Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors.
Infection of gastric mucosa by Helicobacter pylori induces an inflammatory response with increased levels of proinflammatory cytokines. Among them, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 induce the activation of signaling pathways that regulate genes expression, such as MUC2 and MUC4 intestinal mucins ectopically detected in gastric tumors. This study evaluated if the predominant inflammatory cell type correlates with MUC2 and MUC4 expression in human intestinal gastric tumors (n=78). In addition, we analyzed the regulatory effects of the associated inflammatory signaling pathways on their expression in gastric cancer cell lines, and in a mouse model with hyperactivated STAT3 signaling pathway. Tumors with predominant lymphoplasmocytic infiltrate (chronic inflammation), presented higher levels of MUC2 and were more differentiated than tumors with predominant polymorphonuclear infiltrate (acute inflammation). These differences can be attributed to specific cytokines, because TNF-alpha and IL-1beta induced MUC2 but no MUC4 expression in gastric cancer cell lines. The two groups of tumors expressed similar levels of MUC4 that correlated with the expression of STAT3 transcription factor, implicated in the activation of genes through the IL-6 pathway. In gastric tissues from gp130(+/+), gp130(Y757F/Y757F) and gp130(Y757F/Y757F) Stat3(-/+) mice, Muc2 was not detected, whereas Muc4 was found in the gastric tumors developed in the gp130(Y757F/Y757F) mice, with hyperactivated STAT3. These data indicate that the signaling pathways associated with the inflammatory response can modulate the expression of MUC2 and MUC4 intestinal mucin genes, in human and mouse gastric tumors.
Mejías-Luque
R
R
IMIM-Hospital del Mar, Programa de Recerca en Càncer, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain.
Lindén
S K
SK
Garrido
M
M
Tye
H
H
Najdovska
M
M
Jenkins
B J
BJ
Iglesias
M
M
Ernst
M
M
de Bolós
C
C
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D055271:Mucin 5AC / Q000235:genetics; D055262:Mucin-2 / Q000235:genetics*; D055264:Mucin-4 / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D013045:Species Specificity; D013274:Stomach Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology
C524625:MUC2 protein, human; C524658:MUC4 protein, human; C524678:MUC5AC protein, human; C524626:Muc2 protein, mouse; C524659:Muc4 protein, mouse; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D055262:Mucin-2; D055264:Mucin-4; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse