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CircVPRBP inhibits nodal metastasis of cervical cancer by impeding RACK1 O-GlcNAcylation and stability
Chunyu Zhang1, Hongye Jiang1, Li Yuan1
1Department of Obstetrics and Gynecology, the First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China.
Abstract:
Lymph node (LN) metastasis is one of the most malignant clinical features in patients with cervical cancer (CCa). Understanding the mechanism of lymph node metastasis will provide treatment strategies for patients with CCa. Circular RNAs (circRNA) play a critical role in the development of human cancers. However, the role and mechanism of circRNAs in lymph node metastasis remain largely unknown. Here, it is reported that loss expression of circRNA circVPRBP was closely associated with LN metastasis and poor survival of CCa patients. In vitro and in vivo assays showed that circVPRBP overexpression notably inhibited lymphangiogenesis and LN metastasis, whereas RfxCas13d mediated silencing of circVPRBP promoted lymphangiogenesis and the ability of the cervical cancer cells to metastasize to the LNs. Mechanistically, circVPRBP could bind to RACK1 and shield the S122 O-GlcNAcylation site to promote RACK1 degradation, resulting in inhibition of Galectin-1 mediated lymphangiogenesis and LN metastasis in CCa. Taken together, the results demonstrate that circVPRBP is a potential prognostic biomarker and a novel therapeutic target for LN metastasis in CCa patients.
Insights
Loss of circVPRBP expression correlates with lymph node metastasis in cervical cancer. Restoring circVPRBP inhibits cancer spread by affecting lymphangiogenesis and RACK1 degradation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Lymph node (LN) metastasis is a critical factor in cervical cancer (CCa) progression and patient survival.
- Circular RNAs (circRNAs) are implicated in various cancers, but their role in CCa lymph node metastasis is not well understood.
Purpose of the Study:
- To investigate the role and mechanism of circVPRBP in cervical cancer lymph node metastasis.
- To determine if circVPRBP can serve as a prognostic biomarker or therapeutic target for CCa.
Main Methods:
- In vitro and in vivo experiments were conducted to assess the function of circVPRBP.
- RfxCas13d was used for circVPRBP silencing.
- Mechanistic studies involved investigating the interaction between circVPRBP, RACK1, and Galectin-1.
Main Results:
- Reduced circVPRBP expression was significantly associated with LN metastasis and poorer survival in CCa patients.
- Overexpression of circVPRBP suppressed lymphangiogenesis and LN metastasis.
- Silencing circVPRBP promoted lymphangiogenesis and metastasis.
- Mechanistically, circVPRBP binds RACK1, preventing O-GlcNAcylation and subsequent degradation, thereby inhibiting Galectin-1 mediated lymphangiogenesis and metastasis.
Conclusions:
- circVPRBP acts as a tumor suppressor in CCa lymph node metastasis.
- circVPRBP is a potential prognostic biomarker for CCa.
- circVPRBP represents a novel therapeutic target for inhibiting CCa LN metastasis.
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