OPCML is a highly conserved glycosyl phosphatidylinositol (GPI)-anchored protein belonging to the IgLON family of cell adhesion molecules. OPCML functions as a tumor suppressor and is silenced in over 80% of ovarian cancers by loss of heterozygosity and by epigenetic mechanisms. OPCML inactivation is also observed in many other cancers suggesting a conservation of tumor suppressor function. Although epigenetic silencing and subsequent loss of OPCML expression correlate with poor progression-free and overall patient survival, its mechanism of action is only starting to be fully elucidated. Recent discoveries have demonstrated that OPCML exerts its tumor suppressor effect by inhibiting several cancer hallmark phenotypes in vitro and abrogating tumorigenesis in vivo, by downregulating/inactivating a specific spectrum of Receptor Tyrosine Kinases (RTKs), including EphA2, FGFR1, FGFR3, HER2, HER4, and AXL. This modulation of RTKs can also sensitize ovarian and breast cancers to lapatinib, erlotinib, and anti-AXL therapies. Furthermore, OPCML has also been shown to function in synergy with the tumor suppressor phosphatase PTPRG to inactivate pro-metastatic RTKs such as AXL. Recently, the identification of inactivating point mutations and the elucidation of the crystal structure of OPCML have provided valuable insights into its structure-function relationships, giving rise to its potential as an anti-cancer therapeutic.

OPCML 是一种高度保守的糖基磷脂酰肌醇 (GPI) 锚定蛋白，属于 IgLON 细胞粘附分子家族。OPCML作为肿瘤抑制因子发挥作用，在超过 80% 的卵巢癌中由于杂合性缺失和表观遗传机制而被沉默。OPCML在许多其他癌症中也观察到失活，这表明肿瘤抑制功能的保守。尽管表观遗传沉默和随后的 OPCML 表达丧失与无进展和总体患者生存率低相关，但其作用机制才刚刚开始得到充分阐明。最近的发现表明，OPCML 通过下调/失活特定谱的受体酪氨酸激酶 (RTK)，包括 EphA2、FGFR1、FGFR3、HER2、HER4，在体外抑制几种癌症标志性表型并在体内消除肿瘤发生，从而发挥其肿瘤抑制作用，和 AXL。RTK 的这种调节还可以使卵巢癌和乳腺癌对拉帕替尼、厄洛替尼和抗 AXL 疗法敏感。此外，OPCML 还显示出与肿瘤抑制磷酸酶 PTPRG 协同作用，以灭活促转移性 RTK，例如 AXL。最近，失活点突变的鉴定和 OPCML 晶体结构的阐明为其结构 - 功能关系提供了有价值的见解，使其具有作为抗癌治疗剂的潜力。