Involvement of Circulating Cell-Free Mitochondrial DNA and Proinflammatory Cytokines in Pathogenesis of Chronic Obstructive Pulmonary Disease and Lung Cancer

Abstract

Objective: Circulating cell-free mitochondrial DNA (cf-MtDNA) has been reported in patients with chronic obstructive pulmonary disease (COPD) and lung cancers. However, inter-relationships among the three biological events have not been well-characterized. Therefore, our investigation was conducted to better understand the role of cf-MtDNA on pathogenesis of the two diseases. Methods: Plasma samples were collected from 64 non-small cell lung cancer (NSCLC) patients (before therapy), 45 patients with COPD and 62 healthy individuals. cf-MtDNA copy numbers were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and cytokines were determined using a human ELISA kit. Results: Our data indicate that smoking statuses of the patients and controls were significantly associated with increased cf-MtDNA in plasma samples. Furthermore, NSCLC patients had significantly higher cf-MtDNA copy numbers than COPD patients (p < 0.03) and normal controls (p < 0.02), together with elevated proinflammatory cytokines over the controls (p < 0.05). Our study shows that the copy numbers for the NSCLC patients were positively associated with their subsequent metastasis but inversely associated with their overall survival. Conclusion:Our study indicates certain lung injury (e.g., from cigarette smoking) was responsible for the release of cf-MtDNA and proinflammatory cytokines into plasmas among our patients and controls. The increase in cf-MtDNA copy numbers was significantly associated with the development of both COPD and NSCLC, with increase in interleukin 6, and from our 5-year follow-up, with poor prognosis among the NSCLC patients. Therefore, with further validation, cf-MtDNA can be considered for use as diagnostic and prognostic biomarkers for NSCLC.

The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation

“…The mtDNA deletion is Δ-mtDNA 4977 , the most commonly considered a somatic mutation, which increases with age during the progression of mitochondrial dysfunction [ 63 ]. Free-circulating mtDNA (cf-mtDNA) is another favored non-invasive biomarker for multiple diseases; for example, it has been used to diagnose various cancers [ 64 , 65 , 66 , 67 ]. Recently, cf-mtDNA has been used as a predictive marker of the age-related phenotype [ 68 , 69 , 70 ].…”

The Role of Mitochondrial miRNAs in the Development of Radon-Induced Lung Cancer

“…With the growth of lung tumors, mtDNA depletion is also observed, which was associated with a low metastatic potential and an unfavorable prognosis of survival for patients with lung cancer [ 132 ]. However, as for freely circulating mtDNA, it is worth noting that in the case of exposure to aggressive factors, such as tobacco smoke, radon, or asbestos, an increase in the level of cf-MtDNA and proinflammatory cytokines in the plasma of patients with NSCLC occurs, which correlates with the poor prognosis of the survival rate [ 133 ]. It was noted that cf-mtDNA levels increased in patients with radon-induced lung cancer and in healthy donors living in areas with high radon levels [ 134 ].…”

Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers in cancer patients

“…Recently, amounting studies have con rmed the presence of tumor-derived circulating cell free mtDNA (ccf-mtDNA) in patients with many types of cancer [20][21][22] . Moreover, several studies have revealed the remarkably smaller fragment size of ccf-mtDNA when compared with ccf-nDNA 23 , and shown signi cantly increased copy numbers in hepatocellular carcinoma 23 , lung cancer 24 , breast cancer 25 and colorectal cancer 26 .…”