科研之友
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摘要
Mucins reportedly play numerous key roles in carcinogenesis, including in tumor invasion, regulation of differentiation and tumor cell proliferation. We investigated the effect of Muc5AC, a secreted mucin, on the invasiveness/migratory capability of gastric cancer cells and the prognostic significance of Muc5AC in gastric cancer patients. The clinicopathological and prognostic significance of Muc5AC expression was validated using immunohistochemical analysis in 412 gastric cancer patients. Differential gene expression was investigated using complementary DNA microarray analysis of 48 fresh tumor tissue samples. Silencing of Muc5AC by using a small hairpin RNA-containing lentivirus increased the invasion and migration of SNU216 and AGS cells as well as Akt phosphorylation and the expression of vascular endothelial growth factor and matrix metalloproteinase-7, which were blocked by inhibitors of the phosphatidylinositol 3-kinase/Akt pathway. Loss of Muc5AC expression was significantly associated with tumor progression (advanced T stage; p = 0.004), lymph node metastases (p = 0.001), lymphovascular invasion (p < 0.0001), and increased tumor size (p = 0.027). Lower MUC5AC expression was identified as an independent poor prognostic factor in diffuse-type gastric cancer by using the Cox regression proportional hazard model (hazard ratio, 2.39; p = 0.043). Complementary DNA microarray analysis revealed 86 differentially expressed genes, including genes related to metastasis and invasion, in gastric cancer tissues with high (25%) and low (<25%) Muc5AC expression levels. Low Muc5AC expression increased the invasion and migration of gastric cancer cells and could be a useful biomarker of poor prognosis in gastric cancer. What's new? While various mucins play numerous key roles in carcinogenesis, the functional consequences of Muc5AC expression and the mechanisms underlying its role in gastric cancer remain poorly understood. Here the authors demonstrated that Muc5AC silencing induced increase of gastric cancer cell invasion and migration, identifying PI3K/Akt signaling pathway as a possible mechanism. Low Muc5AC expression was also associated with poor prognosis and predicted aggressiveness in gastric cancer. Muc5AC may thus play a significant role in the invasiveness/migratory capability of gastric cancer cells and could be used as a predictive biomarker for the evaluation of prognosis or aggressiveness in gastric cancer patients.
- 出版日期2014-1-1
