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Characterization of mtdsRNA levels in Non-Small Cell Lung Carcinoma (NSCLC)

ABSTRACT: Mitochondrial double-stranded RNA (mtdsRNA) is exported to the cytoplasm when mitochondrial RNA degradation is impaired, serving as a novel Damage-Associated Molecular Pattern (DAMP) for mitochondrial stress. The mtdsRNA has been detected in certain cancers, but its prevalence and functional role remain largely unexplored. Moreover, mtdsRNA is not readily detected in large computational datasets. Here, we used comprehensive computational characterization of NSCLC cell lines and identified elevated light-strand transcription in a subset of cell lines, suggesting a potential for mtdsRNA formation. Our work allowed us to stratify NSCLC lines into groups with high and low mtdsRNA abundance. Despite high cytoplasmic mtdsRNA levels in some lines, we did not observe consistent activation of Type-I interferon (IFN-l) response or ADAR editing. RT-qPCR analysis revealed that only USP18 transcripts were significantly regulated in a subset of NSCLC lines, indicating a partial or suppressed IFN-I response. Strand-specific RT-qPCR also revealed no bias in mitochondrial gene expression to account for this phenomenon. These results suggest that basal mtdsRNA accumulation does not robustly activate IFN-I signaling and may be tolerated in NSCLC. The monoclonal J2 antibody, which detects mtdsRNA, consistently emerged as a reliable marker of intracellular dsRNA burden and could serve as a functional readout of mitochondrial RNA dysregulation. This approach may help stratify tumors based on its immunogenic potential, independent of genomic mutations. Importantly, we report that mtdsRNA is upregulated in a subset of NSCLC cell lines, representing a potential new marker for mitochondrial dysfunction in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319333 | GEO | 2026/02/16

REPOSITORIES: GEO

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Project description:Non-small cell lung cancer (NSCLC) has a poor prognosis and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells, and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater anti-proliferative capacity than specific mitochondrial complex-I inhibitors. The treament downregulated genes mediating hypoxia-inducible factor (HIF)-1a stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of HIF-1a signaling. HIF-1a knockdown and stabilization experiments suggested that canagliflozin mediates anti-proliferative effects, in part, through suppression of HIF-1a. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin’s transcriptional reprogramming. HDAC2 knockdown eliminated HIF-1a levels and enhanced the anti-proliferative effects of canagliflozin. HDAC2-regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.

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Characterization of mtdsRNA levels in Non-Small Cell Lung Carcinoma (NSCLC)

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