Humphries Brock A, Wang Zhishan, Yang Chengfeng
Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.
Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, 1095 V A Drive, Lexington, KY 40536, USA.
Cancers (Basel). 2020 Apr 28;12(5):1092. doi: 10.3390/cancers12051092.
The small Rho GTPases regulate important cellular processes that affect cancer metastasis, such as cell survival and proliferation, actin dynamics, adhesion, migration, invasion and transcriptional activation. The Rho GTPases function as molecular switches cycling between an active GTP-bound and inactive guanosine diphosphate (GDP)-bound conformation. It is known that Rho GTPase activities are mainly regulated by guanine nucleotide exchange factors (RhoGEFs), GTPase-activating proteins (RhoGAPs), GDP dissociation inhibitors (RhoGDIs) and guanine nucleotide exchange modifiers (GEMs). These Rho GTPase regulators are often dysregulated in cancer; however, the underlying mechanisms are not well understood. MicroRNAs (miRNAs), a large family of small non-coding RNAs that negatively regulate protein-coding gene expression, have been shown to play important roles in cancer metastasis. Recent studies showed that miRNAs are capable of directly targeting RhoGAPs, RhoGEFs, and RhoGDIs, and regulate the activities of Rho GTPases. This not only provides new evidence for the critical role of miRNA dysregulation in cancer metastasis, it also reveals novel mechanisms for Rho GTPase regulation. This review summarizes recent exciting findings showing that miRNAs play important roles in regulating Rho GTPase regulators (RhoGEFs, RhoGAPs, RhoGDIs), thus affecting Rho GTPase activities and cancer metastasis. The potential opportunities and challenges for targeting miRNAs and Rho GTPase regulators in treating cancer metastasis are also discussed. A comprehensive list of the currently validated miRNA-targeting of small Rho GTPase regulators is presented as a reference resource.
小Rho GTP酶调节影响癌症转移的重要细胞过程，如细胞存活和增殖、肌动蛋白动力学、黏附、迁移、侵袭及转录激活。Rho GTP酶作为分子开关，在活性GTP结合构象和非活性二磷酸鸟苷（GDP）结合构象之间循环。已知Rho GTP酶活性主要受鸟嘌呤核苷酸交换因子（RhoGEFs）、GTP酶激活蛋白（RhoGAPs）、GDP解离抑制剂（RhoGDIs）和鸟嘌呤核苷酸交换修饰剂（GEMs）调节。这些Rho GTP酶调节剂在癌症中常失调，但其潜在机制尚不清楚。微小RNA（miRNAs）是一大类负向调节蛋白质编码基因表达的小非编码RNA，已证明在癌症转移中起重要作用。最近的研究表明，miRNAs能够直接靶向RhoGAPs、RhoGEFs和RhoGDIs，并调节Rho GTP酶的活性。这不仅为miRNA失调在癌症转移中的关键作用提供了新证据，还揭示了Rho GTP酶调节的新机制。本综述总结了最近令人兴奋的发现，表明miRNAs在调节Rho GTP酶调节剂（RhoGEFs、RhoGAPs、RhoGDIs）中起重要作用，从而影响Rho GTP酶活性和癌症转移。还讨论了靶向miRNAs和Rho GTP酶调节剂治疗癌症转移的潜在机遇和挑战。列出了目前已验证的靶向小Rho GTP酶调节剂的miRNA的综合清单作为参考资源。
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