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MEG3 is a prognostic factor for CRC and promotes chemosensitivity by enhancing oxaliplatin-induced cell apoptosis
Lixia Li1, Jian Shang1, Yupeng Zhang1
1Department of Gastroenterology/Hepatology, Zhongnan Hospital of Wuhan University, The Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, Hubei 430071, P.R. China.
Abstract:
A major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to oxaliplatin-based chemotherapy. Recently, studies have shown that long non-coding RNAs (lncRNAs) play an important role in drug resistance. Using HiSeq sequencing methods, we identified that lncRNAs show differential expression levels in oxaliplatin-resistant (OxR) and non-resistant CRC patients. RT-qPCR was then performed in tissues and serum samples, and lncRNA MEG3 was verified to be downregulated in non-responding patients and to have considerable discriminating potential to identify responding patients from non-responding patients. Moreover, decreased serum MEG3 expression was associated with poor chemoresponse and low survival rate in CRC patients receiving oxaliplatin treatment. Subsequently, OxR cell lines were established, and MEG3 was significantly downregulated in HT29 OxR and SW480 OxR cells. In addition, overexpression of MEG3 with pMEG3 reversed oxaliplatin resistance in both CRC cell lines. Flow cytometric apoptosis analysis indicated that MEG3 promoted CRC cell apoptosis. More importantly, MEG3 enhanced oxaliplatin‑induced cell cytotoxicity in CRC. In conclusion, our integrated approach demonstrated that decreased expression of lncRNA MEG3 in CRC confers potent poor therapeutic efficacy, and that MEG3 promotes chemosensitivity by enhancing oxaliplatin-induced cell apoptosis. Thus, overexpression of MEG3 may be a future direction by which to develop a novel therapeutic strategy to overcome oxaliplatin resistance of CRC patients.
Insights
Decreased long non-coding RNA MEG3 (lncRNA MEG3) expression in colorectal cancer (CRC) predicts poor response to oxaliplatin chemotherapy. Restoring MEG3 levels may overcome chemoresistance by enhancing oxaliplatin-induced apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemoresistance to oxaliplatin is a primary challenge in advanced colorectal cancer (CRC) treatment.
- Long non-coding RNAs (lncRNAs) are increasingly recognized for their role in modulating drug resistance.
- Identifying molecular markers for chemoresistance is crucial for improving CRC patient outcomes.
Purpose of the Study:
- To investigate the role of lncRNAs in oxaliplatin resistance in colorectal cancer.
- To identify specific lncRNAs that can serve as biomarkers for chemoresponse and therapeutic targets.
- To elucidate the mechanism by which lncRNA MEG3 influences oxaliplatin sensitivity in CRC.
Main Methods:
- HiSeq sequencing to identify differentially expressed lncRNAs in oxaliplatin-resistant (OxR) and non-resistant CRC patients.
- RT-qPCR validation in tumor tissues and serum samples to assess lncRNA MEG3 expression.
- Establishment and analysis of OxR CRC cell lines (HT29 OxR, SW480 OxR).
- In vitro experiments involving MEG3 overexpression (using pMEG3) and flow cytometric apoptosis analysis.
Main Results:
- lncRNA MEG3 was found to be significantly downregulated in oxaliplatin-resistant CRC patients and cell lines.
- Decreased serum MEG3 expression correlated with poor chemoresponse and reduced survival rates.
- Overexpression of MEG3 in CRC cells reversed oxaliplatin resistance and promoted oxaliplatin-induced apoptosis and cytotoxicity.
Conclusions:
- Reduced expression of lncRNA MEG3 is associated with poor therapeutic efficacy in oxaliplatin-treated CRC patients.
- MEG3 enhances chemosensitivity by promoting oxaliplatin-induced apoptosis in colorectal cancer cells.
- Therapeutic strategies involving MEG3 restoration hold potential for overcoming oxaliplatin resistance in CRC.
