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Long Noncoding RNA CRNDE/PRC2 Participated in the Radiotherapy Resistance of Human Lung Adenocarcinoma Through
Ming Zhang1, Change Gao2, Yi Yang1
1Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, P.R. China.
Abstract:
Long noncoding RNAs (lncRNAs), a new class of functional regulators involved in human tumorigenesis, have been attracting the increasing attention of researchers. The lncRNA colorectal neoplasia differentially expressed (CRNDE) gene, transcribed from chromosome 16 on the strand opposite the adjacent IRX5 gene, was originally found to be increased in CRC and was reported to be abnormally expressed in many cancers. However, its potential role and the molecular mechanism underlying the radioresistant phenotype formation of lung adenocarcinoma (LAD) remain unclear. In our present study, we identified that CRNDE was significantly upregulated in LAD tissue and radioresistant LAD cell lines. A high level of CRNDE expression was significantly correlated with poor differentiation, TNM stage, lymph node metastasis, radiotherapy response, and a significantly shorter overall survival. Gain- and loss-of-function tests revealed that CRNDE could influence the radiosensitivity of LAD cells by affecting the G1/S transition and causing apoptosis of LAD cells in vitro. Additionally, the mechanistic investigations showed that CRNDE could interact with PRC2 and recruit its core component EZH2 to p21 (CDKN1A) promoter regions and repress its transcription. Furthermore, rescue experiments were performed to confirm that CRNDE oncogenic function was partly through regulating p21. In conclusion, our data suggest that CRNDE may function as an oncogene by modulating p21, finally contributing to the radioresistant phenotype formation of LAD cells.
Insights
Long noncoding RNA CRNDE promotes radioresistance in lung adenocarcinoma by inhibiting p21 expression. This finding offers potential therapeutic targets for improving lung adenocarcinoma treatment outcomes.
Area of Science:
- Molecular Oncology
- Cancer Biology
- RNA Biology
Background:
- Long noncoding RNAs (lncRNAs) are emerging regulators in human tumorigenesis.
- Colorectal neoplasia differentially expressed (CRNDE) is implicated in various cancers, but its role in lung adenocarcinoma (LAD) radioresistance is unknown.
Purpose of the Study:
- To investigate the role and molecular mechanism of CRNDE in the radioresistant phenotype of LAD.
- To determine the correlation between CRNDE expression and clinical features and prognosis in LAD patients.
Main Methods:
- Quantitative real-time PCR to assess CRNDE expression in LAD tissues and cell lines.
- Gain- and loss-of-function assays to evaluate CRNDE's impact on LAD cell radiosensitivity, cell cycle, and apoptosis.
- Chromatin immunoprecipitation and Western blotting to elucidate the interaction of CRNDE with PRC2/EZH2 and its effect on p21 transcription.
Main Results:
- CRNDE was significantly upregulated in LAD tissues and radioresistant cell lines, correlating with poor differentiation, advanced TNM stage, lymph node metastasis, and shorter survival.
- CRNDE overexpression enhanced LAD cell radioresistance by affecting G1/S transition and apoptosis.
- CRNDE interacted with PRC2 and EZH2 to repress p21 transcription, and CRNDE's oncogenic function was partly mediated by p21 regulation.
Conclusions:
- CRNDE acts as an oncogene in LAD, contributing to radioresistance by modulating p21 expression.
- CRNDE represents a potential biomarker for predicting radiotherapy response and prognosis in LAD.
- Targeting CRNDE may offer a novel therapeutic strategy for overcoming radioresistance in lung adenocarcinoma.
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