Oncogenic effects of RAB27B through exosome independent function in renal cell carcinoma including sunitinib-resistant
Oncogenic effects of RAB27B through exosome independent function in renal cell carcinoma including sunitinib-resistant
复制标题
DOI：
10.1371/journal.pone.0232545
复制
发表时间：
2020-05-07
期刊：
影响因子：
3.7
通讯作者：
Enokida, Hideki
中科院分区：
文献类型：
--
作者：
Tsuruda, Masafumi;Yoshino, Hirofumi;Enokida, Hideki
Exosome是40-100 nm的纳米级细胞外小泡。它们从多种类型的细胞中释放出来，进入细胞外空间，从而将它们的成分转移到受体细胞。胞外体作为参与细胞内通讯的新型结构正受到越来越多的关注。RAB27B是参与外体分泌的主要蛋白之一，已有报道在几种癌症中具有致癌作用。近年来，以舒尼替尼为代表的分子靶向药物被广泛用于治疗转移性或复发性肾细胞癌。然而，对舒尼替尼的内在或获得性耐药已成为一个主要问题。本研究旨在阐明RAB27B在肾癌中的作用，包括对舒尼替尼的耐药性及其在外体中的作用。生物信息学分析表明，RAB27B的高表达与肾癌的进展有关。RAB27B蛋白在肾癌细胞系中的表达明显高于正常肾细胞系。此外，与亲本细胞相比，所有耐舒尼替尼的肾癌细胞株的RAB27B蛋白表达均增强。虽然RAB27B对肾癌细胞的外切体没有特异的作用，但功能丧失研究表明，RAB27B的敲除抑制了细胞的增殖、迁移和侵袭活动。此外，还观察到RAB27B下调对舒尼替尼耐药肾癌细胞的抗肿瘤作用。RNA序列和通路分析表明，RAB27B的致癌作用可能与MAPK和VEGF信号通路有关。这些结果表明，RAB27B是一个预后标志物和一个新的治疗靶点，在对舒尼替尼敏感和耐药的肾癌中。进一步的分析将提高我们对肾细胞癌中舒尼替尼耐药的理解。
Exosomes are 40-100 nm nano-sized extracellular vesicles. They are released from many cell types and move into the extracellular space, thereby transferring their components to recipient cells. Exosomes are receiving increasing attention as novel structures participating in intracellular communication. RAB27B is one of the leading proteins involved in exosome secretion, and oncogenic effects have been reported in several cancers. In recent years, molecularly targeted agents typified by sunitinib are widely used for the treatment of metastatic or recurrent renal cell carcinoma (RCC). However, intrinsic or acquired resistance to sunitinib has become a major issue. The present study aimed to elucidate the role of RAB27B in RCC including sunitinib-resistant and its role in exosomes. Bioinformatic analyses revealed that high expression of RAB27B correlates with progression of RCC. The expression of RAB27B protein in RCC cell lines was significantly enhanced compared with that in normal kidney cell lines. Furthermore, RAB27B protein expression was enhanced in all of the tested sunitinib-resistant RCC cell lines compared to parental cells. Although no specific effect of RAB27B on exosomes was identified in RCC cells, loss-of-function studies demonstrated that knockdown of RAB27B suppressed cell proliferation, migration and invasive activities. Moreover, anti-tumor effects of RAB27B downregulation were also observed in sunitinib-resistant RCC cells. RNA sequence and pathway analysis suggested that the oncogenic effects of RAB27B might be associated with MAPK and VEGF signaling pathways. These results showed that RAB27B is a prognostic marker and a novel therapeutic target in sunitinib-sensitive and -resistant RCCs. Further analyses should improve our understanding of sunitinib resistance in RCC.