Yang Min-Hui, Hu Zhi-Yan, Xu Chuan, Xie Lin-Ying, Wang Xiao-Yan, Chen Shi-You, Li Zu-Guo
Department of Pathology, Nanfang Hospital, Southern Medical University, China; Key Laboratory of Transcriptome and Proteome for Human Major Diseases of the Ministry of Education and Guangdong Province, Guangzhou 510515, Guangdong Province, China.
Department of Physiology & Pharmacology, University of Georgia, Athens, GA, USA.
Biochim Biophys Acta. 2015 Jan;1852(1):166-74. doi: 10.1016/j.bbadis.2014.11.013. Epub 2014 Nov 18.
Our previous studies have shown that the 3' end of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in colorectal cancer (CRC) cell proliferation and migration/invasion in vitro. The role and mechanism of MALAT1 in CRC metastasis in vivo, however, remain largely unknown. In the present study, we found that MALAT1 was up-regulated in human primary CRC tissues with lymph node metastasis. Overexpression of MALAT1 via RNA activation promoted CRC cell proliferation, invasion and migration in vitro, and stimulated tumor growth and metastasis in mice in vivo. Conversely, knockdown of MALAT1 inhibited CRC tumor growth and metastasis. MALAT1 regulated at least 243 genes in CRC cells in a genome-wide expression profiling. Among these genes, PRKA kinase anchor protein 9 (AKAP-9) was significantly up-regulated at both mRNA and protein levels. AKAP-9 was highly expressed in CRC cells with metastatic potential and human primary CRC tissues with lymph node metastasis, but not in normal cells or tissues. Importantly, knockdown of AKAP-9 blocked MALAT1-mediated CRC cell proliferation, migration and invasion. These data indicate that MALAT1 may promote CRC tumor development via its target protein AKAP-9.
我们之前的研究表明，转移相关肺腺癌转录本1（MALAT1）的3'端在体外参与结直肠癌（CRC）细胞的增殖和迁移/侵袭。然而，MALAT1在体内CRC转移中的作用和机制仍 largely未知。在本研究中，我们发现MALAT1在伴有淋巴结转移的人原发性CRC组织中上调。通过RNA激活过表达MALAT1可促进体外CRC细胞的增殖、侵袭和迁移，并在体内刺激小鼠肿瘤生长和转移。相反，敲低MALAT1可抑制CRC肿瘤生长和转移。在全基因组表达谱分析中，MALAT1在CRC细胞中调控至少243个基因。在这些基因中，蛋白激酶A锚定蛋白9（AKAP-9）在mRNA和蛋白水平均显著上调。AKAP-9在具有转移潜能的CRC细胞和伴有淋巴结转移的人原发性CRC组织中高表达，但在正常细胞或组织中不表达。重要的是，敲低AKAP-9可阻断MALAT1介导的CRC细胞增殖、迁移和侵袭。这些数据表明，MALAT1可能通过其靶蛋白AKAP-9促进CRC肿瘤发展。
