MUTATIONAL ANALYSIS OF MITOCHONDRIAL tRNA GENES IN PATIENTS WITH LUNG CANCER
He ZF, Zheng LC, Xie DY, Yu SS, Zhao J
*Corresponding Author: Dr. Jun Zhao, First Affiliated Hospital, Soochow University, Shizi Road, 215006, Suzhou, People’s Republic of China. Tel./Fax: +86-0512-65223637. E-mail: zhaojsz001@163.com
page: 45

DISCUSSION

In this study, we screened mt-tRNA mutations in patients with lung cancer. To the best of our knowledge, this is the first report dealing with the association between mttRNA mutations and lung cancer. Lung cancer is a common type of cancer diagnosed all over the world. Screening options for this disease are very limited and only 15.0% of cases are diagnosed at an early stage [12]. Thus, there is an urgent need for developing a biomarker for early detection for lung cancer. Mitochondrial tRNA genes are hot-spots for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation, disrupting this primary function affects protein synthesis and expression, folding and function of oxidative phosphorylation enzymes [13]. However, we noticed that a certain amount of tRNA mutations have been wrongly classified as “pathogenic,” as in a recent article concerning the association between mt-tRNA mutations and thyroid carcinoma [14]. In this study, we investigated the possible relationship between mt-tRNA mutations and lung cancer by employing PCR-Sanger sequencing. As a result, five mt-tRNA mutations were identified, including tRNAAla T5655C, tRNAArg T10454C, tRNALeu(CUN) A12330G, tRNASer(UCN) T7505C and tRNAThr G15927A. Of these, the T5655C mutation was located at the acceptor arm of tRNAAla, disrupted the highly conserved base-pairing (1A-72U). An in vitro processing analysis showed that the T5655C mutation reduced the efficiency of tRNAAla precursor 5’ end cleavage catalyzed by RNase P [15]. Moreover, a significant decreased of tRNAAla steady-state level was also observed in cybrid cells containing this mutation. While the homoplasmic T10454C mutation was localized at the T loop of tRNAArg (conventional position 55), this mutation was implicated to be associated with longevity and non syndromic hearing loss [16,17]. However, a previous study showed that the T10454C mutation may not modulate the phenotypic manifestation of deafness- associated mitochondrial 12S rRNA A1555G mutation [18], thus, we proposed that the T10454C mutation was a neutral polymorphism (Table 2). In addition, the A12330G mutation occurred at the acceptor arm of tRNALeu(CUN) gene, disrupting the highly conserved base-pairing (6T-67A), and may result in failure in tRNA metabolism. A previous study showed that this mutation, combined with the well known ND5 T12338C mutation, may account for the high penetrance and expressivity of essential hypertension in a Han Chinese family [19]. Moreover, the T7505C mutation was first described in a Han Chinese family with maternally transmitted non syndromic hearing impairment [20], structurally, the T7505C mutation was localized at the second base-pairing (10A-20U) on the D-stem of tRNASer(UCN). The phylogenetic analysis of this mutation and mtDNAs from the other 10 vertebrates revealed that the nucleotide A at the conventional position 10 in tRNASer(UCN) was extremely evolutionarily conserved [21], ~65.0% reductions in the level of tRNASer(UCN) were observed in the lymphoblastoid cell lines carrying this mutation [20]. Furthermore, the homoplasmic G15927A in the anticodon stem of tRNAThr was also described in a Han Chinese family with maternally inherited hearing loss [22]; later, this mutation was reported to be associated with coronary heart disease [23]. Northern blot analysis of the cell lines with the G15927A mutation revealed ~80.0% decrease in the steady-state level of tRNAThr, in addition, ~39.0% reduction in aminoacylated efficiency of tRNAThr was observed in mutant cells derived from the family members carrying the G15927A mutation. An increasing production of reactive oxygen species was observed in the mutant cells carrying the G15927A mutation. Therefore, we proposed that the G15927A mutation was a pathogenic mutation associated with lung cancer. Based on these findings, we proposed that the molecular mechanism underlying these mt-tRNA mutations in the carcinogenesis of lung cancer may be as follows: first, these mutations disrupted the mt-tRNA secondary structure and subsequently resulted in failure in tRNA metabolism such as a CCA addition, posttranscriptional modification and aminoacylation [24]. Whatever the consequence may be, the expected net effect would be a decrease in mitochondrial protein synthesis. Defects in mitochondrial translation consequently leads to a respiratory phenotype and a decline in adenosine triphosphate (ATP) production below the threshold level required for normal cell function, thus, contributing to the tumorigenesis of lung cancer. In summary, this is the first report concerning the association between mt-tRNA mutations and lung cancer. The main limitation of this study was the sample size. Further studies including more samples are needed to verify the conclusions. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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