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RAN contributes to bortezomib resistance in multiple myeloma via regulating the Wnt/PCP pathway
Linmeng Li1, Lu Xu2
1Department of Clinical Laboratory, Zhuji People's Hospital of Zhejiang Province, Zhejiang, China.
Abstract:
Previous studies have shown that Ras-Related Nuclear Protein (RAN), a member of the RAS superfamily, is a small GTPase and an important oncogene in several cancers. However, its role in multiple myeloma (MM) and its potential contribution to drug resistance remain undetermined. Bioinformatics was employed to analyze differentially expressed genes in MM samples. RT-qPCR and western blotting were utilized for protein transcription and expression analysis. The CCK-8 assay was adopted to evaluate cell proliferation, and in vivo animal experiments were conducted to validate the results. The findings reveal that RAN represents one of the most significantly aberrant genes in MM, with its expression significantly elevated in both MM tissues and cells. Genetic manipulation experiments demonstrated that RAN promotes MM cell proliferation by activating the Wnt/PCP pathway. Concurrently, RAN governs the response of MM cells to the anti-cancer drug bortezomib (BTZ). Knockdown of RAN leads to increased sensitivity to BTZ. Mechanistic studies indicate that RAN influences drug response by regulating the activation of the JNK/c-Jun axis, thereby affecting the therapeutic response of MM cells. In summary, the upregulated expression of RAN in MM leads to BTZ resistance via activation of the Wnt/PCP pathway, potentially serving as a novel therapeutic target for MM.
Insights
Ras-Related Nuclear Protein (RAN) is upregulated in multiple myeloma (MM), promoting cancer growth and resistance to bortezomib (BTZ) by activating the Wnt/PCP pathway. Targeting RAN could offer a new therapeutic strategy for MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ras-Related Nuclear Protein (RAN), a RAS superfamily GTPase, is implicated as an oncogene in various cancers.
- The specific role of RAN in multiple myeloma (MM) and its impact on drug resistance are not well understood.
Purpose of the Study:
- To investigate the role of RAN in the development and progression of multiple myeloma.
- To determine the effect of RAN on bortezomib (BTZ) resistance in MM.
- To elucidate the molecular mechanisms by which RAN influences MM cell proliferation and drug response.
Main Methods:
- Bioinformatic analysis of differentially expressed genes in MM samples.
- Quantitative reverse transcription PCR (RT-qPCR) and Western blotting for gene and protein expression analysis.
- Cell proliferation assays (CCK-8) and in vivo animal studies to validate findings.
Main Results:
- RAN expression is significantly elevated in MM tissues and cells, identifying it as a key aberrant gene.
- RAN promotes MM cell proliferation via activation of the Wnt/PCP pathway.
- RAN knockdown increases MM cell sensitivity to bortezomib (BTZ) by regulating the JNK/c-Jun axis.
Conclusions:
- Upregulated RAN in MM contributes to bortezomib (BTZ) resistance through Wnt/PCP pathway activation.
- RAN influences drug response by modulating the JNK/c-Jun signaling pathway.
- RAN represents a potential novel therapeutic target for overcoming bortezomib (BTZ) resistance in multiple myeloma.
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