Abstract
Drosha is an RNA III-like enzyme that has an aberrant expression in some tumors. Our previous studies showed the aberrant Drosha in gastric tumors. However, the roles of nuclear Drosha, the main regulator of microRNA (miRNA) biogenesis, in gastric cancer (GC) progression remain poorly understood. In this study, we demonstrated that nuclear Drosha is significantly associated with cell invasion of GC and that Drosha silence impedes the tumor invasion. Knockdown of Drosha led to a set of dysregulated miRNAs in GC cells. Multiple targets of these miRNAs were the members in cell migration, invasion and metastasis-associated signaling (e.g. ECM-receptor interaction, focal adhesion, p53 signaling and MAPK signaling pathway) revealed by bioinformatics analysis. LAMC2 (a key element of ECM-receptor signaling) and CD82 (a suppressor of p53 signaling) are the targets of miR-622 and miR-197, respectively. High levels of LAMC2 and low levels of CD82 were significantly related to the worse outcome for GC patients. Furthermore, overexpression of LAMC2 and knockdown of CD82 markedly promoted GC cell invasion and activated EGFR/ERK1/2-MMP7 signaling via upregulation of the expression of phosphorylated (p)-EGFR, p-ERK1/2 and MMP7. Our findings suggest that nuclear Drosha potentially has a role in the development of GC.
Highlights
Gastric cancer (GC) is the most common gastrointestinal cancer with high morbidity and mortality in China
To understand whether high levels of nuclear Drosha are a bad predictor for patients with GC, we further detected Drosha expression in gastric tumor tissues by IHC staining
Consistent with our previous findings, the nuclear Drosha was significantly higher in gastric adenocarcinoma than that in the tumor in situ and normal gastric tissues
Summary
Gastric cancer (GC) is the most common gastrointestinal cancer with high morbidity and mortality in China. Aberrant expressions of Drosha are closely related to carcinogenesis and cancer progression. It is inseparable that the role of aberrant Drosha in the tumor progression may be dependent on miRNAs, which have referred to tumor initiation and development as oncogenes or tumor suppressor genes through negative regulation of hundreds of target genes at the post-transcriptional level.[7] Dysregulated miRNAs are detected in different kinds of cancers, including colorectal carcinoma,[8] breast cancer[9] and GC,[4] and involved in tumor pathology, diagnosis, treatment, prognosis and other processes. The silence of Drosha expression using interfering RNA in GC led to impeded tumor cell invasion and change of miRNA profiles. Our study provides a mechanistic insight into the function of Drosha in gastric metastasis via an altered miRNA profile
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