Department of Medical Laboratory Sciences, Hunter College, School of Arts and Sciences, New York, New York, USA.
J Cell Biochem. 2021 Oct;122(10):1295-1301. doi: 10.1002/jcb.29948. Epub 2021 May 13.
Rab proteins are GTPases involved in all stages of vesicular transport and membrane fusion in mammalian cells. Individual Rab proteins localize to specific cellular organelles and regulate a specific membrane trafficking pathway. Recent studies suggest an important role for Rab proteins in cancer. Rab3 isoforms (Rab3A, Rab3B, Rab3C, and Rab3D) are expressed almost exclusively in neurons and secretory cells. In this review, the role of Rab3 isoforms in a variety of tumor types is discussed. Of the four Rab3 isoforms, Rab3D has been studied most extensively in cancer cells and this isoform appears to play an oncogenic role in breast, colon, esophageal, skin, and brain tumors. Overexpression of Rab3A and Rab3C was observed in gliomas and colon cancers, respectively. Increased expression of the Rab3 isoforms is related to increased proliferation, migration, and invasiveness. Moreover, high Rab3 isoform levels are often associated with decreased survival and advanced pathological stage in clinical samples. Rab3 isoform-dependent activation of the AKT pathway has been observed in several studies. Although the effects of Rab3 isoforms on cancer cell growth and function have been examined in many tumor types, a number of important questions remain. Are the Rab3-positive vesicles in cancer cells actually secretory in nature? If so, are the contents of these vesicles secreted in a regulated or constitutive manner? How does Rab3-regulated secretion affect cellular signaling and tumor growth? Finally, can Rab3 isoforms be therapeutically manipulated in cancer cells? The fact that knockout of a single Rab3 isoform does not affect viability, at least in mouse models, suggests that targeting of these proteins may be a safe and effective treatment strategy for tumor cells expressing any of the Rab3 isoforms.
Rab 蛋白是参与哺乳动物细胞中囊泡运输和膜融合所有阶段的 GTPases。个别 Rab 蛋白定位于特定的细胞器官，并调节特定的膜运输途径。最近的研究表明 Rab 蛋白在癌症中起着重要作用。Rab3 同工型（Rab3A、Rab3B、Rab3C 和 Rab3D）几乎仅在神经元和分泌细胞中表达。在这篇综述中，讨论了 Rab3 同工型在各种肿瘤类型中的作用。在这四种 Rab3 同工型中，Rab3D 在癌细胞中的研究最为广泛，这种同工型似乎在乳腺癌、结肠癌、食管癌、皮肤癌和脑肿瘤中发挥致癌作用。在神经胶质瘤和结肠癌中分别观察到 Rab3A 和 Rab3C 的过表达。Rab3 同工型的表达增加与增殖、迁移和侵袭能力增强有关。此外，在临床样本中，Rab3 同工型水平升高与存活率降低和病理分期进展有关。在几项研究中观察到 Rab3 同工型依赖性 AKT 通路的激活。尽管已经在许多肿瘤类型中研究了 Rab3 同工型对癌细胞生长和功能的影响，但仍有许多重要问题有待解决。癌细胞中的 Rab3 阳性囊泡实际上是否具有分泌性质？如果是这样，这些囊泡的内容物是以受调控还是组成性方式分泌的？Rab3 调节的分泌如何影响细胞信号转导和肿瘤生长？最后，能否在癌细胞中对 Rab3 同工型进行治疗性操作？事实上，在至少在小鼠模型中，敲除单个 Rab3 同工型不会影响活力，这表明针对这些蛋白质可能是表达任何 Rab3 同工型的肿瘤细胞的一种安全有效的治疗策略。
