Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44
Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44
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Cosmc 破坏介导的异常 O-糖基化通过 CD44 损伤抑制乳腺癌细胞生长
DOI：
10.2147/cmar.s234735
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发表时间：
2020-01-01
影响因子：
3.3
通讯作者：
Wen, Tao
中科院分区：
文献类型：
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作者：
Du, Tan;Jia, Xingyuan;Wen, Tao
背景乳腺癌仍然是全世界女性最致命的恶性肿瘤。 O-糖基化异常与许多人类疾病密切相关，其中包括乳腺癌；然而，其在癌症发展中的确切作用尚不清楚。 Cosmc 是一种内质网定位的伴侣，可调节蛋白质的 O-糖基化。 Cosmc 功能障碍导致 T 合酶失活并表达截短的 O 聚糖，例如 Tn 抗原。在这里，我们通过体外和体内实验研究了 Cosmc 破坏介导的异常 O-糖基化对乳腺癌细胞发育的影响。材料和方法我们使用CRISPR/Cas-9系统删除了两种乳腺癌细胞系（MCF7、T47D）中的Cosmc基因，然后测量了Tn抗原的表达水平。通过 RTCA、集落形成和体内实验检查 Tn 阳性细胞的增殖。还确定了 Cosmc 缺陷对糖蛋白 CD44 和 MAPK 途径的影响。结果体外和体内研究均表明，与相应对照相比，Cosmc 缺陷显着抑制了乳腺癌细胞的生长。从机制上讲，Cosmc 破坏损害了 CD44 的蛋白表达和相关的 MAPK 信号通路；后者在细胞增殖中起着至关重要的作用。 CD44 的重建基本上逆转了观察到的改变，证实 CD44 需要正常的 O-糖基化才能正确表达和激活相关信号通路。结论 这项研究表明，Cosmc 缺陷介导的异常 O-糖基化抑制乳腺癌细胞生长，这可能是由 CD44 表达受损介导的。
Background Breast cancer remains the most lethal malignancy in women worldwide. Aberrant O-glycosylation is closely related to many human diseases, including breast carcinoma; however, its precise role in cancer development is insufficiently understood. Cosmc is an endoplasmic reticulum-localized chaperone that regulates the O-glycosylation of proteins. Cosmc dysfunction results in inactive T-synthase and expression of truncated O-glycans such as Tn antigen. Here we investigated the impact of Cosmc disruption-mediated aberrant O-glycosylation on breast cancer cell development through in vitro and in vivo experiments. Materials and Methods We deleted the Cosmc gene in two breast cancer cell lines (MCF7, T47D) using the CRISPR/Cas-9 system and then measured the expression levels of Tn antigen. The proliferation of Tn-positive cells was examined by RTCA, colony formation and in vivo experiments. The effects of Cosmc deficiency on glycoprotein CD44 and MAPK pathway were also determined. Results Both in vitro and in vivo studies showed that Cosmc deficiency markedly suppressed breast cancer cell growth compared with the corresponding controls. Mechanistically, Cosmc disruption impaired the protein expression of CD44 and the associated MAPK signaling pathway; the latter plays a crucial role in cell proliferation. Reconstitution of CD44 substantially reversed the observed alterations, confirming that CD44 requires normal O-glycosylation for its proper expression and activation of the related signaling pathway. Conclusion This study showed that Cosmc deficiency-mediated aberrant O-glycosylation suppressed breast cancer cell growth, which was likely mediated by the impairment of CD44 expression.