Analysis of the mitochondrial 4977 bp deletion in patients with hepatocellular carcinoma

Abstract

Mutations in the mitochondrial (mt) genome that result in mt dysfunction, have long been proposed to play important roles in the pathogenesis of hepatocellular carcinoma (HCC). Among these, the common mtDNA 4977 bp deletion is one of the most frequent mutations observed in various cancers. To understand the relationship between the mtDNA 4977 bp deletion and HCC, we performed mutational screening for the presence of this deletion in 105 HCC patients and 69 unrelated healthy subjects. After nested-polymerase chain reaction (nested-PCR) amplification, we found that there were 10 patients carrying the mtDNA 4977 bp deletion, and this deletion was absent in control subjects. Moreover, HCC patients carrying this deletion showed a marked increase in reactive oxygen species (ROS) level and mtDNA copy number when compared with the healthy controls. Taken together, our data indicated that the mtDNA 4977 bp deletion may play important role in the carcinogenesis of HCC, possibly via the alternation of mtDNA copy number and oxidative stress.

Prenatal Lipopolysaccharide Exposure Promotes Dyslipidemia in the Male Offspring Rats

“…Consequently, the loss of any complex may be at least partly responsible for impaired ATP biogenesis. The 4977-bp “common” deletion, although found in low abundance, is frequently observed in the pathogenesis of chronic liver disorders, atherosclerosis and aging-related diseases, indicating mitochondrial damage (Botto et al, 2001 ; Pavicic and Richard, 2009 ; Guo et al, 2017 ). In this study, we found evidence of hepatic mitochondrial dysfunction and mitochondrial DNA (MtDNA) damage in offspring from dam received LPS stimulation during pregnancy, as confirmed by the loss of ATP content, diminished membrane potential, decline in protein expression and activity of mitochondrial respiratory complexes, as well as increased level of 4977-bp MtDNA common deletion, suggesting a precedent for “priming” of the mitochondria, which persisted into adulthood.…”

Molecular Changes Induced by Oxidative Stress that Impair Human Sperm Motility

“…One of the best-described large-scale mtDNA deletions is the specific 4977 bp deletion (mtDNA 4977 ), which occurs between nucleotides 8470 and 13447 and eliminates seven genes encoding four subunits of Complex I (ND3, ND4, ND4L, partial ND5), one subunit of Complex IV (COIII) and two subunits of ATP-synthase (ATP6 and partial ATP8); all of which are crucial for OXPHOS (depicted in Figure 3). Accordingly, mtDNA 4977 has been linked to a spectrum of disorders, including heart disease, different forms of cancer and mitochondrial diseases [143][144][145][146]. Notably, this mutation has also been reported to accumulate in different human tissues as a consequence of natural aging [147].…”

ROS as a Novel Indicator to Predict Anticancer Drug Efficacy

“…They are also regarded as a double-edged sword in cancer cells since low doses of ROS can promote cell proliferation and invasion, whereas excessive levels of ROS cause oxidative damage to proteins, lipids, RNA and DNA which consequently induce cell death [6,7]. Therefore, a slight increase of ROS is associated with the initiation and progression of cancer [4,8], but high levels of ROS can induce cell death by activating several signalling pathways resulting in cell apoptosis [6,7]. For example, in cancer cells with wild type p53, DNA damage by ROS induces apoptosis in a mitochondria-dependent manner via activation of the p53/BAX signalling pathway [4].…”

“…Furthermore, defective mitochondrial oxidative metabolism in tumour cells also render higher ROS levels [9], and therefore ROS induction is a promising approach to cancer therapy [4,8].…”