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HHLA3 Silencing Suppresses KRAS-Mutant Non-Small-Cell Lung Cancer Cell Progression Through Triggering MYEOV-Mediated
Zhimiao Tang1, Jia Ye1, Dong Chen1
1Department of Cardiothoracic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine (Jinhua Central Hospital), Jinhua, Zhejiang, China.
Abstract:
KRAS mutation is one of the most common mutational events in non-small-cell lung cancer (NSCLC). However, due to the complex signaling pathways and high biological heterogeneity of KRAS-mutant NSCLC, the current clinical treatment for patients with KRAS mutations still faces many difficulties. The oncogenic effector in KRAS-mutant NSCLC was screened using GEO data sets. CCK-8, colony formation, transwell, and flow cytometry were conducted to assess the malignant phenotype of KRAS-mutant NSCLC cells. The indicators intracellular Fe2+, ROS, GSH, and MDA levels were employed to reflect the ferroptosis of cells. The mechanism of myeloma overexpressed (MYEOV) in KRAS-mutant NSCLC was explored from the perspective of noncoding RNA (ncRNA) and validated by rescue experiments. MYEOV presented a high expression trend in KRAS-mutant NSCLC specimens. MYEOV silencing effectively repressed the malignant phenotype and promoted ferroptosis of NSCLC cells carrying KRAS mutations. Based on bioinformation analysis and a series of rescue experiments, we established the HHLA3/miR-139-5p/MYEOV regulatory network in KRAS-mutant NSCLC cells and disclosed that HHLA3 served as a molecular sponge for miR-139-5p to regulate MYEOV expression. The mechanism of MYEOV and its ncRNA network affecting the progression of KRAS-mutant NSCLC revealed in this study intends to provide a theoretical basis for KRAS-mutant NSCLC treatment.
Insights
Myeloma overexpressed (MYEOV) drives KRAS-mutant non-small-cell lung cancer (NSCLC) progression. Targeting the HHLA3/miR-139-5p/MYEOV network may offer new therapeutic strategies for NSCLC patients with KRAS mutations.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- KRAS mutations are frequent in non-small-cell lung cancer (NSCLC), presenting significant therapeutic challenges due to complex signaling and heterogeneity.
- Identifying novel oncogenic drivers and regulatory networks is crucial for developing effective treatments for KRAS-mutant NSCLC.
Purpose of the Study:
- To screen oncogenic effectors in KRAS-mutant NSCLC using GEO datasets.
- To investigate the role of myeloma overexpressed (MYEOV) and its noncoding RNA (ncRNA) regulatory network in KRAS-mutant NSCLC progression.
- To explore potential therapeutic targets for KRAS-mutant NSCLC.
Main Methods:
- Bioinformatic screening of GEO datasets to identify oncogenic effectors.
- In vitro assays (CCK-8, colony formation, Transwell, flow cytometry) to assess cellular phenotypes.
- Measurement of intracellular indicators (Fe2+, ROS, GSH, MDA) to evaluate ferroptosis.
- Rescue experiments to validate the regulatory network (HHLA3/miR-139-5p/MYEOV).
Main Results:
- MYEOV was found to be highly expressed in KRAS-mutant NSCLC specimens.
- Silencing MYEOV inhibited the malignant phenotype and induced ferroptosis in KRAS-mutant NSCLC cells.
- A regulatory network HHLA3/miR-139-5p/MYEOV was established, with HHLA3 acting as a molecular sponge for miR-139-5p to modulate MYEOV expression.
Conclusions:
- MYEOV plays a critical role in the progression of KRAS-mutant NSCLC.
- The HHLA3/miR-139-5p/MYEOV regulatory axis influences KRAS-mutant NSCLC malignancy and ferroptosis.
- This study provides a theoretical basis for targeting MYEOV and its ncRNA network in KRAS-mutant NSCLC treatment.
