AKAP-9 promotes colorectal cancer development by regulating Cdc42 interacting protein 4.
AKAP-9 promotes colorectal cancer development by regulating Cdc42 interacting protein 4.
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DOI：
10.1016/j.bbadis.2016.03.012
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Li ZG
中科院分区：
文献类型：
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作者：
Hu ZY;Liu YP;Xie LY;Wang XY;Yang F;Chen SY;Li ZG
我们以前的研究表明，PRKA激酶锚定蛋白9(AKAP-9)参与了结直肠癌(CRC)细胞的体外增殖和迁移。然而，AKAP-9在体内是否对结直肠癌的发生或转移起重要作用仍不清楚。在本研究中，我们发现AKAP-9在人类结直肠癌组织中的表达显著高于配对的正常组织。事实上，AKAP-9水平与大肠癌的侵袭深度和转移密切相关。此外，AKAP-9表达越高，患者的生存率越低。在培养的CRC细胞中，AKAP-9基因敲除抑制了细胞的增殖、侵袭和迁移。在体内，AKAP-9缺乏也抑制了结直肠癌的生长和转移。在机制上，AKAP-9与CDC42相互作用蛋白4(CIP4)相互作用并调节其表达。大肠癌细胞中CIP4水平与AKAP-9水平呈正相关。在功能上，AKAP-9在转化生长因子-β-1诱导的结直肠癌细胞上皮-间充质转化中起重要作用，而CIP4在介导AKAP-9的功能中起关键作用。重要的是，CIP4在人结直肠癌组织中的表达显著上调。综上所述，我们的结果表明，AKAP-9通过调控CIP4介导的结直肠癌细胞上皮-间充质转化促进结直肠癌的发生和转移。
Our previous studies have shown that PRKA kinase anchor protein 9 (AKAP-9) is involved in colorectal cancer (CRC) cell proliferation and migration in vitro. However, whether or not AKAP-9 is important for CRC development or metastasis in vivo remains unknown. In the present study, we found that AKAP-9 expression was significantly higher in human colorectal cancer tissues than the paired normal tissues. In fact, AKAP-9 level correlated with the CRC infiltrating depth and metastasis. Moreover, the higher AKAP-9 expression was associated with the lower survival rate in patients. In cultured CRC cells, knockdown of AKAP-9 inhibited cell proliferation, invasion, and migration. AKAP-9 deficiency also attenuated CRC tumor growth and metastasis in vivo. Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues. Taken together, our results demonstrated that AKAP-9 facilitates CRC development and metastasis via regulating CIP4-mediated epithelial-mesenchymal transition of CRC cells.