Abstract
Micro RNAs (miRs) are small non-coding RNAs aberrantly expressed in human tumors. Here, we aim to identify miRs whose deregulated expression leads to the activation of oncogenic pathways in human gastric cancers (GCs). Thirty nine out of 123 tumoral and matched uninvolved peritumoral gastric specimens from three independent European subsets of patients were analyzed for the expression of 851 human miRs using Agilent Platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by qPCR. miR-204 falls into a group of eight miRs differentially expressed between tumoral and peritumoral samples. Downregulation of miR-204 has prognostic value and correlates with increased staining of Bcl-2 protein in tumoral specimens. Ectopic expression of miR-204 inhibited colony forming ability, migration and tumor engraftment of GC cells. miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil. Altogether, these findings suggest that modulation of aberrant expression of miR-204, which in turn releases oncogenic Bcl-2 protein activity might hold promise for preventive and therapeutic strategies of GC.
Highlights
Micro RNAs, a class of non-coding small RNAs exert a pivotal role in several biological processes ranging from development and differentiation to apoptosis and proliferation. miRs control gene expression tightly by degrading messenger RNAs and inhibiting translation.[3]
There is growing experimental evidence that downregulation of large sets of miRs has a pivotal role in tumorigenesis independently from the type of the analyzed tumor.[10]
We found that mixed polyclonal population of GTL-16 or N87 Gastric cancer (GC) cell lines overexpressing miR-204 (GTL-16/miR-204; N87/miR-204) exhibited a statistically significant reduced ability to form colonies when compared with control cells (GTL-16/EV; N87/EV) (Figure 3a and Supplementary Figure 3a)
Summary
Micro RNAs (miRs), a class of non-coding small RNAs exert a pivotal role in several biological processes ranging from development and differentiation to apoptosis and proliferation. miRs control gene expression tightly by degrading messenger RNAs (mRNAs) and inhibiting translation.[3]. We document by profiling simultaneously the expression of 851 human miRs that gastric tumors exhibit selected differentially expressed miRs when compared with their matched peritumoral samples in an European collection. Among those miRs, we identify miR-204 that is statistically significantly downregulated in GC samples derived from three independent subsets of patients (n 1⁄4 123) compared with their respective matched peritumoral tissues. We show that miR-204 downregulation is a prognostic factor in GC patients These findings underline tumor suppression activity of miR-204 in GCs whose inactivation release oncogenic Bcl-2 protein activity. This might contribute, at least in part, to the poor response of gastric tumors to conventional anticancer therapy
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