Decreased Muc5AC expression is associated with poor prognosis in gastric cancer

Abstract

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 5 0.004), lymph node metastases (p 5 0.001), lymphovascular invasion (p < 0.0001), and increased tumor size (p 5 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 5 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.Mucins are a group of diverse, complex, highly glycosylated extracellular proteins that are major components of the mucus gel covering the gastric mucosa.

Mucin Expression in Endoscopic Ultrasound-Guided Fine-Needle Aspiration Specimens Is a Useful Prognostic Factor in Pancreatic Ductal Adenocarcinoma

“…In contrast, in gastric cancer where MUC5AC is heavily expressed under normal condition, a decrease in MUC5AC during pathologic development from the high expression normal level is associated with a poor prognosis 17 . Normal pancreatic ductal epithelia show no MUC5AC expression 10 .…”

Abrogation of MUC5AC Expression Contributes to the Apoptosis and Cell Cycle Arrest of Colon Cancer Cells

“…Interestingly, decreased MUC5AC expression was associated with increased aggressiveness of gastric cancers, including tumor invasion and lymph node metastasis, which indicated that MUC5AC has a distinct function in different cancers. 22 However, the mechanism of mucins in the development of cancer has not been well clarified. Deregulation of transmembrane mucine (e.g., MUC1) is involved in constitutive activation of growth and survival pathways such as the Wnt/b-catenin and nuclear factor-jB pathways through their CT for the survival and proliferation of tumor.…”

Gli Regulates MUC5AC Transcription in Human Gastrointestinal Cells

“…Based on these backgrounds, we focused on MUC5AC , which is a well-established gastric marker gene [6], [14] and is often used for the clinical assessment of gastric cancer [15]. There have been many previous reports investigating the expression of MUC5AC and prognosis of gastric cancer, but the association between expression of MUC5AC and malignant potential of gastric cancer is still controversial [16], [17], [18], [19]. Nevertheless, MUC5AC is one the most evident gastric marker clearly decreased in the process of intestinal metaplasia [14], [20].…”