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miR-335 Restrains the Aggressive Phenotypes of Ovarian Cancer Cells by Inhibiting COL11A1
Yi-Hui Wu1,2, Yu-Fang Huang3, Tzu-Hao Chang4
1Department of Medical Research, Chi Mei Medical Center, Liouying, Tainan 736, Taiwan.
Abstract:
High collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. MicroRNAs (miRNAs) are dysregulated in multiple cancers, including epithelial ovarian carcinoma (EOC); however, the regulation of COL11A1 by miRNAs in EOC remains unclear. We examined the role of miRNAs in regulating COL11A1 expression. We identified miR-509 and miR-335 as the candidate miRNAs through an online database search. EOC cell treatment with miR-335 mimics abrogated COL11A1 expression and suppressed cell proliferation and invasion, besides increasing the sensitivity of EOC cells to cisplatin. Conversely, treatment with miR-335 inhibitors prompted cell growth/invasiveness and chemoresistance of EOC cells. miR-335 inhibited COL11A1 transcription, thus reducing the invasiveness and chemoresistance of EOC cells via the Ets-1/MMP3 and Akt/c/EBPβ/PDK1 axes, respectively. Furthermore, it did not directly regulate PDK1 but increased PDK1 ubiquitination and degradation through COL11A1 inhibition. In vivo findings highlighted significantly decreased miR-335 mRNA expressions in EOC samples. Furthermore, patients with low miR335 levels were susceptible to advanced-stage cancer, poor response to chemotherapy, and early relapse. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.
Insights
MicroRNA-335 (miR-335) suppresses ovarian cancer progression by downregulating collagen type XI alpha 1 (COL11A1). Lower miR-335 levels correlate with advanced cancer, chemoresistance, and relapse, suggesting miR-335 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- High collagen type XI alpha 1 (COL11A1) expression is linked to tumor progression and poor survival in various cancers.
- MicroRNA (miRNA) dysregulation is common in epithelial ovarian carcinoma (EOC), but COL11A1 regulation by miRNAs in EOC is not well understood.
Purpose of the Study:
- To investigate the role of miRNAs in regulating COL11A1 expression in epithelial ovarian carcinoma (EOC).
- To explore the therapeutic potential of miR-335 in EOC treatment.
Main Methods:
- Bioinformatic analysis to identify candidate miRNAs targeting COL11A1.
- In vitro experiments using EOC cell lines treated with miR-335 mimics and inhibitors.
- Analysis of signaling pathways (Ets-1/MMP3, Akt/c/EBPβ/PDK1) involved in miR-335-mediated regulation.
- In vivo studies using EOC patient samples.
Main Results:
- miR-335 mimics reduced COL11A1 expression, suppressed EOC cell proliferation and invasion, and enhanced cisplatin sensitivity.
- miR-335 inhibitors increased EOC cell growth, invasiveness, and chemoresistance.
- miR-335 targets COL11A1 transcription, impacting Ets-1/MMP3 and Akt/c/EBPβ/PDK1 pathways, and promotes PDK1 degradation.
- Lower miR-335 mRNA levels in EOC tissues correlated with advanced stage, poor chemotherapy response, and early relapse.
Conclusions:
- miR-335 plays a crucial role in inhibiting COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival.
- miR-335 demonstrates potential as a therapeutic target for epithelial ovarian carcinoma.
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