PIK3CD induces cell growth and invasion by activating AKT/GSK-3β/β-catenin signaling in colorectal cancer
PIK3CD induces cell growth and invasion by activating AKT/GSK-3β/β-catenin signaling in colorectal cancer
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PIK3CD 通过激活结直肠癌中的 AKT/GSK-3 β/β-catenin 信号传导诱导细胞生长和侵袭
DOI：
10.1111/cas.13931
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发表时间：
2019-03-01
期刊：
影响因子：
5.7
通讯作者：
Zhong, Jian-Feng
中科院分区：
文献类型：
--
作者：
Chen, Jing-Song;Huang, Jiong-Qiang;Zhong, Jian-Feng
由PIK 3 CD编码的磷酸肌醇3-激酶（PI 3 K）的催化亚基p110 δ与一些人实体瘤有关。然而，其在结直肠癌（CRC）中的作用在很大程度上仍然未知。在这里，我们发现PIK 3CD在结肠癌组织和CRC细胞系中过表达，并且是结肠癌患者总生存期（OS）的独立预测因子。PIK 3 CD的异位过表达显著促进了CRC细胞的体外生长、迁移和侵袭以及体内肿瘤的生长。相比之下，通过特异性小干扰RNA或艾代拉里斯抑制PIK 3CD显著抑制CRC细胞体外生长、迁移和侵袭以及体内肿瘤生长。此外，PIK 3CD过表达增加AKT活性，β-连环蛋白和T细胞因子/淋巴增强因子（TCF/LEF）转录活性的核转位，并降低糖原合成酶激酶3 β（GSK-3 β）活性，而PIK 3CD抑制表现出相反的效果。此外，PIK 3CD介导的细胞生长、迁移和侵袭通过阻断AKT信号传导或耗尽β-连环蛋白而逆转。此外，结肠癌组织中PIK 3 CD表达与β-catenin异常表达呈正相关，是结肠癌患者OS的独立预测因子。综上所述，我们的研究结果表明，PIK 3 CD是CRC中的独立预后因子，并且PIK 3 CD通过激活AKT/GSK-3 β/β-连环蛋白信号传导诱导CRC细胞生长、迁移和侵袭，这表明PIK 3 CD可能是CRC的新的预后生物标志物和潜在的治疗靶点。
The catalytic subunit p110 delta of phosphoinositide 3-kinase (PI3K) encoded by PIK3CD has been implicated in some human solid tumors. However, its roles in colorectal cancer (CRC) remain largely unknown. Here we found that PIK3CD was overexpressed in colon cancer tissues and CRC cell lines and was an independent predictor for overall survival (OS) of patients with colon cancer. The ectopic overexpression of PIK3CD significantly promoted CRC cell growth, migration and invasion in vitro and tumor growth in vivo. In contrast, inhibition of PIK3CD by specific small-interfering RNA or idelalisib dramatically suppressed CRC cell growth, migration and invasion in vitro and tumor growth in vivo. Moreover, PIK3CD overexpression increased AKT activity, nuclear translocation of beta-catenin and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activity and decreased glycogen synthase kinase 3 beta (GSK-3 beta) activity, whereas PIK3CD inhibition exhibited the opposite effects. Furthermore, PIK3CD-mediated cell growth, migration and invasion were reversed by blockade of AKT signaling or depletion of beta-catenin. In addition, PIK3CD expression in colon cancer tissues positively correlated with beta-catenin abnormal expression, which was an independent predictor for OS of colon cancer patients. Taken together, our findings demonstrate that PIK3CD is an independent prognostic factor in CRC and that PIK3CD induces CRC cell growth, migration and invasion by activating AKT/GSK-3 beta/beta-catenin signaling, suggesting that PIK3CD might be a novel prognostic biomarker and a potential therapeutic target for CRC.