originating from lung adenocarcinoma and squamous cell carcinoma subtypes, respectively. In addition, comparative analyses were performed using the data from clinical NSCLC specimens (515 lung adenocarcinomas and 502 lung squamous cell carcinomas) in the Cancer Genome Atlas (TCGA) database. Results: TCGA data analysis revealed significant downregulation of TSPX in NSCLC tumors compared to adjacent non-cancerous tissues (Wilcoxon matched pairs signed rank test p < 0.0001). Notably, the TSPX expression levels were inversely correlated with the cancer stage, and higher TSPX levels were associated with better clinical outcomes and improved survival in lung adenocarcinoma, a subtype of NSCLC (median survival extended by 510 days; log-rank test, p = 0.0025). RNA-seq analysis of the TSPX-overexpressing NSCLC cell lines revealed that TSPX regulates various genes involved in the cancer-related signaling pathways and cell viability, consistent with the suppression of cell proliferation in cell culture assays. Notably, various potential downstream targets of TSPX that correlated with patient survival (log-rank test, p = 0.016 to 4.3 × 10-10) were identified, including EGFR pathway-related genes AREG, EREG, FOSL1, and MYC, which were downregulated. Conclusions: Our results suggest that TSPX plays a critical role in suppressing NSCLC progression by downregulating pro-oncogenic genes, particularly those in the EGFR signaling pathway, and upregulating the tumor suppressors, especially in lung adenocarcinoma. These findings suggest that TSPX is a potential biomarker and therapeutic target for NSCLC management.
Insights
TSPX, an X-linked tumor suppressor, is downregulated in non-small cell lung cancer (NSCLC). Its restoration suppresses tumor growth and improves survival, identifying TSPX as a potential therapeutic target for NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumor suppressor protein X (TSPX) is an X-linked gene implicated in non-small cell lung cancer (NSCLC).
- Its precise role and regulatory mechanisms in NSCLC progression remain largely uncharacterized.
- This study investigates TSPX function and its downstream targets in NSCLC.
Purpose of the Study:
- To elucidate the functional role of TSPX in non-small cell lung cancer (NSCLC).
- To identify downstream targets regulated by TSPX.
- To correlate TSPX expression with clinical outcomes in NSCLC patients.
Main Methods:
- RNA-sequencing (RNA-seq) and pathway enrichment analyses were performed on TSPX-overexpressing NSCLC cell lines.
- Comparative analysis utilized The Cancer Genome Atlas (TCGA) database for clinical NSCLC specimens.
- Statistical analyses included Wilcoxon signed-rank test and log-rank test for survival analysis.
Main Results:
- TSPX was significantly downregulated in NSCLC tumors compared to adjacent non-cancerous tissues (p < 0.0001).
- Higher TSPX levels correlated with better clinical outcomes and prolonged survival in lung adenocarcinoma (p = 0.0025).
- TSPX overexpression suppressed NSCLC cell proliferation and downregulated pro-oncogenic genes, including EGFR pathway members (AREG, EREG, FOSL1, MYC).
Conclusions:
- TSPX acts as a tumor suppressor in NSCLC by inhibiting pro-oncogenic gene expression.
- TSPX downregulation is linked to advanced cancer stage and poorer prognosis.
- TSPX represents a promising biomarker and therapeutic target for NSCLC management, particularly in lung adenocarcinoma.
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