Introduction
Gastric cancer (GC) is highly prevalent in Asia, and is the one of the leading causes of mortality, following lung cancer and liver cancer, in Korea (1). Its development has been revealed to be a multi-step process, ranging from chronic gastritis to atrophy, intestinal metaplasia, dysplasia and, finally, invasive cancer (2). The major histological type of GCs are adenocarcinomas, which are subdivided into intestinal type, diffuse type and mixed/unclassifiable type by Lauren classification (3). Previous studies have demonstrated that intestinal and diffuse types of GC evolve via distinct genetic pathways (3–6).
Telomeres, which contain TTAGGG repeat sequences in humans, are nucleoprotein complexes that cap each end of a eukaryotic chromosome (7). Mitochondrial DNA (mtDNA) differs from nuclear DNA, and multiple copies of mtDNA are present in each mitochondrion (8). Previous studies have demonstrated that telomere length (TL) and the mtDNA copy number (mtCN) are associated with numerous diseases, particularly specific types of cancer (9–12). In a number of examined cancer types, TL and mtCN changes were significantly associated with clinical and prognostic characteristics, suggesting an early and important effect on carcinogenesis (10–12). Previous studies have demonstrated a sequential accumulation of mitochondrial genetic changes during the progression from chronic gastritis to cancer via intestinal metaplasia and dysplasia (11–14).
Recent studies have indicated that TL and mtCN are positively correlated in healthy individuals and in pregnant females (15–17). Genetic changes in the telomeres and mtDNA independently serve important roles in cellular senescence (18). mtDNA damage caused by cellular senescence may contribute to the production of reactive oxygen species (ROS), resulting in telomere shortening (18). Past reviews have emphasized the importance of the telomere-p53-mitochondrion axis for cancer, suggesting that this may be targeted in future cancer therapy (19,20). Our recent studies (21,22) have also investigated these genetic changes in GC; however, their association has yet to be studied in cancer tissue samples.
In the present study, TL and mtCN were evaluated in GC, including 27 diffuse and 82 intestinal type tissue samples. The results of the present study may aid improvements in the current understanding of GC, through identifying the role of mtDNA and TL in GC pathogenesis.
Discussion
The present study identified that TL is positively correlated with mtCN in GC tissues and paired normal tissues; this was consistent with the results of previous studies conducted on healthy volunteers (15–17). A correlation between TL and mtCN was initially identified in a study of 129 healthy elderly females (15); in a further study, it was also demonstrated in healthy adults and pregnant females (16,17). Furthermore, certain neuropsychiatric conditions were also associated with TL shortening and mtCN increase, although detailed data concerning their association were not presented (25). Taken together, there is a positive correlation between TL alteration and mtCN not only in healthy individuals, but also in cancer tissues.
The clinicopathological significance of TL and mitochondrial genetic change has been previously studied in GC by a number of groups (11,12,14,21,22). TL was previously demonstrated to differ in GC according to Helicobacter pylori infection status, microsatellite instability (MSI), and non-steroidal anti-inflammatory drug use (26–29). Although TL change was identified in gastric carcinogenesis, it was not associated with clinicopathological features or prognosis in the present study. However, Pascua et al (27) reported that a combination of TL with MSI status has prognostic value. Mitochondrial genetic change has been frequently studied in GC, and our previous study (30) identified mtMSI to be a novel genetic marker for GC susceptibility. It was demonstrated that mtMSI was present in 10.2% of GC samples and 12.5% of gastric dysplasia samples, and that mtMSI was associated with a poor prognosis and an increased potential for progression.
In the present study, TL was marginally shorter in intestinal type GC, as compared with in diffuse type GC, whereas TL and mtCN did not have any significant association with clinical characteristics. However, a notable association was identified in GC tissues; in accordance with previous studies on healthy individuals (15–17,25), mtCN and TL were identified to be correlated with each other in normal and cancerous tissues obtained from patients with GC. A positive association was also identified in intestinal type GC, but not in the diffuse type. These results suggest that the normal positive correlation between telomeres and mitochondrial function is disrupted during the carcinogenesis of diffuse type GC, inducing TL change. Therefore, loss of the co-regulation of telomere length and mitochondrial copy number may serve a pivotal initiating role in gastric carcinogenesis. However, the survival analysis from the present study did not observe that this affected the clinical characteristics and further progression of GC.
Mitochondria and telomeres are considered to be key instigators of natural ageing (18). Mitochondrial dysfunction or genetic change during aging may be associated with the aging process through increased ROS production and decreased adenosine triphosphate generation (18). A previous study demonstrated that mitochondrial biogenesis and energy production were decreased in telomerase-deficient mice with severe telomere dysfunction (17). It has been hypothesized that telomere change influences not only oxidative defense mechanisms but also mitochondrial functions, including biogenesis and metabolism, in transcriptomic, molecular, genetic and functional analyses of various cells and organs, including proliferative and post-mitotic tissues (16,17). Therefore, this telomere-mitochondria axis may explain how shortened telomeres can cause mitochondrial change. The results of the present study support this hypothesis, suggesting that deregulation of the telomere-mitochondria axis, as caused by aging or other physiological factors, triggers the carcinogenesis of diffuse type GC.
In summary, TL and mtCN are correlated in normal and cancerous stomach tissues. Additionally, abnormal regulation of the telomere-mitochondria axis was identified in diffuse type GC, although the mechanism underlying this process remains unclear. Therefore, a change in the regulation of mitochondria and telomeres may be essential for diffuse GC carcinogenesis, suggesting that this signaling pathway could be targeted for cancer prevention. Furthermore, this result improves current understanding of how telomere change may contribute not only to age-associated disorders, but also to tumorigenesis.