MUC5AC-CD44 轴在结直肠癌进展和化疗耐药中的分子意义。
Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance.
机构信息
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
出版信息
Mol Cancer. 2020 Feb 25;19(1):37. doi: 10.1186/s12943-020-01156-y.
BACKGROUND
Differential expression of mucins has been associated with several cancers including colorectal cancer (CRC). In normal physiological conditions, secretory mucin MUC5AC is not expressed in the colonic mucosa, whereas its aberrant expression is observed during development of colon cancer and its precursor lesions. To date, the molecular mechanism of MUC5AC in CRC progression and drug resistance remains obscure.
METHODS
MUC5AC expression was determined in colon tissue microarray by immunohistochemistry. A RNA interference and CRISPR/Cas9-mediated system was used to knockdown/knockout the MUC5AC in CRC cell lines to delineate its role in CRC tumorigenesis using in vitro functional assays and in vivo (sub-cutaneous and colon orthotopic) mouse models. Finally, CRC cell lines and xenograft models were used to identify the mechanism of action of MUC5AC.
RESULTS
Overexpression of MUC5AC is observed in CRC patient tissues and cell lines. MUC5AC expression resulted in enhanced cell invasion and migration, and decreased apoptosis of CRC cells. MUC5AC interacted with CD44 physically, which was accompanied by the activation of Src signaling. Further, the presence of MUC5AC resulted in enhanced tumorigenesis and appearance of metastatic lesions in orthotopic mouse model. Additionally, up-regulation of MUC5AC resulted in resistance to 5-fluorouracil (5-FU) and oxaliplatin, and its knockout increased sensitivity to these drugs. Finally, we observed that up-regulation of MUC5AC conferred resistance to 5-FU through down-regulation of p53 and its target gene p21 and up-regulation of β-catenin and its target genes CD44 and Lgr5.
CONCLUSION
Our findings suggest that differential expression of secretory mucin MUC5AC results in enhanced tumorigenesis and also confers chemoresistance via CD44/β-catenin/p53/p21 signaling.
背景
黏蛋白的差异表达与包括结直肠癌（CRC）在内的多种癌症有关。在正常生理条件下，分泌型黏蛋白 MUC5AC 不在结肠黏膜中表达，而在结肠癌及其前体病变的发展过程中观察到其异常表达。迄今为止，MUC5AC 在 CRC 进展和耐药中的分子机制仍不清楚。
方法
通过免疫组织化学法在结肠组织微阵列中测定 MUC5AC 的表达。使用 RNA 干扰和 CRISPR/Cas9 介导的系统在 CRC 细胞系中敲低/敲除 MUC5AC，以使用体外功能测定和体内（皮下和结肠原位）小鼠模型来描绘其在 CRC 肿瘤发生中的作用。最后，使用 CRC 细胞系和异种移植模型来确定 MUC5AC 的作用机制。
结果
在 CRC 患者组织和细胞系中观察到 MUC5AC 的过度表达。MUC5AC 的表达导致 CRC 细胞的侵袭和迁移增强，凋亡减少。MUC5AC 与 CD44 物理相互作用，伴随着Src 信号的激活。此外，MUC5AC 的存在导致了在原位小鼠模型中肿瘤发生和转移病变的出现增加。此外，MUC5AC 的上调导致对 5-氟尿嘧啶（5-FU）和奥沙利铂的耐药性，其敲除增加了对这些药物的敏感性。最后，我们观察到 MUC5AC 的上调通过下调 p53 及其靶基因 p21 和上调 β-连环蛋白及其靶基因 CD44 和 Lgr5 来赋予对 5-FU 的耐药性。
结论
我们的研究结果表明，分泌型黏蛋白 MUC5AC 的差异表达导致肿瘤发生增强，并通过 CD44/β-连环蛋白/p53/p21 信号通路赋予化学耐药性。
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