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Differential expression of mucins h
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.(#br)METHODS(#br)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.(#br)RESULTS(#br)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.(#br)CONCLUSION(#br)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.
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粘蛋白的差异表达已经与包括结肠直肠癌（CRC）在内的几种癌症相关。在正常生理条件下，分泌性粘蛋白MUC5AC在结肠粘膜中不表达，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然不清楚。免疫组织化学法测定结肠组织芯片中的METHODS（MUC5AC）表达。RNA干扰和CRISPR / Cas9介导的系统用于敲除/敲除CRC细胞系中的MUC5AC，以使用体外功能测定和体内（皮下和结肠原位）小鼠模型描述其在CRC肿瘤发生中的作用。最后，CRC细胞系和异种移植模型被用于确定MUC5AC的作用机制。（#br）结果（#br）在CRC患者组织和细胞系中观察到MUC5AC的过表达。MUC5AC表达导致增强的细胞侵袭和迁移，并减少CRC细胞的凋亡。MUC5AC在物理上与CD44相互作用，伴随着Src信号的激活。此外，在原位小鼠模型中，MUC5AC的存在导致增强的肿瘤发生和转移灶的出现。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，
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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.(#br)METHODS(#br)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.(#br)RESULTS(#br)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.(#br)CONCLUSION(#br)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.
正在翻译中..
粘蛋白的差异表达与包括结直肠癌在内的多种癌症有关。在正常生理条件下，分泌性粘蛋白MUC5AC在结肠黏膜中不表达，而在结肠癌及其前体病变的发生发展过程中，其表达异常。迄今为止，MUC5AC在大肠癌进展和耐药中的分子机制尚不清楚。采用RNA干扰和CRISPR/Cas9介导的系统，通过体外功能测定和体内（皮下和结肠原位）小鼠模型，敲除大肠癌细胞株中的MUC5AC，阐明其在大肠癌发生中的作用。最后，利用大肠癌细胞系和异种移植模型研究MUC5AC的作用机制。MUC5AC的表达增强了大肠癌细胞的侵袭和迁移，减少了大肠癌细胞的凋亡。MUC5AC与CD44在生理上相互作用，并激活Src信号。此外，在原位小鼠模型中，MUC5AC的存在导致肿瘤发生增强和转移病灶的出现。此外，MUC5AC的上调导致对5-氟尿嘧啶（5-FU）和奥沙利铂的耐药，其基因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，上调β-catenin及其靶基因CD44和Lgr5，从而产生对5-FU的耐药性。（#br）结论（#br）我们的发现提示分泌性MUC5AC的差异表达可导致肿瘤的发生，同时也可导致肿瘤的发生CD44/β-catenin/p53/p21信号转导介导的化疗耐药。<BR>
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