Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling
Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling
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BEST4 通过激活 PI3K/Akt 信号传导在结直肠癌中的致癌潜力
DOI：
10.1038/s41388-021-02160-2
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发表时间：
2022-01-21
期刊：
影响因子：
8
通讯作者：
Wu，Hua
中科院分区：
文献类型：
--
作者：
He，Xiao-Shun;Ye，Wen-Long;Wu，Hua
BEST4 是斑黄蛋白家族的成员，在人类肠上皮细胞中发挥着关键作用。然而，其在结直肠癌（CRC）中的作用和机制仍然很大程度上难以捉摸。在这里，我们研究了 BEST4 在 CRC 中的作用和临床意义。我们的结果表明，BEST4 表达在临床 CRC 样本中上调，其高水平表达与晚期 TNM（肿瘤、淋巴结、远处转移）分期、LNM（淋巴结转移）和不良生存相关。功能研究表明，BEST4 的异位表达促进 CRC 细胞增殖和转移，而 BEST4 的缺失在体外和体内均产生相反的效果。从机制上讲，BEST4 与磷脂酰肌醇-3-激酶 (PI3K) 的 p85α 调节亚基结合并促进 p110 激酶活性；这会导致 Akt 信号传导激活以及 MYC 和 CCND1 表达，它们是细胞增殖和转移的关键调节因子。在临床样本中，BEST4的表达与磷酸化Akt、MYC和CCND1的表达呈正相关。 Akt 活性的药理学抑制显着抑制 BEST4 介导的 Akt 信号传导以及 CRC 细胞的增殖和转移。重要的是，CRC 细胞中的表皮生长因子 (EGF) 也增强了 BEST4 和 p85α 之间的相互作用。在治疗上，BEST4 抑制有效地使 CRC 细胞对体内吉非替尼治疗敏感。总而言之，我们的研究结果表明，BEST4 通过调节 BEST4/PI3K/Akt 信号传导在结直肠癌发生和转移中具有致癌潜力，突出了结直肠癌治疗的潜在策略。
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.
Ca2+激活的Cl-在切除的膜斑中的人类Bestrophin-4的电流。
影响因子：
3.8
作者：
Tsunenari, Takashi;Nathans, Jeremy;Yau, King-Wai
通讯作者：
Yau, King-Wai
长非编码 RNA NONHSAT062994 通过失活 Akt 信号传导抑制结直肠癌
影响因子：
--
作者：
He XS;Guo LC;Du MZ;Huang S;Huang RP;Zhan SH;Gu DM;Liu WS;Wang XM;Wu H;Gan WJ
通讯作者：
Gan WJ