SGCE Promotes Breast Cancer Stem Cells by Stabilizing EGFR
SGCE Promotes Breast Cancer Stem Cells by Stabilizing EGFR
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SGCE 通过稳定 EGFR 促进乳腺癌干细胞
DOI：
10.1002/advs.201903700
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发表时间：
2020-06-08
期刊：
影响因子：
15.1
通讯作者：
Jiao, Baowei
中科院分区：
文献类型：
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作者：
Zhao, Lina;Qiu, Ting;Jiao, Baowei
乳腺癌干细胞（BCSC）是导致化疗耐药、高度转移和预后不良的原因，尤其是在三阴性乳腺癌（TNBC）中。CD 24（低）CD 44（高）和高醛脱氢酶1（ALDH 1）细胞亚群（CD 24（低）CD 44（高）ALDH 1（+））表现出非常高的肿瘤起始能力。在目前的研究中，在CD 24（低）CD 44（高）和ALDH 1（+）细胞群体中以单细胞分辨率分析了上调的基因，并在两个BCSC群体中鉴定了高表达的膜蛋白SGCE。进一步的结果表明，SGCE消耗减少BCSC自我更新，化疗耐药性，和转移在体外和体内，部分通过影响细胞外基质（ECM）的积累。对于潜在的机制，SGCE充当表皮生长因子受体（EGFR）与其E3泛素化连接酶（c-Cbl）之间相互作用的海绵分子，从而抑制EGFR溶酶体降解以稳定EGFR蛋白。SGCE敲低促进了对EGFR酪氨酸激酶抑制剂（TKI）的敏感性，为解读目前临床试验中靶向EGFR的失败提供了新的线索，并突出了BCSC干性调节的新候选者。
Breast cancer stem cells (BCSCs) are responsible for resistance to chemotherapy, high degree of metastasis, and poor prognosis, especially in triple-negative breast cancer (TNBC). The CD24(low)CD44(high) and high aldehyde dehydrogenase 1 (ALDH1) cell subpopulation (CD24(low)CD44(high) ALDH1(+)) exhibit very high tumor initiating capacity. In the current study, the upregulated genes are analyzed in both CD24(low)CD44(high) and ALDH1(+) cell populations at single-cell resolution, and a highly expressed membrane protein, SGCE, is identified in both BCSC populations. Further results show that SGCE depletion reduces BCSC self-renewal, chemoresistance, and metastasis both in vitro and in vivo, partially through affecting the accumulation of extracellular matrix (ECM). For the underlying mechanism, SGCE functions as a sponge molecule for the interaction between epidermal growth factor receptor (EGFR) and its E3 ubiquitination ligase (c-Cbl), and thus inhibits EGFR lysosomal degradation to stabilize the EGFR protein. SGCE knockdown promotes sensitivity to EGFR tyrosine kinase inhibitors (TKIs), providing new clues for deciphering the current failure of targeting EGFR in clinical trials and highlighting a novel candidate for BCSC stemness regulation.