蛋白激酶B
癌症研究
PI3K/AKT/mTOR通路
生物
转移
癌变
信号转导
结直肠癌
异位表达
细胞生长
癌症
细胞生物学
细胞培养
遗传学
作者
Xiaoshun He,Wen-Long Ye,Yu-Juan Zhang,Xiaoqin Yang,Feng Liu,Jing-Ru Wang,Xiao-Lu Ding,Yun Yang,Ruo-Nan Zhang,Yuanyuan Zhao,Hai-Xia Bi,Linxin Guo,Wen-Juan Gan,Hua Wu
出处
期刊:Oncogene
[Springer Nature]
日期:2022-01-21
卷期号:41 (8): 1166-1177
被引量:13
标识
DOI:10.1038/s41388-021-02160-2
摘要
BEST4 is a member of the bestrophin protein family that plays a critical role in human intestinal epithelial cells. However, its role and mechanism in colorectal cancer (CRC) remain largely elusive. Here, we investigated the role and clinical significance of BEST4 in CRC. Our results demonstrate that BEST4 expression is upregulated in clinical CRC samples and its high-level expression correlates with advanced TNM (tumor, lymph nodes, distant metastasis) stage, LNM (lymph node metastasis), and poor survival. Functional studies revealed that ectopic expression of BEST4 promoted CRC cell proliferation and metastasis, whereas the depletion of BEST4 had the opposite effect both in vitro and in vivo. Mechanistically, BEST4 binds to the p85α regulatory subunit of phosphatidylinositol-3-kinase (PI3K) and promotes p110 kinase activity; this leads to activation of Akt signaling and expression of MYC and CCND1, which are critical regulators of cell proliferation and metastasis. In clinical samples, the expression of BEST4 is positively associated with the expression of phosphorylated Akt, MYC and CCND1. Pharmacological inhibition of Akt activity markedly repressed BEST4-mediated Akt signaling and proliferation and metastasis of CRC cells. Importantly, the interaction between BEST4 and p85α was also enhanced by epidermal growth factor (EGF) in CRC cells. Therapeutically, BEST4 suppression effectively sensitized CRC cells to gefitinib treatment in vivo. Taken together, our findings indicate the oncogenic potential of BEST4 in colorectal carcinogenesis and metastasis by modulating BEST4/PI3K/Akt signaling, highlighting a potential strategy for CRC therapy.
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