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Long noncoding RNA TOB1-AS1, an epigenetically silenced gene, functioned as a novel tumor suppressor by sponging
Jihang Yao1, Zhenghong Li1, Ziwei Yang2
1Department of Gynecology, The First Hospital of China Medical University Shenyang 110001, Liaoning, China.
Abstract:
Cervical cancer is one of the most common cancers in females, accounting for a majority of cancer-related deaths in worldwide. Long non-coding RNAs (lncRNAs) have been identified as critical regulators in many tumor-related biological processes. Thus, investigation into the function and mechanism of lncRNAs in the development of cervical cancer is very necessary. In this study, we found that the expression of TOB1-AS1 was significantly decreased in cervical cancer tissues compared with the adjacent normal tissues. The methylation status of TOB1-AS1-related CpG island was analyzed using methylation specific PCR and bisulfite sequencing analysis, revealing that the aberrant hypermethylation of TOB1-AS1-related CpG island was frequently observed in primary tumors and cervical cancer cells. The expression of TOB1-AS1 in cervical cancer cells could be reversed by demethylation agent treatment. Functionally, overexpression of TOB1-AS1 significantly inhibited cell proliferation, cell cycle progression, invasion and induced apoptosis, while knockdown of TOB1-AS1 exhibited the opposite effect. Furthermore, it was determined that TOB1-AS1 was able to bind and degrade the expression of miR-27b. Upregulation of miR-27b promoted cell growth, cell cycle transition from G1 phase to S phase, and invasion and reduced apoptosis, phenomenon could be reversed by TOB1-AS1. Inhibition of miR-27b attenuated the promotive effect of si-TOB1-AS1 on cellular processes. Upregulation of TOB1-AS1 also suppressed tumor growth in vivo. Clinically, methylation of TOB1-AS1 and low expression of TOB1-AS1 was significantly correlated with tumor stage and tumor size, respectively. Univariate and multivariate analyses confirmed that low level of TOB1-AS1 was an independent risk factor for death. In conclusion, we suggested that the epigenetically silenced TOB1-AS1 was unable to restrain miR-27b, which contributed to cervical cancer progression.
Insights
Epigenetically silenced TOB1-AS1, a long non-coding RNA, promotes cervical cancer progression by failing to suppress miR-27b. Restoring TOB1-AS1 inhibits tumor growth and improves patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Cervical cancer is a leading cause of cancer-related deaths globally.
- Long non-coding RNAs (lncRNAs) are crucial regulators in cancer development.
- Understanding lncRNA mechanisms in cervical cancer is essential.
Purpose of the Study:
- Investigate the role and mechanism of TOB1-AS1 in cervical cancer.
- Determine the relationship between TOB1-AS1, miR-27b, and cervical cancer progression.
- Evaluate TOB1-AS1 as a potential biomarker and therapeutic target.
Main Methods:
- Analysis of TOB1-AS1 expression in cervical cancer tissues and cell lines.
- Methylation-specific PCR and bisulfite sequencing to assess CpG island methylation.
- In vitro functional assays (proliferation, cell cycle, invasion, apoptosis) upon TOB1-AS1 manipulation.
- In vivo tumor growth assays.
- Correlation analysis between TOB1-AS1 methylation/expression and clinical parameters.
Main Results:
- TOB1-AS1 expression was significantly decreased in cervical cancer tissues due to aberrant hypermethylation.
- Overexpression of TOB1-AS1 inhibited proliferation, invasion, and promoted apoptosis; knockdown had opposite effects.
- TOB1-AS1 directly targeted and degraded miR-27b; miR-27b promoted cervical cancer progression.
- Low TOB1-AS1 expression correlated with advanced tumor stage and size, and was an independent risk factor for mortality.
- Upregulation of TOB1-AS1 suppressed tumor growth in vivo.
Conclusions:
- Epigenetic silencing of TOB1-AS1 by hypermethylation contributes to cervical cancer progression.
- The TOB1-AS1/miR-27b axis plays a critical role in regulating cervical cancer cell behavior.
- TOB1-AS1 is a potential prognostic biomarker and therapeutic target for cervical cancer.
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