ANALYSIS OF THE MITOCHONDRIAL 4977 bp DELETION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA
Guo ZS1,§,*, Jin CL2,§, Yao ZJ1, Wang YM1, Xu BT3,* §The first two authors contributed equally for this study.
*Corresponding Author: Dr. Zhen-Shan Guo or Dr. Bo-Tao Xu, Zhuji People’s Hospital, Jianmin Road 9, Taozhu Street, Shaoxing, 311800, People’s Republic of China. Tel./Fax: +86-0575-81782103. E-mail: Dr. Zhen-Shan Guo: guozs001@126.com; Dr. Bo-Tao Xu: 375640722@qq.com
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DISCUSSION

In the present study, we investigated the frequency of the mtDNA 4977 bp deletion in patients with HCC. The mtDNA mutations have been implicated in various human diseases including cancer [11], a long-term process that involves multiple steps driven by different genetic and epigenetic alternations. Among these, the 4977 bp deletion is one of the first described and most studied mtDNA mutations, Kao et al. [12] initially demonstrated that two 13 bp direct repeats, present at nucleotides (nts) 8470-8482 and 13447-13459 bp position, which are prone to 4977 bp deletion in mtDNA [12]. Both animal studies and cell model analysis showed the mtDNA 4977 bp deletion played an important role during the course of tumorigenesis [13,14]. However, the results of various studies dissecting the role of this mutation in cancer development are conflicting. For example, the study of Ye et al. [15] found there was no correlation between the common mtDNA 4977 bp deletion and cancer risk, while Tseng et al. [16] demonstrated that the detection frequency of common deletions was higher in adjacent normal tissue than carcinoma tissue in their 60 breast cancer patients from Taiwan. In this study, we found a positive correlation between mtDNA 4977 bp deletion and HCC, we noticed that this mutation had a high frequency in HCC patients (9.52%), whereas this deletion was absent in healthy subjects and normal tissues, suggesting that the 4977 bp deletion may served as a molecular marker for HCC. Mitochondrial DNA depletion had been associated with infantile neurogenetic disorders that caused unexplained weakness, hypotonia and developmental delays in early childhood [17]. Moreover, alternations in mtDNA content had been reported in many types of cancer, and multiple mechanisms had been proposed including deregulation of mtDNA replication [18,19]. Loss of mtDNA copy number control was associated with aging and was likely to be linked to either nuclear or mtDNA mutations [20]. In the current study, we found that, compared with the healthy subjects, the mtDNA content in HCC patients was much higher possibly due to increased oxidative damage to the replication machinery [21,22]. Because the common mtDNA deletion has been suggested as an indicator of oxidative damage, we further investigated the generation of ROS in blood samples of HCC and healthy controls. The ROS in mitochondria were by-products of the β oxidation pathway for fatty acid metabolism and they were generated via electron leakage from mitochondrial electron transport resulting in the activation of oncogenic pathways [23]. In our study, we showed that the ROS level was higher in HCC patients than those matched control individuals (Figure 3). At lower concentrations, ROS were important signaling molecules involved in cellular proliferation, migration, and apoptosis [24,25]. However, at higher concentrations, these molecules could be useful against pathogens, resulting in increased leukocyte and platelet activation, and increased leukocyte recruitment [26], which finally caused the oxidative stress that was responsible for HCC. In conclusion, our investigation provided that the mtDNA 4977 bp deletion played a putative role in the pathogenesis of HCC, we also found that tumor with this common deletion, mtDNA content could be increased probably due to a retrograde effect. Furthermore, we proposed that the 4977 bp deletion may be served as a potential biomarker for HCC, possibly via the alternation of mtDNA content and increasing the ROS production.



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