Reduced expression of miR-22 in gastric cancer is related to clinicopathologic characteristics or patient prognosis

Gastric cancer is the fourth most prevalent forms of human cancers and the second leading cause of cancer-related death in the world, especially in East Asian countries. Its incidence rate is 20 per 100,000 annually [1]. According to its histological subtypes, gastric cancer can be divided into two groups: the intestinal type and the diffuse type. The former is characterized by expansive growth and liver metastasis; whereas the latter is characterized by infiltrative growth and peritoneal dissemination [2‐4]. They are both associated with Helicobacter pylori infection that contributes to more than 80% of cases [5]. Nowadays, gastrectomy remains the mainstay treatment for gastric cancer, but the prognosis for advanced stage patients is still very poor. The median survival time for patients with gastric cancer is only 6–9 months [6]. In China, the 5-year overall survival rate of patients with gastric cancer is lower than 40%, although recent advances in chemotherapy and surgical techniques [7]. This is primarily attributed to the following reasons: lack of diagnostic markers for early detection, weak prognostic value of histological indicators, limited efficiency of current treatment for advanced disease and lack of molecular markers utilized for targeted therapy [8‐10]. Therefore, it is of great significance to make a better understanding of gastric carcinogenesis and to identify novel molecular markers for the improvement of clinical management of patients with gastric cancer.

MicroRNAs (miRNAs) are a recently discovered category of small (19 ~ 24 nucleotides), non-protein-coding and single-stranded endogenous RNA molecules [11]. miRNAs function as regulators of approximately 60% protein-coding genes’ expression mainly at the post-transcriptional level by binding to the sequences in the 3′ untranslated regions (3′-UTR) of their targeted mRNAs resulting in translational repression or gene silencing [12]. As they are involved in regulation of wide array of biological processes including cell proliferation, differentiation, apoptosis, metastasis, angiogenesis and immune response, miRNAs have been considered to be new approaches of tumor biomarkers for early cancer diagnosis and prognosis. They may play roles in the development and progression of cancers similar to those played by oncogenes or tumor suppressor genes. Recent studies have identified a number of miRNAs with aberrant expression in gastric cancer. For example, the comparison of miRNAs deregulated in gastric cancer revealed a significant increase of several tumor-associated miRNAs such as miR-21, -25 and -106a and miRNAs from the miR-17-92 cluster [13]; based on the cluster analyses, eight miRNAs (including miR-100, -143 and −145) were upregulated specifically in diffuse-type, while four miRNA (miR-202, -373, -494 and −498) in intestinal-type gastric cancer [14]. In our previous study, we found that the downregulation of miR-206 was significantly correlated with tumor progression and may be a potent prognostic marker of gastric cancer [15]. According to our literature retrieval, miR-22 has been demonstrated to play important roles in different types of cancer, such as hepatocellular carcinoma, breast cancer, colon cancer, lung cancer, and prostate cancer [16‐22]. However, its roles in tumorigenesis of gastric cancer are still unknown. Because of its involvement in several tumors in digestive system (hepatocellular carcinoma and colon cancer), we hypothesized that miR-22 might play a role in gastric cancer. Thus, the aim of the present study was to investigate the expression patterns and clinical implications of miR-22 in gastric cancer.

Accumulating evidences have demonstrated that miRNAs play important roles in various physiological and pathological processes, and have a robust association with carcinogenesis. miRNAs have been considered to be novel biomarkers for various cancers. Among human miRNAs, miR-22 is located at a fragile cancer-relevant genomic region in chromosome 17 (17p13.3), and is mapped to an exon of the C17orf91 gene [24]. This miRNA plays unique roles in specific cell types. For example, it regulates PPAR-alpha and BMP7 signaling pathways in human chondrocytes [25], and the differentiation of a monocyte cell line [26]. Recent studies have demonstrated that miR-22 is deregulated in many types of cancers and is involved in various cellular processes related to carcinogenesis, including cell growth, apoptosis, motility, and cell cycle. Zhang et al. [16] indicated that miR-22 was downregulated in hepatocellular carcinoma and had considerable potential in identification of the prognosis; Xiong et al. [17] found that miR-22 was frequently downregulated in ERα-positive human breast cancer cell lines and clinical samples; Li et al. [18] identified miR-22 as a potential metastasis-inhibitor in ovarian cancer; Yamakuchi et al. [19] found that miR-22 expression in human colon cancer was lower than in normal colon tissue, and it might have an anti-angiogenic effect in this cancer; Ling et al. [20] observed the downregulation of miR-22 in lung cancer tissues and lung cancer cell lines, and also suggested that miR-22 might exhibit excellent anti-lung cancer activity in vitro and in vivo. All these studies suggest that miR-22 may act as a tumor suppressor. In contrast, Poliseno et al. [21] showed that miR-22 was aberrantly overexpressed in human prostate cancer; Liu et al. [22] have reported that miR-22 might act as a micro-oncogene in transformed human bronchial epithelial cells induced by anti-BPDE. These controversial findings of miR-22 in cancer development suggest the diverse roles of miR-22 in different types of cancer. In the present study, we confirmed that miR-22 expression was frequently reduced in gastric cancer tissues than in their normal adjacent mucosa. Moreover, the downregulation of miR-22 was found to be more frequently occurred in gastric cancer tissues with great extent of lymph node and distant metastases, and with an advanced stage.

To our knowledge, the invasion and metastasis of tumor cells are major causes of mortality in cancer patients. Therefore, the potential value of miR-22 as a prognostic marker is of interest. Yet, there has been only one study that has attempted to identify the prognostic value of miR-22 for hepatocellular carcinoma. Using 160 primary hepatocellular carcinoma cases, Zhang et al. [16] found that low miR-22 expression correlated with poor overall survival. In line with this finding, we analyzed not only the Kaplan-Meier survival curve but also applied Cox multivariate analysis to clarify the prognostic value of miR-22 in gastric cancer. Notably, we demonstrated that low miR-22 expression in gastric cancer tissues significantly correlated with poorer overall survival. Furthermore, in Cox multivariate analysis, miR-22 expression in gastric cancer tissues showed a significant association with overall survival.

In conclusion, our data offer the convincing evidence that the reduced expression of miR-22 was significantly associated with malignant development of gastric cancer and may be a novel prognostic marker of this disease. miR-22 might have potentials in the application of cancer therapy for patients with gastric cancer. However, our study is limited by the number of study cases with relatively small subgroups. Further investigations with a larger number of cases would allow us to evaluate miR-22 in a variety of clinical settings and help us better understand its unique role in cancer progression.