Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway

Abstract

Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to proliferation, migration and invasion, and on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT-PCR were used to identify proteins and signalling pathways involved. MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of β-catenin expression, localization and activity and decreased expression of several of its target genes. xenografts of MUC5B-deficient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/β-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis.

Long non-coding RNA MUC5B-AS1 promotes metastasis through mutually regulating MUC5B expression in lung adenocarcinoma

“…Our data suggest that MUC5B-AS1 acts as an oncogenic lncRNA that promotes cell migration by upregulating the expression of MUC5B in lung cancer. Previous studies have suggested that MUC5B could promote the cancer cell migration through the ERK1/2 signaling pathway 38 or Wnt/β-catenin signaling pathway 39 . Based on the fact that MUC5B-AS1 expression levels were highly positively correlated with MUC5B mRNA and exerted its function through MUC5B in lung cancer cells, we further verified the prognostic significance of MUC5B mRNA.…”

High-dimensional mediation analysis in survival models

“…Besides, other methylation sites with negative log-hazard mediation effect have not been reported so far, and they may be the potential biomarkers to extend survival time for lung cancer patients. Take cg07690349 as an example, the gene MUC5B (cg07690349 locates) is one of the secreted mucins which are large O-glycosylated proteins that participate in the protection of underlying mucosae in normal adults [46].…”

Tepotinib Inhibits the Epithelial–Mesenchymal Transition and Tumor Growth of Gastric Cancers by Increasing GSK3β, E-Cadherin, and Mucin 5AC and 6 Levels

“…The mRNA levels of MUC5B are increased in gastrointestinal cancers, but those of MUC5AC and MUC6 are decreased in GC [ 34 ]. MUC5B affects gastrointestinal carcinogenesis by inducing the Wnt/β-catenin pathway [ 35 ]. In addition, MUC5B expression has been positively correlated with the poor prognoses of gastric carcinomas [ 36 , 37 , 38 ].…”