title: MiRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer.
abstract: The molecular mechanism underlying cancer invasiveness and metastasis of gastric carcinoma remains elusive. Here, we reported significant decrease in microRNA (miRNA)-34a and significant increase in phosphorylated epidermal growth factor receptor (EGFR) and matrix metalloproteinase-7 (MMP7) in the resected gastric carcinoma from the patients, compared with adjacent normal tissue. Moreover, strong correlation was detected among these three factors. To examine whether a causal link exists, we used two human gastric carcinoma lines, SNU-5 and HGC27, to study the molecular basis of miRNA-34a, EGFR signaling, and MMP7 activation. We found that EGF-induced EGFR phosphorylation in SNU-5 or HGC27 cells activated MMP7 and consequently cancer invasiveness. Both an inhibitor for EGFR and an inhibitor for Akt significantly inhibited the EGF-induced activation of MMP7, suggesting a phosphatidylinositol 3-kinase (PI3K) signaling cascade dependent pathway. Moreover, miRNA-34a levels were not affected by EGF-induced EGFR phosphorylation. However, overexpression of miRNA-34a antagonized EGF-induced MMP7 activation without affecting EGFR phosphorylation in SNU-5 or HGC27 cells. Taken together, our data suggest that miRNA-34 inhibits EGFR signaling via downstream PI3K signaling cascades to regulate MMP7 expression in gastric carcinoma. Thus, miRNA-34a, EGFR, and MMP7 appear to be promising therapeutic targets for preventing the metastasis of gastric carcinoma.
authors: Department of Gastroenterology, Fuzhou General Hospital of Nanjing Command, 156 West Second Ring Road, Fuzhou, 350025, China.
authors: Gang
authors: G
authors: Liu
authors: Chuanshen
authors: C
authors: Jiang
authors: Dazhou
authors: D
authors: Li
authors: Rong
authors: R
authors: Wang
authors: Wen
authors: W
authors: Wang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7