Silencing of brain-expressed X-linked 2 (BEX2) promotes colorectal cancer metastasis through the Hedgehog signaling pathway
Silencing of brain-expressed X-linked 2 (BEX2) promotes colorectal cancer metastasis through the Hedgehog signaling pathway
复制标题
脑表达的 X 连锁 2 (BEX2) 沉默通过 Hedgehog 信号通路促进结直肠癌转移
DOI：
10.7150/ijbs.38431
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Ding, Kefeng
中科院分区：
文献类型：
--
作者：
Tan, Yinuo;Hu, Yeting;Ding, Kefeng
结直肠癌的发病率呈上升趋势，而肿瘤转移是导致预后不良的主要原因之一。据报道，BEX2参与了几种类型的癌症的肿瘤发展，但它在转移性结直肠癌中的作用在很大程度上仍不清楚。在此，我们证明了BEX2基因敲除导致了结直肠癌细胞在体内外迁移和转移能力的增强，并且在BEX2基因敲除细胞中的重新表达可以逆转这种增强的迁移能力。RNA-Seq结果表明，BEX2基因敲除后，Hedgehog信号通路被激活，Hedgehog信号通路抑制剂GANT61和GDC-0449可以逆转BEX2-/-结直肠癌细胞的迁移增强。我们还证明了BEX2沉默后Zic2的核转位可以激活Hedgehog信号通路，而Zic2基因敲除则取消了BEX2-/-细胞的迁移增强，并抑制了Hedgehog信号通路。综上所述，我们的研究结果表明，BEX2通过将Zic2保留在结直肠癌细胞的胞浆中来负向调节Hedgehog信号通路，从而抑制结直肠癌细胞的迁移和转移。
The incidence of colorectal cancer is increasing, and cancer metastasis is one of the major causes of poor outcomes. BEX2 has been reported to be involved in tumor development in several types of cancer, but its role in metastatic colorectal cancer remains largely undefined. Herein, we demonstrated that BEX2 knockout resulted in enhanced migratory and metastatic potential in colorectal cancer cells both in vitro and in vivo, and re-expression of BEX2 in knockout cells could reverse the enhanced migratory capacity. RNA-Seq results indicated that the hedgehog signaling pathway was activated after BEX2 knockout; moreover, the hedgehog signaling inhibitors, GANT61 and GDC-0449 could reverse the migratory enhancement of BEX2-/- colorectal cancer cells. We also demonstrated that the nuclear translocation of Zic2 after BEX2 silencing could activate the hedgehog signaling pathway, while Zic2 knockdown abrogated the migratory enhancement of BEX2-/- cells and inhibited the hedgehog signaling pathway. In summary, our findings suggest that BEX2 negatively modulates the hedgehog signaling pathway by retaining Zic2 in the cytoplasm in colorectal cancer cells, thereby inhibiting migration and metastasis of colorectal cancer cells.