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c-Rel is a Novel Oncogene in Lung Squamous Cell Carcinoma Regulating Cell Proliferation and Migration
Renru Luo1, Qiongyu Liu1, Zheyu Hu1
1Department of histology and embryology, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China.
Abstract:
Lung squamous cell carcinoma (LUSC) accounts for approximately 25% to 30% of lung cancers, but largely no targeted therapy is available against it, calling for identification of new oncogenes in LUSC growth for new therapeutic targets. In this study, REL was identified through a screening for oncogenes that are highly amplified in human LUSC. Its expression was associated with poor prognosis in LUSC patients. Furthermore, knockdown of c-Rel in LUSC cell lines lead to significant decrease in cell proliferation and migration. Mechanistically, c-Rel knockdown suppressed NFκB pathway by blocking phosphorylation of IκB. Consistently, pharmaceutic inhibition of c-Rel also. In orthotopic xenograft lung cancer mouse model, c-Rel knockdown inhibited the tumor growth. Cancer cell proliferation and epithelial-mesenchymal-transition (EMT) of the tumors were impaired by c-Rel knockdown. Finally, it's confirmed in precision-cut tumor slices of LUSC that deletion of c-Rel inhibits the NFκB pathway and cancer cell growth. Accordingly, we hypothesize that c-Rel promotes the activation of the NFκB pathway by promoting the phosphorylation of IκB in LUSC. Our study reveals REL as a novel LUSC oncogene and provides new insights into the molecular regulation of LUSC, which will provide new therapeutic targets for the treatment of squamous lung cancer.
Insights
The study identifies REL as a novel oncogene driving lung squamous cell carcinoma (LUSC) growth. Inhibiting REL, a key driver of the NFκB pathway, significantly reduces LUSC progression and offers new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Lung squamous cell carcinoma (LUSC) lacks targeted therapies, necessitating the discovery of new oncogenes.
- Identifying novel oncogenes is crucial for developing effective LUSC treatments.
Purpose of the Study:
- To identify and characterize novel oncogenes involved in LUSC development.
- To investigate the role of the identified oncogene, REL, in LUSC cell proliferation, migration, and the NFκB pathway.
- To evaluate REL as a potential therapeutic target for LUSC.
Main Methods:
- Screening for amplified oncogenes in human LUSC.
- Gene knockdown and pharmaceutical inhibition of REL in LUSC cell lines and xenograft models.
- Analysis of NFκB pathway activation (IκB phosphorylation).
- Assessment of cell proliferation, migration, and epithelial-mesenchymal-transition (EMT).
- Validation in precision-cut tumor slices.
Main Results:
- REL was identified as a highly amplified oncogene in LUSC, associated with poor prognosis.
- Knockdown of c-Rel significantly decreased LUSC cell proliferation and migration.
- c-Rel inhibition suppressed the NFκB pathway by blocking IκB phosphorylation.
- Tumor growth, proliferation, and EMT were impaired in vivo and in tumor slices upon c-Rel knockdown.
- REL promotes LUSC via NFκB pathway activation.
Conclusions:
- REL is a novel oncogene that drives LUSC growth and progression.
- Targeting REL and the NFκB pathway presents a promising therapeutic strategy for LUSC.
- This study provides new insights into LUSC molecular regulation and potential treatment avenues.
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