Pęcak Aleksandra, Skalniak Łukasz, Pels Katarzyna, Książek Mirosław, Madej Mariusz, Krzemień Dobrosława, Malicki Stanisław, Władyka Benedykt, Dubin Adam, Holak Tad A, Dubin Grzegorz
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
Nucleic Acid Ther. 2020 Oct;30(5):289-298. doi: 10.1089/nat.2019.0833. Epub 2020 May 6.
CD44 is a type I transmembrane glycoprotein interacting with a number of extracellular components, including hyaluronic acid (HA). CD44-HA axis is involved in a variety of processes, including adhesion, migration, differentiation, trafficking, and others. CD44 is overexpressed in several cancers where binding of HA induces signal transduction leading to activation of antiapoptotic proteins and factors linked to drug resistance. As such, CD44 has been implicated in cancer growth, progression, and metastasis. It has been convincingly demonstrated that blocking CD44-HA interaction decreases cancer cell survival and metastasis. In this study, using selection, we have developed DNA aptamers recognizing a HA-binding domain of CD44 with high affinity and specificity. The aptamers bind to CD44 with nanomolar affinities and efficiently inhibit the growth of leukemic cancer cells characterized by high expression of CD44. The selectivity is demonstrated by an irrelevant effect on cells characterized by low CD44 levels. The obtained aptamers broaden the existing landscape of potential approaches to the development of antitumor strategies based on inhibition of the CD44 axis.
CD44是一种I型跨膜糖蛋白，可与多种细胞外成分相互作用，包括透明质酸（HA）。CD44-HA轴参与多种过程，包括黏附、迁移、分化、运输等。CD44在几种癌症中过表达，其中HA的结合诱导信号转导，导致抗凋亡蛋白和与耐药性相关的因子激活。因此，CD44与癌症的生长、进展和转移有关。有令人信服的证据表明，阻断CD44-HA相互作用可降低癌细胞的存活率和转移能力。在本研究中，我们通过筛选开发出了能以高亲和力和特异性识别CD44的HA结合域的DNA适配体。这些适配体以纳摩尔亲和力与CD44结合，并有效抑制以CD44高表达为特征的白血病癌细胞的生长。对以低CD44水平为特征的细胞无相关影响，证明了其选择性。所获得的适配体拓宽了基于抑制CD44轴开发抗肿瘤策略的现有潜在方法。
