Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, D-48149 Münster, Germany.
Molecules. 2019 Apr 23;24(8):1607. doi: 10.3390/molecules24081607.
Sonic hedgehog (Shh) signaling plays a tumor-promoting role in many epithelial cancers. Cancer cells produce soluble a Shh that signals to distant stromal cells that express the receptor Patched (Ptc). These receiving cells respond by producing other soluble factors that promote cancer cell growth, generating a positive feedback loop. To interfere with reinforced Shh signaling, we examined the potential of defined heparin and heparan sulfate (HS) polysaccharides to block Shh solubilization and Ptc receptor binding. We confirm in vitro and in vivo that proteolytic cleavage of the N-terminal Cardin-Weintraub (CW) amino acid motif is a prerequisite for Shh solubilization and function. Consistent with the established binding of soluble heparin or HS to the Shh CW target motif, both polysaccharides impaired proteolytic Shh processing and release from source cells. We also show that HS and heparin bind to, and block, another set of basic amino acids required for unimpaired Shh binding to Ptc receptors on receiving cells. Both modes of Shh activity downregulation depend more on HS size and overall charge than on specific HS sulfation modifications. We conclude that heparin oligosaccharide interference in the physiological roles of HS in Shh release and reception may be used to expand the field of investigation to pharmaceutical intervention of tumor-promoting Shh functions.
声波刺猬（Shh）信号在许多上皮癌中发挥着促进肿瘤的作用。癌细胞产生可溶性 Shh，向表达受体 Patched（Ptc）的远处基质细胞发出信号。这些接收细胞通过产生其他促进癌细胞生长的可溶性因子做出反应，从而产生正反馈环。为了干扰强化的 Shh 信号，我们研究了特定肝素和硫酸乙酰肝素（HS）多糖阻断 Shh 溶解和 Ptc 受体结合的潜力。我们在体外和体内证实，N 端 Cardin-Weintraub（CW）氨基酸基序的蛋白水解切割是 Shh 溶解和功能的前提。与可溶性肝素或 HS 与 Shh CW 靶基序的已知结合一致，这两种多糖都损害了 Shh 的蛋白水解处理和从源细胞释放。我们还表明，HS 和肝素结合并阻断另一组碱性氨基酸，这些氨基酸对于 Shh 与接收细胞上的 Ptc 受体的无干扰结合是必需的。Shh 活性下调的这两种模式都更依赖于 HS 的大小和总电荷，而不是特定的 HS 硫酸化修饰。我们得出结论，肝素寡糖对 HS 在 Shh 释放和接收中的生理作用的干扰可能用于扩大研究领域，以进行促进肿瘤的 Shh 功能的药物干预。
