Gastric Cancer: Increased Numbers of Myeloid-Derived Suppressor Cells Are Found in Gastric Cancer Patients

Abstract

Gastric cancer is one of the most common neoplasms, ranking as the second leading cause of cancer-related deaths worldwide. The predominant factor associated to gastric cancer is Helicobacter pylori infection, which leads to a chronic inflammatory response and subsequent oxyntic atrophy. Parietal cell loss result in two types of metaplasia, the intestinal metaplasia (IM) characterized by the presence of cells with goblet cell morphology and spasmolytic polypeptide-expressing metaplasia (SPEM) that shows morphological characteristics of the deep antral glands and express trefoil factor 2 (spasmolytic polypeptide). Although metaplastic lesions are considered neoplastic precursors, their direct association to cancer is still in debate. Similar to other cancers, gastric cancers are marked by global gene expression alterations. MicroRNAs (miRNAs) are small noncoding RNAs involved in the post-transcriptional regulation of gene expression and an increasing number of studies has been showing their aberrant expression in cancer. In order to identify miRNAs involved in the early stages of gastric cancer we performed a miRNA profiling on laser capture micro-dissected IM and SPEM cells from patient lesions. Using a qRT-PCR approach for quantitation of 754 human miRNAs, we identified 77 miRNAs differentially expressed in the metaplastic samples (greater than two-fold) in comparison to normal chief cells. The highest number of dysregulated miRNAs was observed in IM,which showed 45 up-regulated and 25 down-regulatedmiRNAs. In SPEM, 28 miRNAs were found up-regulated (21 of them also up-regulated in IM), whereas no down-regulation was detected. Some of the up-regulated miRNAs have already been associated to cancer in general (miR-26-a, miR-191, miR-155), as well as specifically to gastric cancer (miR-18b, miR-196b and miR-106a). However, the regulation of some of the top up-regulated miRNAs revealed here including miR-802, miR-922 and miR-622 are still poorly characterized in cancer. In a comparison with a previous mRNA profiling study performed on a similar group of samples, we observed that 108 out of the 568 mRNAs found up-regulated in IM are predicted targets of the 26 microRNAs down-regulated in IM, revealing a potential mechanism for the regulation of those genes in gastric metaplasia. Particularly interesting are 4 members of the miR-30 family, with 31 predicted mRNA targets amongst those up-regulated in IM. Although miR-30 family members have been described as down-regulated in gastric cancer, no data on their targets in this neoplasia is currently available. An extended characterization of the microRNAs identified here will provide a better understanding of their function in gastric metaplasia and progression to neoplasia, as well as might reveal useful early stage biomarkers or therapeutic targets.