Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA.
Oncol Rep. 2020 Jun;43(6):1945-1963. doi: 10.3892/or.2020.7550. Epub 2020 Mar 18.
Cerebral cavernous malformations (CCMs) are microvascular anomalies in the brain that result in increased susceptibility to stroke. Three genes have been identified as causes of CCMs: cerebral cavernous malformations 1 [(CCM1) also termed Krev interaction trapped 1 (KRIT1)], cerebral cavernous malformation 2 [(CCM2) also termed MGC4607] and cerebral cavernous malformation 3 [(CCM3) also termed programmed cell death 10 (PDCD10)]. It has been demonstrated that both CCM1 and CCM3 bind to CCM2 to form a CCM signaling complex (CSC) with which to modulate multiple signaling cascades. CCM proteins have been reported to play major roles in microvascular angiogenesis in human and animal models. However, CCM proteins are ubiquitously expressed in all major tissues, suggesting an unseen broader role of the CSC in biogenesis. Recent evidence suggests the possible involvement of the CSC complex during tumorigenesis; however, studies concerning this aspect are limited. This is the first report to systematically investigate the expression patterns of CCM proteins in major human tumors using real‑time quantitative PCR, RNA‑fluorescence in situ hybridization, immunohistochemistry and multicolor immunofluorescence imaging. Our data demonstrated that differential expression patterns of the CSC complex are correlated with certain types and grades of major human cancers, indicating the potential application of CCM genes as molecular biomarkers for clinical oncology. Our data strongly suggest that more efforts are needed to elucidate the role of the CSC complex in tumorigenesis, which may have enormous clinical potential for cancer diagnostic, prognostic and therapeutic applications.
脑内海绵状血管畸形（CCMs）是脑内的微小血管异常，导致中风易感性增加。已经确定了三个基因是 CCMs 的原因：脑内海绵状血管畸形 1（CCM1）也称为 Krev 相互作用捕获 1（KRIT1）、脑内海绵状血管畸形 2（CCM2）也称为 MGC4607 和脑内海绵状血管畸形 3（CCM3）也称为程序性细胞死亡 10（PDCD10）。已经证明 CCM1 和 CCM3 都与 CCM2 结合，形成具有调节多种信号级联反应的 CCM 信号复合物（CSC）。CCM 蛋白已被报道在人类和动物模型中发挥重要作用在微血管血管生成。然而，CCM 蛋白在所有主要组织中都广泛表达，这表明 CSC 在生物发生中具有未被发现的更广泛的作用。最近的证据表明 CSC 复合物可能在肿瘤发生过程中参与其中；然而，关于这方面的研究有限。这是第一篇使用实时定量 PCR、RNA 荧光原位杂交、免疫组织化学和多色免疫荧光成像系统地研究 CCM 蛋白在主要人类肿瘤中的表达模式的报告。我们的数据表明，CSC 复合物的差异表达模式与某些类型和分级的主要人类癌症相关，表明 CCM 基因作为临床肿瘤学的分子生物标志物具有潜在的应用。我们的数据强烈表明，需要更多的努力来阐明 CSC 复合物在肿瘤发生中的作用，这可能对癌症诊断、预后和治疗应用具有巨大的临床潜力。
