Alkaline phosphatase downregulation promotes lung adenocarcinoma metastasis via the c-Myc/RhoA axis.
Alkaline phosphatase downregulation promotes lung adenocarcinoma metastasis via the c-Myc/RhoA axis.
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碱性磷酸酶下调通过 c-Myc/RhoA 轴促进肺腺癌转移
DOI：
10.1186/s12935-021-01919-7
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发表时间：
2021-04-15
影响因子：
5.8
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Lou Z;Lin W;Zhao H;Jiao X;Wang C;Zhao H;Liu L;Liu Y;Xie Q;Huang X;Huang H;Zhao L
研究背景肺腺癌（LUAD）的转移显著降低了患者的生存率，因此抑制肺癌细胞的转移能力将大大延长患者的生存期。碱性磷酸酶（ALPL）是一种同源二聚体的细胞表面磷酸水解酶，据报道在前列腺癌和卵巢癌细胞迁移中起着有争议的作用;然而，ALPL在LUAD中的功能及其相关机制尚不清楚。采用软琼脂法、transwell法和肺转移法检测ALPL在LUAD进展中的作用。采用qPCR、荧光素酶启动子报告基因分析和western blot等方法，探讨ALPL促进LUAD转移的分子机制。结果LUAD患者ALPL表达下调，低ALPL患者的无病生存率明显降低。进一步的研究表明，ALPL在LUAD细胞系中的过表达并不显著影响细胞增殖，但它确实显著减弱了小鼠模型中的肺转移。在LUAD中ALPL下调导致磷酸化（p）-ERK的量减少。结论ALPL通过影响p-ERK/c-Myc/RhoA轴特异性抑制LUAD细胞的转移，为临床LUAD的靶向治疗提供理论依据。
BackgroundLung adenocarcinoma (LUAD) metastasis significantly reduces patient survival; hence inhibiting the metastatic ability of lung cancer cells will greatly prolong patient survival. Alkaline phosphatase (ALPL), a homodimeric cell surface phosphohydrolase, is reported to play a controversial role in prostate cancer and ovarian cancer cell migration; however, the function of ALPL in LUAD and the related mechanisms remain unclear.MethodsTCGA database was used to analysis the expression of ALPL, and further verification was performed in a cohort of 36 LUAD samples by qPCR and western blot. Soft-agar assay, transwell assay and lung metastasis assay were employed to detect the function of ALPL in LUAD progression. The qPCR, luciferase promoter reporter assay and western blot were used to clarify the molecular mechanisms of ALPL in promoting metastasis in LUAD.ResultsALPL was downregulated in LUAD, and the disease-free survival rate of patients with low ALPL was significantly reduced. Further studies showed that overexpression of ALPL in LUAD cell lines did not significantly affect cell proliferation, but it did significantly attenuate lung metastasis in a mouse model. ALPL downregulation in LUAD led to a decrease in the amount of phosphorylated (p)-ERK. Because p-ERK promotes the classical c-Myc degradation pathway, the decrease in p-ERK led to the accumulation of c-Myc and therefore to an increase inRhoAtranscription, which enhanced LUAD cell metastasis.ConclusionALPL specially inhibits the metastasis of LUAD cells by affecting the p-ERK/c-Myc/RhoA axis, providing a theoretical basis for the targeted therapy of clinical LUAD.
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