Abstract
Here, we employed a bioinformatics approach to identify novel molecular determinants to predict tumor progression and overall survival in gastric cancer patients. In particular, we directly assessed whether nuclear-derived mRNA species encoding proteins involved in mitochondrial protein translation and OXPHOS are able to successfully predict clinical outcome in gastric cancer. As such, using in silico validation, we have now established the prognostic value of these mitochondrial biomarkers, in a defined population of gastric cancer patients. In this context, we interrogated 5 year follow-up data collected from a group of N = 359 gastric cancer patients. Importantly, in this group of cancer patients, Ki67 and PCNA (conventional markers of cell proliferation) were associated with tumor progression, as might be expected. Using this simplified informatics approach, we identified ∼75 new individual mitochondrial gene probes that effectively predicted tumor progression, with hazard-ratios (HR) of up to 2.22 (p < 2.1e-10). These mitochondrial mRNA transcripts included heat shock proteins/chaperones, membrane proteins, anti-oxidants, enzymes involved in genome maintenance, as well as mitochondrial ribosomal proteins (MRPs) and numerous members of the OXPHOS complexes. In addition, we combined 8 mitochondrial protein transcripts (NDUFS5, VDAC3, ATP5O, IMMT, MRPL28, COX5B, MRPL52, PRKDC), to generate a compact gastric mitochondrial gene signature, associated with a HR of 2.77 (p = 1.4e-14). As a result of this analysis and validation, we strongly suggest that proteins involved in mitochondrial protein translation and OXPHOS should be considered as targets for new drug discovery, for the treatment of gastric cancers. The mitochondrial markers we identified here could also be used as companion diagnostics, to predict clinical outcomes, as well as the patient response to therapy. This should allow a more successful and personalized approach to gastric cancer diagnosis and therapy.
Highlights
Gastric cancer, known as stomach cancer, starts as an infectious disease that drives the development of chronic inflammation and ulcerated lesions, located within the stomach wall lining
We suggest that the new mitochondrial markers that we developed here may be useful for selecting new “druggable” targets for innovative drug development, to prevent treatment failure and improve overall survival
As a consequence of our K-M analyses, we believe that the mitochondrial ribosome would be an attractive new target for developing novel inhibitors of mitochondrial protein translation in cancer cells; mitochondrial chaperones, the oxidative phosphorylation (OXPHOS) complexes and the mitochondrial ATP-synthase may be suitable drug targets
Summary
Known as stomach cancer, starts as an infectious disease that drives the development of chronic inflammation and ulcerated lesions, located within the stomach wall lining. In most cases of gastric cancer, these lesions are morphologically defined as epithelial carcinomas [1,2,3]. The gastric cancer cells migrate and metastasize to the lymph nodes, the abdomen, bones, lungs and the liver. The most common etiology of gastric cancer is chronic infection with Helicobacter pylori, a bacterium, which represents ~50-70% of the cases [4,5,6]. The diagnosis of gastric cancer is confirmed by an endoscopic biopsy, www.impactjournals.com/oncotarget revealing an invasive carcinoma. The disease is most common in Asian countries, especially in South Korea and Japan, among others [1,2,3,4,5,6]
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