Interaction of MUC1 with β‐catenin modulates the Wnt target Gene cyclinD1 in H. pylori‐induced gastric cancer

Abstract

Beta-catenin can function as an oncogene when it is translocated to the nucleus, binds to T-cell factor (TCF) or lymphoid enhance factor and transactivate its target gene. The mechanism responsible for the activation of Wnt signaling pathway in the Cytotoxin-associated antigen A (CagA) Helicobacter pylori (H. pylori)-infected gastric carcinoma has not been elucidated. We hypothesize that whether interaction of MUC1 with beta-catenin modulates the Wnt signaling and its target gene cyclinD1 in CagA H. pylori-infected gastric carcinoma. The result demonstrate that binding of MUC1 CT with Protein Kinase C delta (PKC delta), tyrosine phosphorylation of MUC1 CT, and CagA are strongly associated with the interaction of MUC1 with beta-catenin in CagA H. pylori-infected gastric carcinoma. A statistically significant difference (chi(2) = 24.49; P< 0.001) was found when the binding of MUC1 CT and beta-catenin was compared to subcellular localization of beta-catenin. We also observed significant statistical correlation (chi(2) = 14.885; P < 0.001) between the cyclinD1 overexpression and the subcellular localization of beta-catenin. The overexpression of cyclinD1 was significantly higher (chi(2) = 13.785; P < 0.002) in advanced gastric carcinoma with CagA H. pylori infection. In addition cyclinD1 overexpression was significantly higher (chi(2) = 37.267; P < 0.001) with the interaction of MUC1 CT with beta-catenin in advanced gastric cancer. These findings indicate that MUC1 CT plays a role in the intracellular signaling through its interaction with beta-catenin and upregulate the Wnt target gene cyclinD1 in CagA H. pylori-infected gastric carcinoma.

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…This study reported significant CagA-dependent upregulation of the Wnt target genes CCND1, Axin2 and the zebrafish c-myc ortholog myca. Moreover, CagA infection can lead to advanced gastric carcinoma through the upregulation of cyclin D1 [225] . It is thought that CagA promotes the phosphorylation of MUC1, which is a glycoprotein expressed on the apical borders of secretory epithelial cells, thereby facilitating its interaction with b-catenin, and the subsequent transcriptional activation of cyclin D1 [225] .…”

“…Moreover, CagA infection can lead to advanced gastric carcinoma through the upregulation of cyclin D1 [225] . It is thought that CagA promotes the phosphorylation of MUC1, which is a glycoprotein expressed on the apical borders of secretory epithelial cells, thereby facilitating its interaction with b-catenin, and the subsequent transcriptional activation of cyclin D1 [225] . In addition, gene expression profile analyzed in H. pylori-infected and uninfected patients undergoing chronic superficial gastritis showed that the E3 ubiquitin-protein ligase RNF138, which is involved in the ubiquitination and degradation of TCF/LEF, was downregulated by H. pylori [226,227] .…”

Lesiones gástricas en pacientes infectados con Helicobacter pylori: expresión de RAGE (receptor de productos de glicosilización avanzada) y otros inmunomarcadores

“…Componentes de la vía Wnt como β-catenina y GSK3β serían factores vinculantes entre cáncer e inflamación 27,28 y activadores de la transcripción de ciclina-D1 29,30 un importante regulador del ciclo celular sobreexpresado en cáncer 31 . Los resultados observados en el presente estudio: alto porcentaje de inmunomarcación a nivel de membrana plasmática/ citoplasma para MUC-1 como el mayor porcentaje de casos positivos en el grupo displasia/CIS a nivel nuclear para β-catenina y β-catenina fosforilada, citoplasmático y nuclear para ciclina-D1 y citoplasmático para GSK3β son coherentes con lo expuesto y concordantes con la literatura [42][43][44][45][46][47][48] . El caso de MUC-1 es particularmente interesante ya que su unión con H. pylori potenciaría la activación de las señales de transducción de vías que controlan el crecimiento celular 23 .…”

Effect of the Jianpi Bushen Prescription on expressions of the Wnt3a and Cyclin D1 genes in radiation-damaged mice

“…Cyclin D1 controls the speed of cell proliferation by regulating the cell cycle (Dai et al, 2012). Cyclin D1 can also be used as a downstream target gene of the Wnt/b-catenin signal transduction pathway, and may initiate the pathway in some cases (Udhayakumar et al, 2007;Zhang et al, 2012a).…”