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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Clinical Relevance and Tumor Growth Suppression of Mitochondrial ROS Regulators along NADH:Ubiquinone Oxidoreductase
Jiao Zhu1, Xiaobo Zheng2, Dan Lu1
1Department of Otorhinolaryngology Head & Neck Surgery, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
Mitochondrial reactive oxygen species (mitoROS) are a double-edged sword in cancer progression, connoting the ROS-dependent malignant transformation and the oxidative stress-induced cell death. However, the underlying role of mitoROS in thyroid cancer remains unclear. Here, we collected 35 prominent mitoROS regulators to stratify 510 thyroid cancer patients in TCGA cohort through consensus clustering. Three molecular subtypes (cluster 1/2/3) were identified, among which cluster 1 (mitoROSlow) was preferentially associated with unfavorable prognosis. Individually, there were 12 regulators with a high expression that predicted a significantly favorable progression-free survival. The NADH:Ubiquinone Oxidoreductase Subunit B3 (NDUFB3) had a highest impact. NDUFB3 knockdown significantly reduced mitoROS levels in BCPAP and C643 cells. Bioinformatically, the consistency between NDUFB3 expression and cluster 1/2/3 was confirmed; lower expression of NUDFB3 was associated with a poor clinical outcome. Pathway analysis of differentially expressed genes in the NDUFB3low and NDUFB3high cohorts revealed a predominance of oxidative phosphorylation pathway changes. Consistently, mitochondrial functions, including oxygen consumption rate, ATP levels, complex I activity, mitoROS levels, and the expression of mitochondrially encoded NADH:Ubiquinone oxidoreductase core subunit 5, were significantly increased in NDUFB3-overexpressed BCPAP cells or C643 cells. The in vivo NDUFB3 overexpression and sideroxylin treatment significantly suppressed tumor growth and prolonged survival, concurrently elevating mitoROS levels ex vivo in mouse xenograft models. Conversely, NDUFB3 knockdown had the opposite effect. Together, these findings implicated the importance of mitoROS regulators in predicting clinical outcomes of patients with thyroid cancer. Our findings may pave the way for developing a mitoROS-based treatment for thyroid cancer patients.
Insights
Mitochondrial reactive oxygen species (mitoROS) play a complex role in thyroid cancer. NDUFB3, a mitoROS regulator, predicts patient outcomes and influences tumor growth, suggesting potential for mitoROS-based therapies.
Area of Science:
- Oncology
- Mitochondrial Biology
- Cancer Genomics
Background:
- Mitochondrial reactive oxygen species (mitoROS) have dual roles in cancer, promoting malignancy and cell death.
- The specific involvement of mitoROS in thyroid cancer progression is not well understood.
Purpose of the Study:
- To investigate the role of mitoROS regulators in thyroid cancer.
- To identify molecular subtypes based on mitoROS regulators and assess their prognostic significance.
- To explore the function of NADH:Ubiquinone Oxidoreductase Subunit B3 (NDUFB3) in thyroid cancer.
Main Methods:
- Consensus clustering of 510 thyroid cancer patients using 35 mitoROS regulators from TCGA.
- Analysis of gene expression, clinical outcomes, and pathway enrichment.
- Experimental validation using cell lines (BCPAP, C643) and mouse xenograft models, involving NDUFB3 knockdown/overexpression and sideroxylin treatment.
Main Results:
- Three molecular subtypes were identified, with a low mitoROS subtype (cluster 1) associated with unfavorable prognosis.
- High expression of 12 mitoROS regulators, notably NDUFB3, predicted favorable progression-free survival.
- NDUFB3 overexpression suppressed tumor growth and prolonged survival by increasing mitoROS, while NDUFB3 knockdown had opposite effects.
Conclusions:
- MitoROS regulators are crucial for predicting thyroid cancer outcomes.
- NDUFB3 is a key player in thyroid cancer progression, influencing mitochondrial function and tumor growth.
- Targeting mitoROS pathways, particularly involving NDUFB3, may offer novel therapeutic strategies for thyroid cancer.
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