Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer

Wen Yi Hung, Chew Wun Wu, Pen Hui Yin, Chun Ju Chang, Anna Fen Yau Li, Chin Wen Chi, Yau Huei Wei, Hsin Chen Lee*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

63 Scopus citations

Abstract

Background: Somatic mutation in mitochondrial DNA (mtDNA) has been proposed to contribute to initiation and progression of human cancer. In our previous study, high frequency of somatic mutations was found in the D-loop region of mtDNA of gastric cancers. However, it is unclear whether somatic mutations occur in the coding region of mtDNA of gastric cancers. Methods: Using DNA sequencing, we studied 31 gastric cancer specimens and corresponding non-cancerous stomach tissues. Moreover, a human gastric cancer SC-M1 cell line was treated with oligomycin to induce mitochondrial dysfunction. Cisplatin sensitivity and cell migration were analyzed. Results: We identified eight somatic mutations in the coding region of mtDNAs of seven gastric cancer samples (7/31, 22.6%). Patients with somatic mutations in the entire mtDNA of gastric cancers did not show significant association with their clinicopathologic features. Among the eight somatic mutations, five point mutations (G3697A, G4996A, G9986A, C12405T and T13015C) are homoplasmic and three mutations (5895delC, 7472insC and 12418insA) are heteroplasmic. Four (4/8, 50%) of these somatic mutations result in amino acid substitutions in the highly conserved regions of mtDNA, which potentially lead to mitochondrial dysfunction. In addition, in vitro experiments in SC-M1 cells revealed that oligomycin-induced mitochondrial dysfunction promoted resistance to cisplatin and enhanced cell migration. N-acetyl cysteine was effective in the prevention of the oligomycin-enhanced migration, which suggests that reactive oxygen species generated by defective mitochondria may be involved in the enhanced migration of SC-M1 cells. General Significance: Our results suggest that somatic mtDNA mutations and mitochondrial dysfunction may play an important role in the malignant progression of gastric cancer.

Original languageEnglish
Pages (from-to)264-270
Number of pages7
JournalBiochimica et Biophysica Acta - General Subjects
Volume1800
Issue number3
DOIs
StatePublished - 03 2010
Externally publishedYes

Keywords

  • Drug resistance
  • Gastric cancer
  • Migration
  • Somatic mutation
  • mtDNA

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