Circulating Cell-Free mtDNA Content as a Non-invasive Prognostic Biomarker in HCC Patients Receiving TACE and Traditional Chinese Medicine

Abstract

Hepatocellular carcinoma (HCC) accounts for 70–85% of liver cancer, and about 85% of HCC are hepatitis B virus-related (HBV-HCC) in China. Transarterial chemoembolization (TACE) combined with traditional Chinese medicine (TCM) has been reported as an effective treatment. Potential biomarkers to stratify patients who may benefit from this treatment are needed. In this study, we aimed to evaluate whether circulating cell-free mitochondrial DNA (ccf-mtDNA) content was associated with the outcome of HCC patients, especially of those who received the combination treatment of TACE and TCM. Univariate and multivariate Cox analyses were conducted to evaluate the association between ccf-mtDNA content and the overall survival of HBV-HCC patients. Kaplan–Meier analysis was used to compare the survival differences between patients with low and high ccf-mtDNA content. In a hospital-based cohort with 141 HBV-HCC patients, there was no statistically significant association between the ccf-mtDNA content and the overall survival of HBV-HCC patients in the univariate analysis, but a borderline significant association was found in the multivariate analyses. In a subcohort of 50 HBV-HCC patients who received TACE and TCM treatment, high ccfDNA content conferred an increased death risk with a hazard ratio of 4.01 (95% confidence interval: 1.25–12.84, p = 0.019) in the multivariate analysis. Kaplan–Meier survival analysis also showed that patients with high ccf-mtDNA content had unfavorable survival (log rank p = 0.097). Our findings suggest that ccf-mtDNA content is a potential non-invasive prognostic biomarker in HCC patients receiving TACE and TCM treatment.

Artificial intelligence as a ploy to delve into the intricate relationship between genetics and mitochondria in MASLD patients

“…Moreover, a huge percentage of mtDNA mutations in D-loop region, enhancing mtDNA-CN, negatively associated with HCC clinicopathological profile (32,33). Similarly, serum ccf-mtDNA fragments derived from respiratory chain raised in MASH patients, particularly in those with significant fibrosis, and were proposed as prognostic tumoral markers (34)(35)(36).…”

Common methods in mitochondrial research (Review)

“…Moreover, after the mitochondria are separated from cells or tissues, the dNA in the remaining material is extracted (kits can be used) and the dNA of the sample can be sequenced. qPcR or chromatin immunoprecipitation (chIP) experimental methods can be used to detect the level of ccF-mtdNA, among which chIP is often used to verify the binding of mtdNA to downstream signaling pathways, such as TLR9 inflammatory pathway or cGAS signaling pathway (335,(363)(364)(365)(366)(367)(368)(369)(370)(371). As a dNA sensor in the cytoplasm, cGAS can recognize ccF-mtdNA and then catalyze the formation of the second messenger cGAMP (2'3'-cGAMP) to activate the interferon-stimulated gene-dependent signaling pathway.…”

Targeting mitochondria in dermatological therapy: beyond oxidative damage and skin aging

“…Information Classification: General As our understanding of the complexity and profound impact of mitochondrial function/dysfunction on tissue physiology is rapidly expanding (Table 1), it becomes critical to also explore extracellular, paracrine and long-distance effects of mitochondrial activities, such as the release of mitochondrial DNA (mtDNA) into the extracellular space and circulation, especially in human physiology and pathology. For example, we now know that the accumulation of dysfunctional mitochondria and release of mtDNA into the cytoplasm and out into the extracellular milieu and circulation can activate a myriad of pattern recognition receptors and innate immune responses [54][55][56][57]. Again, human skin and skin appendage organ culture are ideal assay systems at this emerging mitochondrial research front.…”