Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis
Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis
复制标题
缺氧诱导因子和 RAB22A 介导微泡形成，刺激乳腺癌侵袭和转移
DOI：
10.1073/pnas.1410041111
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发表时间：
2014-08-05
影响因子：
11.1
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Wang, Ting;Gilkes, Daniele M.;Semenza, Gregg L.
意义 癌细胞从细胞表面释放膜内衬的微泡 (MV)，其中含有可被其他细胞摄取的蛋白质、mRNA 和 microRNA。我们报告说，暴露于氧气供应减少（缺氧）的乳腺癌细胞会增加其 MV 的产生，从而刺激受体乳腺癌细胞的侵袭和转移。缺氧细胞增加MV脱落需要表达缺氧诱导因子（HIF），其激活RAB22A基因的转录，以及小GTP酶RAB22A的表达，这是一种定位于出芽MV的蛋白质。我们的结果描绘了缺氧通过刺激 MV 脱落而增加侵袭和转移的分子机制，并提供了进一步的证据，表明在当前的治疗方案中添加 HIF 抑制剂可能会改善临床结果。细胞外囊泡如外泌体和微泡（MV）由癌细胞脱落，在癌症患者的血浆中检测到，并促进癌症进展，但调节其产生的分子机制尚不清楚。瘤内缺氧在晚期乳腺癌中很常见，并且与转移和患者死亡率增加的风险相关，这在一定程度上是由缺氧诱导因子（HIF）的激活介导的。在本文中，我们报道了人类乳腺癌细胞暴露于缺氧会增加MV脱落，这是由小GTP酶RAB22A的HIF依赖性表达介导的，其与细胞表面的出芽MV共定位。将幼稚乳腺癌细胞与缺氧乳腺癌细胞脱落的MV一起孵育可促进粘着斑形成、侵袭和转移。在乳腺癌患者中，原发肿瘤中的 RAB22A mRNA 过表达与总体生存率和无转移生存率降低相关，并且在原位小鼠模型中，RAB22A 敲低会损害乳腺癌转移。
Significance Cancer cells release from their cell surface membrane-lined microvesicles (MVs), which contain proteins, mRNAs, and microRNAs that can be taken up by other cells. We report that breast cancer cells exposed to decreased oxygen availability (hypoxia) increase their production of MVs, which stimulate invasion and metastasis by recipient breast cancer cells. Increased MV shedding by hypoxic cells requires expression of hypoxia-inducible factors (HIFs), which activate transcription of the RAB22A gene, and expression of the small GTPase RAB22A, which is a protein that localizes to budding MVs. Our results delineate a molecular mechanism by which hypoxia increases invasion and metastasis by stimulating MV shedding and provide further evidence that addition of HIF inhibitors to current treatment regimens may improve clinical outcome. Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.