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METTL3-mediated TUG1 regulation of miR-9 in doxorubicin resistance in HCC
Enliang Li1, Rongshou Wu1, Yuexiao Tang2
1Department of General Surgery, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China.
Aims:
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant human tumors and a main cause of cancer death worldwide. Drug resistance limits the use of doxorubicin (DOX), a proliferation inhibitor used to treat HCC. This study aims to reveal the molecular mechanisms underlying DOX resistance and develop more effective therapies for HCC.
Materials And Methods:
An N6-methyladenosine (m6A) RNA immunoprecipitation sequencing-quantitative real-time polymerase chain reaction experiment was performed to assess m6A RNA methylation in HCC cells. A patient-derived xenograft mouse model was established to investigate the function of a chimeric peptide supramolecular nanoparticle system (SP94 dR/ miR-9 nanoparticles) in vivo.
Results:
We found that the expression levels of METTL3 and TUG1 were upregulated in HCC, which was closely related to poor overall survival. Moreover, METTL3 and TUG1 depletion increased HCC cell sensitivity to DOX. METTL3 silencing repressed TUG1 expression in an m6A-dependent manner. Meanwhile, TUG1 depletion sensitized HCC cells to DOX via EIF5A2 by upregulating miR-9. Furthermore, SP94-dR/miR-9 nanoparticles dramatically enhanced HCC cell sensitivity to DOX by regulating autophagy in vitro and inhibiting tumor growth in vivo.
Significance:
Our data identified a novel molecular pathway comprising the METTL3-m6A-TUG1-miR-9-EIF5A2 signaling axis in HCC, providing new targets for future DOX resistance management.
Insights
Researchers identified a new molecular pathway involving METTL3, m6A, TUG1, miR-9, and EIF5A2 that drives doxorubicin resistance in hepatocellular carcinoma (HCC). This discovery offers novel therapeutic targets for overcoming drug resistance in HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally.
- Doxorubicin (DOX) resistance significantly limits treatment efficacy for HCC patients.
Purpose of the Study:
- To elucidate the molecular mechanisms behind DOX resistance in HCC.
- To identify novel therapeutic targets for enhancing DOX sensitivity in HCC.
Main Methods:
- Utilized N6-methyladenosine (m6A) RNA immunoprecipitation sequencing and qRT-PCR to analyze m6A RNA methylation in HCC cells.
- Established a patient-derived xenograft mouse model to evaluate the in vivo efficacy of SP94-dR/miR-9 nanoparticles.
Main Results:
- Upregulated METTL3 and TUG1 expression correlated with poor HCC survival.
- METTL3 and TUG1 depletion enhanced HCC cell sensitivity to DOX.
- METTL3 positively regulated TUG1 via m6A modification.
- TUG1 depletion sensitized HCC cells to DOX by upregulating miR-9 and EIF5A2.
- SP94-dR/miR-9 nanoparticles improved DOX sensitivity by modulating autophagy and inhibiting tumor growth.
Conclusions:
- Identified a novel METTL3-m6A-TUG1-miR-9-EIF5A2 signaling axis crucial for DOX resistance in HCC.
- This pathway represents a promising target for developing strategies to overcome DOX resistance in HCC management.
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