FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells
FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells
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FRMPD1通过与WWC3相互作用激活Hippo通路抑制肺癌细胞的增殖和侵袭
DOI：
10.2147/cmar.s194512
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发表时间：
2019-01-01
影响因子：
3.3
通讯作者：
Wang, Enhua
中科院分区：
文献类型：
--
作者：
Rong, Xuezhu;Han, Qiang;Wang, Enhua
目的：FERM-domain-containing protein-1（FRMPD 1）/FERM和PDZ domain-containing protein-2（FRMD 2）在包括肺癌在内的恶性肿瘤中的表达及其分子机制尚未见报道。材料与方法：采用免疫组化方法检测肺癌组织中FRMPD 1的表达，并对FRMPD 1的表达与临床病理因素的关系进行统计学分析。通过体内、外功能实验，研究FRMPD 1对肺癌细胞增殖和侵袭的生物学效应。进行免疫印迹、RT-qPCR、双荧光素酶测定和免疫荧光以证明FRMPD 1是否刺激Hippo信号传导。使用免疫共沉淀测定来阐明FRMPD 1通过与WW和含C2结构域的蛋白-3（WWC 3）相互作用在Hippo途径活化中的潜在作用。结果：肺癌组织中FRMPD 1的表达低于正常支气管上皮和正常粘膜下腺体。FRMPD 1表达与患者年龄、TNM分期、淋巴结转移及预后不良呈负相关。此外，FRMPD 1的异位表达显著抑制肺癌细胞的增殖和侵袭，而抑制FRMPD 1的表达则导致相反的效果。在机制上，我们发现FRMPD 1通过其PSD 95/DLG/ZO 1（PDZ）结构域与WWC 3的C端PDZ结合基序相互作用，促进大肿瘤抑制因子-1（LATS 1）的磷酸化，从而抑制yes相关蛋白（雅普）的核转位。结论：FRMPD 1可通过与WWC 3相互作用激活Hippo通路并最终抑制肺癌细胞的恶性行为。本工作将为发现新型肺癌生物标志物和开发靶向药物提供重要的实验基础。
Purpose: The expression of FERM-domain-containing protein-1 (FRMPD1)/FERM and PDZ domain-containing protein-2 (FRMD2) in malignant tumors, including lung cancer, and its underlying molecular mechanism have not been reported yet. Materials and methods: Immunohistochemistry was performed to analyze the expression of FRMPD1 in lung cancer tissues, and statistical analysis was applied to analyze the relationship between FRMPD1 expression and clinicopathological factors. The biological effects of FRMPD1 on lung cancer cell proliferation and invasion were determined by functional experiments both in vivo and in vitro. Immunoblotting, RT-qPCR, dual-luciferase assay, and immunofluorescence were performed to demonstrate whether FRMPD1 stimulates Hippo signaling. Co-immunoprecipitation assays were used to clarify the underlying role of FRMPD1 in Hippo pathway activation via interaction with WW and C2 domain containing protein-3 (WWC3). Results: We found that FRMPD1 expression in lung cancer specimens was lower than that in normal bronchial epithelium and normal submucosal glands. FRMPD1 expression had a negative correlation with age, Tumor-Node-Metastasis (TNM) stage, lymph node metastasis, as well as poor prognosis. Moreover, ectopic expression of FRMPD1 significantly inhibited the proliferation and invasion of lung cancer cells, and inhibition of FRMPD1 expression led to opposite effects. Mechanistically, we found that FRMPD1 interacted with the C-terminal PDZ binding motif of WWC3 via its PSD95/DLG/ZO1 (PDZ) domain and promoted the phosphorylation of large tumor suppressor-1 (LATS1), thus inhibiting the nuclear translocation of yes-associated protein (YAP). Conclusion: FRMPD1 could activate the Hippo pathway and ultimately inhibit the malignant behavior of lung cancer cells through its interaction with WWC3. This work will provide an important experimental basis for the discovery of novel biomarkers of lung cancer and the development of targeted drugs.