CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation
CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation
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CD44v10亚型调节的CD44激活状态决定乳腺癌增殖
DOI：
10.3892/or.2021.7958
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发表时间：
2021-04-01
期刊：
影响因子：
4.2
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Guo, Qian;Liu, Yiwen;Gao, Feng
细胞表面糖蛋白CD44表现出不同的活性状态；然而，CD44的激活过程是否对肿瘤的发生和进展至关重要仍不清楚。本研究的目的是探讨具有不同CD44激活状态的乳腺癌(BCa)细胞是否表现出相似或不同的功能特征，并进一步研究调节CD44活性的机制。 CD44“激活”状态的一个特征是它可以与其主要配体透明质酸 (HA) 结合。 CD44 与 HA 的结合通常受到 CD44 选择性剪接的影响，从而产生决定 CD44 活性的多种 CD44 同工型。使用流式细胞术根据 CD44-HA 结合能力（HA−/低 vs. HAhigh）对 BCa 细胞亚群进行分类。随后，在体外进行细胞增殖和集落形成测定，并通过蛋白质印迹分析CD44表达模式。结果表明，CD44 变体同种型 10 (CD44v10) 在 HA−/低结合亚群的 BCa 细胞中高表达，与 HA 高结合亚群相比，其表现出显着更高的增殖能力。 HA-/低结合亚群中 CD44v10 亚型的敲除诱导 HA 结合能力增加并显着抑制增殖。此外，机制分析发现 CD44v10 通过激活 ERK/p38 MAPK 和 AKT/mTOR 信号传导促进细胞增殖。此外，CD44v10表达的敲除下调了ERK、AKT和mTOR的磷酸化，而p38磷酸化没有观察到改变。总的来说，本研究确定了以 CD44v10 表达为特征的快速生长的 BCa 细胞子集，这可能作为 BCa 的特定治疗靶点。
The cell surface glycoprotein CD44 displays different active statuses; however, it remains unknown whether the activation process of CD44 is critical for tumor development and progression. The aim of the present study was to investigate whether breast cancer (BCa) cells with different activation states of CD44 show similar or distinct functional characteristics and to further examine the mechanisms regulating CD44 activities. A feature for the ‘activated’ state of CD44 is that it can bind to its principal ligand hyaluronan (HA). The binding of CD44 with HA is usually influenced by CD44 alternative splicing, resulting in multiple CD44 isoforms that determine CD44 activities. Flow cytometry was used to sort BCa cell subsets based on CD44-HA binding abilities (HA−/low vs. HAhigh). Subsequently, cell proliferation and colony formation assays were performed in vitro, and CD44 expression patterns were analyzed via western blotting. The results demonstrated that the CD44 variant isoform 10 (CD44v10) was highly expressed in a HA−/low binding subset of BCa cells, which exhibited a significantly higher proliferation capacity compared with the HAhigh binding subpopulation. Knockdown of CD44v10 isoform in HA−/low binding subpopulation induced an increase in HA binding ability and markedly inhibited proliferation. Furthermore, the mechanistic analysis identified that CD44v10 facilitated cell proliferation via activation of ERK/p38 MAPK and AKT/mTOR signaling. Moreover, the knockdown of CD44v10 expression downregulated the phosphorylation of ERK, AKT and mTOR, while no alteration was observed in p38 phosphorylation. Collectively, the present study identified a subset of fast-growing BCa cells characterized by CD44v10 expression, which may serve as a specific therapeutic target for BCa.