Abstract：
Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.
摘要：
基因融合是癌症中常见的体细胞改变，和具有致瘤特征的融合已被确定为癌症和治疗靶标的新驱动因素。很少有研究确定融合基因的致癌能力是否与细胞中干细胞的诱导有关。癌症干细胞（CSC）是有助于癌症进展的细胞亚群，转移,和复发，是癌症侵袭性特征的关键组成部分。这里,我们研究了CD63-BCAR4融合基因诱导的CSC样特性，先前报道为致癌融合，及其对CD63-BCAR4的显着特征增强的转移的潜在贡献。CD63-BCAR4过表达促进永生化支气管上皮细胞中的球体形成。在来自CD63-BCAR4过表达细胞的异种移植小鼠的肿瘤衍生细胞中观察到的显著增强的球体形成活性被BCAR4的沉默抑制。RNA微阵列分析显示ALDH1A1在BCAR4融合过表达细胞中上调。与空载体相比，在CD63-BCAR4过表达细胞的球体中观察到ALDH1A1的活性和表达增加。在BCAR4融合过表达细胞中CD133和CD44水平也升高。NANOG增加,在源自注射了CD63-BCAR4过表达细胞的小鼠的转移性肿瘤细胞中观察到S0X2和0CT-3/4蛋白水平。此外，DEAB,ALDH1A1抑制剂，降低了CD63-BCAR4诱导的迁移活性以及球体形成活性。我们的发现表明，CD63-BCAR4融合通过上调ALDH1A1诱导CSC样特性，这有助于其转移特征。
