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Published on: December 13, 2018
LDH-mediated autophagic full-chain blockade for Multiple Myeloma treatment by targeting circ_0008255/miR-192-5p/ATG2A
Zhenhua Wang1,2, Hefei Ren1, Kun Wang3
1Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China.
Abstract:
Multiple myeloma (MM) is an incurable plasma cell malignancy with limited therapeutic options. Although autophagy dysregulation is implicated in MM pathogenesis, its precise regulation, particularly by circular RNAs (circRNAs), is poorly understood. Through clinical RNA sequencing of primary MM patient samples, we identify an autophagy-associated circRNA, circ_0008255, which is markedly upregulated in MM patients and closely correlated with poor disease prognosis. Functional studies reveal that circ_0008255 promotes MM proliferation and tumor growth by enhancing autophagic activity. Mechanistically, it functions as a competitive endogenous RNA for miR-192-5p, leading to elevated expression of the core autophagy protein, autophagy related 2 homolog A (ATG2A). Furthermore, we developed a biomimetic nanoplatform based on layered double hydroxide (LDH) nanosheets coated with myeloma-derived cell membranes for tumor-specific delivery. This system co-delivers siRNA targeting circ_0008255 to suppress autophagosome initiation, while simultaneously leveraging the lysosome-alkalinizing property of LDH to impair autophagosome-lysosome fusion. Together, these actions enforce a synergistic autophagic full-chain blockade, leading to potent antitumor effects in vitro and in vivo. Overall, our study reveals a central regulatory role of circ_0008255 in myeloma autophagy, offering a promising therapeutic paradigm for MM.
Insights
Circular RNAs regulate autophagy in multiple myeloma (MM). Targeting circ_0008255 with a novel nanoplatform blocks autophagy, inhibiting MM tumor growth and offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Multiple myeloma (MM) is an incurable plasma cell cancer with limited treatment options.
- Autophagy dysregulation is implicated in MM, but its regulation by circular RNAs (circRNAs) is unclear.
Purpose of the Study:
- Identify and characterize novel circRNAs involved in MM pathogenesis.
- Investigate the role of circ_0008255 in MM proliferation and autophagy.
- Develop a targeted therapeutic strategy to block autophagy in MM.
Main Methods:
- Clinical RNA sequencing of primary MM patient samples.
- Functional assays to assess circ_0008255's role in MM proliferation and autophagy.
- Mechanistic studies involving miRNA-RNA interactions (circ_0008255/miR-192-5p/ATG2A axis).
- Development of a biomimetic nanoplatform (LDH nanosheets with MM cell membranes) for co-delivery of siRNA and therapeutic agents.
Main Results:
- Identified circ_0008255 as significantly upregulated in MM patients, correlating with poor prognosis.
- Demonstrated that circ_0008255 promotes MM proliferation and tumor growth by enhancing autophagy.
- Elucidated the mechanism: circ_0008255 acts as a sponge for miR-192-5p, increasing ATG2A expression.
- The nanoplatform effectively delivered siRNA to inhibit circ_0008255 and utilized LDH's properties to block autophagy at multiple stages, showing potent antitumor effects.
Conclusions:
- circ_0008255 plays a critical role in regulating autophagy in multiple myeloma.
- A synergistic autophagic blockade strategy using a novel nanoplatform demonstrates significant therapeutic potential against MM.
- This study presents a promising new therapeutic paradigm for treating multiple myeloma.
