Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1
Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1
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DOI：
10.3892/or.2020.7502
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发表时间：
2020-04-01
期刊：
影响因子：
4.2
通讯作者：
Zhao, Zengren
中科院分区：
文献类型：
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作者：
Jiang, Xia;Li, Dongyun;Zhao, Zengren
结直肠癌（CRC）是世界上第三大常见肿瘤，然而内质网（ER）应激在CRC转移中的作用和机制仍不清楚。转移相关肺腺癌转录物1（MALAT 1）是一种长链非编码RNA（lncRNA），以前与CRC转移相关。已经表明ER应激途径调节lncRNA表达;然而，ER应激对癌症中MALAT 1表达的影响尚不清楚。本研究旨在探讨结直肠癌细胞中ER应激通路、MALAT 1表达和细胞迁移之间的关系。毒胡萝卜素（TG）可诱导ER应激，低剂量TG可诱导HT 29和HCT 116细胞迁移，但对SW 1116和SW 620细胞无诱导作用。这种效应与MALAT 1表达水平的增加有关，因为MALAT 1的敲低阻止了TG诱导的细胞迁移。TG诱导的MALAT 1表达与肌醇需要酶1（IRE 1）表达和蛋白激酶R（PKR）样ER激酶（PERK）信号通路的激活相关。X盒结合蛋白1（XBP 1）和转录激活因子4（ATF 4）结合位点位于MALAT 1基因启动子区，MALAT 1的表达与大肠癌组织标本中XBP 1和ATF 4的表达水平呈正相关。因此，这些研究结果表明，ER应激可能促进CRC细胞的迁移，并通过激活IRE 1/XBP 1和PERK/eIF 2 α/ATF 4信号通路促进CRC的进展。总之，据我们所知，这项研究是第一个报告，lncRNA MALAT 1的表达是由IRE 1/XBP 1途径在CRC中调节。
Colorectal cancer (CRC) is the third most common tumor in the world; however, the role and mechanism of endoplasmic reticulum (ER) stress in CRC metastasis remains largely unclear. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), which has previously been associated with CRC metastasis. It has been suggested that ER stress pathways regulate lncRNA expression; however, the effect of ER stress on MALAT1 expression in cancer is unknown. The present study aimed to investigate the relationship between ER stress pathways, MALAT1 expression and cell migration in CRC cells. ER stress was induced by thapsigargin (TG); low dose TG induced the migration of HT29 and HCT116 cells, but not SW1116 and SW620 cells. This effect was associated with increased expression levels of MALAT1, as the knockdown of MALAT1 prevented TG-induced cell migration. TG-induced MALAT1 expression was associated with inositol-requiring enzyme 1 (IRE1) expression and activation of the protein kinase R (PKR)-like ER kinase (PERK) signaling pathway. X-box-binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) binding sites were predicted to be located in the MALAT1 gene promoter regions and the expression of MALAT1 was positively associated with XBP1 and ATF4 expression levels in CRC tissue samples. Thus, these findings indicated that ER stress may promote the migration of CRC cells and contribute to the progression of CRC through the activation of the IRE1/XBP1 and PERK/eIF2 alpha/ATF4 signaling pathways. In conclusion, to the best of our knowledge, this study is the first report that lncRNA MALAT1 expression is regulated by the IRE1/XBP1 pathway in CRC.