Sorting nexin 10 acts as a tumor suppressor in tumorigenesis and progression of colorectal cancer through regulating chaperone mediated autophagy degradation of p21(Cip1/WAF1).
Sorting nexin 10 acts as a tumor suppressor in tumorigenesis and progression of colorectal cancer through regulating chaperone mediated autophagy degradation of p21(Cip1/WAF1).
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分选 nexin 10 通过调节伴侣介导的 p21 (Cip1/WAF1) 自噬降解，在结直肠癌的肿瘤发生和进展中充当肿瘤抑制因子。
DOI：
10.1016/j.canlet.2018.01.045
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发表时间：
2018
期刊：
影响因子：
9.7
通讯作者：
Shen Xiaoyan
中科院分区：
文献类型：
--
作者：
Zhang;Sulin;Hu;Bin;You;Yan;Yang;Zhiwen;Liu;Zhang Sulin;Hu Bin;You Yan;Yang Zhiwen;Liu Lixin;Tang Huanhuan;Bao Weilian;Guan Yunyun;Shen Xiaoyan
分子伴侣介导的自噬（CMA）是近年来发现的一种与肿瘤发生有关的机制。在这里，我们探讨了分选连接蛋白10（SNX 10）的功能，一种参与维持内体/溶酶体稳态的蛋白质，介导CMA活性及其对小鼠炎症驱动的结直肠癌进展的影响。我们的研究结果表明，SNX 10缺陷通过阻止溶酶体LAMP-2A的降解来增加CMA的活化。在SNX 10 KO细胞中，我们发现p21 Cip 1/WAF 1是CMA的底物，是多种肿瘤抑制途径中的主要效应子，并且由SNX 10介导的CMA激活引起的p21 Cip 1/WAF 1的降低有助于HCT 116细胞的增殖和存活。此外，我们发现SNX 10 KO促进小鼠结肠直肠中的肿瘤发生，这可以通过SNX 10过表达来恢复。此外，SNX 10在人结直肠癌组织中表达显著下调，表现为CMA活性增加，p21 Cip 1/WAF 1表达降低。这些发现表明，SNX 10在小鼠结直肠中作为肿瘤抑制因子，并通过分子伴侣介导的自噬机制驱动炎症相关的结直肠癌。
Chaperone-mediated autophagy (CMA) characterized by the selective degradation of target proteins has been linked with tumorigenesis in recent years. Here, we explored the function of sorting nexin 10 (SNX10), a protein involved in maintaining endosome/lysosome homeostasis, in mediating CMA activity and its impact on the progression of mouse inflammation-driven colorectal cancer. Our results revealed that SNX10 deficiency increased the activation of CMA by preventing the degradation of lysosomal LAMP-2A. In SNX10 KO cells, we disclosed that p21Cip1/WAF1, a master effector in various tumor suppressor pathways, is a substrate of CMA, and decrease of p21Cip1/WAF1caused by SNX10-mediated CMA activation contributes to HCT116 cell proliferation and survival. Moreover, we found that SNX10 KO promoted tumorigenesis in the mouse colorectum which could be restored by SNX10 over-expression. Furthermore, SNX10 was remarkably down-regulated in human CRC tissues which showed the increased activity of CMA and decreased expression of p21Cip1/WAF1. These findings suggest that SNX10 acts as a tumor suppressor in the mouse colorectum and drives inflammation-associated colorectal cancer by a chaperone-mediated autophagy mechanism.