Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer.
Depletion of transmembrane mucin 4 (Muc4) alters intestinal homeostasis in a genetically engineered mouse model of colorectal cancer.
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跨膜粘蛋白4（Muc4）的消耗改变了结肠直肠癌基因工程小鼠模型的肠道稳态。
DOI：
10.18632/aging.203935
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发表时间：
2022-03-07
期刊：
影响因子：
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通讯作者：
Batra SK
中科院分区：
文献类型：
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作者：
Pothuraju R;Pai P;Chaudhary S;Siddiqui JA;Cox JL;Kaur S;Rachagani S;Roy HK;Bouvet M;Batra SK
粘蛋白是覆盖肠上皮细胞的粘液层的组分，其维持生理稳态。改变的粘蛋白表达与疾病进展相关。MUC 4在结直肠癌（CRC）中的表达降低;然而，其在CRC中的肠道病理学中的功能作用和意义尚未得到很好的研究。因此，我们通过在存在结肠特异性诱导型Cre的情况下与Muc 4-/-和Apcflox/flox小鼠杂交来产生基因工程Muc 4敲除（Muc 4-/-）CRC小鼠模型。我们观察到Muc 4的缺乏导致结肠和直肠区域中肉眼可见的肿瘤数量增加，并导致生存率低下。此外，Muc 4的缺乏与杯状细胞功能障碍有关，其中肠内稳态分子（Muc 2和Fam 3D）的表达下调。接下来，我们还观察到Muc 4的损失显示粘液层厚度减少，导致细菌浸润，抗微生物肽减少和促炎细胞因子上调。此外，Apc基因突变导致Wnt/β-连环蛋白信号通路的激活，这与β-连环蛋白的核积累增加及其靶基因的激活相证实：观察到Muc 4-/-小鼠中的细胞周期蛋白D1和c-Myc。我们的结论是，Muc 4的存在是必不可少的肠道内稳态，减少肿瘤负荷，提高总生存率。
Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4-/-) CRC mouse model by crossing with Muc4-/- and Apcflox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads to poor survival. Further, the absence of Muc4 was associated with goblet cell dysfunction where the expression of intestinal homeostasis molecules (Muc2 and Fam3D) was downregulated. Next, we also observed that loss of Muc4 showed reduced thickness of mucus layer, leading to infiltration of bacteria, reduction in anti-microbial peptides, and upregulation of pro-inflammatory cytokines. Further, Apc gene mutation results in activation of the Wnt/β-catenin signaling pathway that corroborated with an increased nuclear accumulation of β-catenin and activation of its target genes: cyclin D1 and c-Myc in Muc4-/- mice was observed. We conclude that the presence of Muc4 is essential for intestinal homeostasis, reduces tumor burden, and improves overall survival.