Abstract
BackgroundMultiple aberrant microRNA expression has been reported in gastric cancer. Among them, microRNA-335-5p (miR-335), a microRNA regulated by DNA methylation, has been reported to possess both tumor suppressor and tumor promoter activities.ResultsHerein, we show that miR-335 levels are reduced in gastric cancer and significantly associate with lymph node metastasis, depth of tumor invasion, and ultimately poor patient survival in a cohort of Amerindian/Hispanic patients. In two gastric cancer cell lines AGS and, Hs 746T the exogenous miR-335 decreases migration, invasion, viability, and anchorage-independent cell growth capacities. Performing a PCR array on cells transfected with miR-335, 19 (30.6%) out of 62 genes involved in metastasis and tumor invasion showed decreased transcription levels. Network enrichment analysis narrowed these genes to nine (PLAUR, CDH11, COL4A2, CTGF, CTSK, MMP7, PDGFA, TIMP1, and TIMP2). Elevated levels of PLAUR, a validated target gene, and CDH11 were confirmed in tumors with low expression of miR-335. The 3′UTR of CDH11 was identified to be directly targeted by miR-335. Downregulation of miR-335 was also demonstrated in plasma samples from gastric cancer patients and inversely correlated with DNA methylation of promoter region (Z = 1.96, p = 0.029). DNA methylation, evaluated by methylation-specific PCR assay, was found in plasma from 23 (56.1%) out of 41 gastric cancer patients but in only 9 (30%) out of 30 healthy donors (p = 0.029, Pearson’s correlation). Taken in consideration, our results of the association with depth of invasion, lymph node metastasis, and poor prognosis together with functional assays on cell migration, invasion, and tumorigenicity are in accordance with the downregulation of miR-335 in gastric cancer.ConclusionsComprehensive evaluation of metastasis and invasion pathway identified a subset of associated genes and confirmed PLAUR and CDH11, both targets of miR-335, to be overexpressed in gastric cancer tissues. DNA methylation of miR-335 may be a promissory strategy for non-invasive approach to gastric cancer.
Highlights
Multiple aberrant microRNA expression has been reported in gastric cancer
Results miR-335 is downregulated in gastric cancer tissues and associated with depth of tumor invasion and lymph node metastasis miR-335 expression was examined in 38 Amerindian/ Hispanic advanced gastric cancer tissues and their matched non-tumor adjacent tissues (NAT), showing a significantly reduced expression in tumors (p = 0.002), (Fig. 1a, b)
Downregulation of miR-335 is associated with poor prognosis in patients with gastric cancer We performed overall survival analysis of patients with gastric cancer using Kaplan-Meier analysis according to levels of miR-335 expression
Summary
Multiple aberrant microRNA expression has been reported in gastric cancer. MicroRNA-335-5p (miR-335), a microRNA regulated by DNA methylation, has been reported to possess both tumor suppressor and tumor promoter activities. Sandoval-Bórquez et al Clinical Epigenetics (2017) 9:114 frequently reported in human neoplasms including gastric cancer [5, 8, 9]. Among relevant miRNAs in cancer, microRNA-335-5p (miR-335) is a transcript of genomic region chromosome 7q32.2, regulated by DNA methylation that has been reported to possess both tumor suppressor and tumor promoter activities depending on the tumor type and stage [10]. In gastric cancer, the role of the miRNA has to be defined, as studies have reported both overexpression and downregulation [11, 12]
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