GOLPH3/CKAP4 promotes metastasis and tumorigenicity by enhancing the secretion of exosomal WNT3A in non-small-cell lung cancer.
GOLPH3/CKAP4 promotes metastasis and tumorigenicity by enhancing the secretion of exosomal WNT3A in non-small-cell lung cancer.
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GOLPH3/CKAP4通过增强非小细胞肺癌外泌体WNT3A的分泌促进转移和致瘤性
DOI：
10.1038/s41419-021-04265-8
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发表时间：
2021-10-21
影响因子：
9
通讯作者：
Gong LY
中科院分区：
文献类型：
--
作者：
Song JW;Zhu J;Wu XX;Tu T;Huang JQ;Chen GZ;Liang LY;Zhou CH;Xu X;Gong LY
癌症转移是非小细胞肺癌(NSCLC)相关死亡的主要原因，占患者死亡的70%以上。远端转移的潜在机制在很大程度上仍不清楚。高尔基体磷蛋白3(GOLPH3)与多发性肿瘤的总生存期呈负相关。在本研究中，我们评估了GOLPH3在非小细胞肺癌远处转移中的作用。GOLPH3在非小细胞肺癌组织中高表达，且与临床分期(P<； 0.001)、T分期(P= 0.001)、N分期(P= 0.007)、M分期(P= 0.001)呈正相关。在功能上，Transwell和伤口愈合分析表明，GOLPH3过表达增强了NSCLC细胞的迁移和侵袭能力。肿瘤球体形成和流式细胞术分析表明，GOLPH3过表达增强了NSCLC细胞的干细胞样表型。尾静脉和心内注射建立的肿瘤转移模型证实了GOLPH3的体内促转移作用。皮下肿瘤形成模型证实，GOLPH3过表达增加了NSCLC细胞的致瘤性。从机理上讲，基因集浓缩分析显示GOLPH3mRNA的表达与WNT激活的基因特征呈正相关。荧光素酶报告和核抽提物分析表明，GOLPH3过表达通过激活Wnt/β-catenin途径增强肿瘤的转移和致瘤性。免疫沉淀-质谱学和基因本体论分析表明，GOLPH3与细胞骨架相关蛋白4(CKAP4)在外切体介导的远端转移中相互作用。我们发现GOLPH3减少了质膜定位的CKAP4的数量，增加了外切小体定位的CKAP4的数量，从而促进了含有CKAP4的外切小体的形成。此外，我们还证明了CKAP4与外体Wnt3a结合可以增强其分泌。因此，GOLPH3/CKAP4轴在促进外体WNT3a分泌以增强和维持NSCLC的干细胞样表型和转移中起着至关重要的作用，从而提示GOLPH3在NSCLC转移中的治疗潜力。
Cancer metastasis is the main cause of mortality associated with non-small-cell lung cancer (NSCLC), accounting for up to 70% of deaths among patients. The mechanisms underlying distal metastasis remain largely unknown. Golgi phosphoprotein 3 (GOLPH3) correlates negatively with overall survival in multiple tumors. In this study, we evaluated the function of GOLPH3 in NSCLC distal metastasis. GOLPH3 was expressed at high levels in samples from patients with NSCLC and was positively associated with clinicopathologic characteristics including clinical stage (P< 0.001), T (P= 0.001), N (P= 0.007), and M (P= 0.001) classification. Functionally, Transwell and wound-healing assays suggested thatGOLPH3overexpression enhances NSCLC cell migration and invasion abilities. Tumor-sphere formation and flow cytometry assays demonstrated that GOLPH3 overexpression enhances a stem cell-like phenotype of NSCLC cells. Metastasis models established by tail vein and intracardiac injection confirmed the pro-metastatic function of GOLPH3 in vivo. A subcutaneous tumor formation model confirmed thatGOLPH3overexpression increased the tumorigenicity of NSCLC cells. Mechanistically, gene set enrichment analysis revealed a positive association ofGOLPH3mRNA expression with WNT-activated gene signatures. Luciferase-reporter and nuclear extract assays showed thatGOLPH3overexpression enhances metastasis and tumorigenicity through activation of the WNT/β-catenin pathway. Immunoprecipitation-mass spectrometry and gene ontology analysis demonstrated that GOLPH3 interacts with cytoskeleton-associated protein 4 (CKAP4) in exosome-mediated distal metastasis. We found that GOLPH3 decreased the amount of plasma membrane-localized CKAP4 and increased the amount of exosome-localized CKAP4 to promote the formation of CKAP4-containing exosomes. Furthermore, we demonstrated that CKAP4 binds exosomal WNT3A to enhance its secretion. Therefore, the GOLPH3/CKAP4 axis plays a crucial role in promoting exosomal-WNT3A secretion to enhance and maintain the stem-like phenotype and metastasis in NSCLC, thus indicating the therapeutic potential of GOLPH3 in patients with NSCLC metastasis.
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影响因子：
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作者：
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DOI：
10.1073/pnas.1200448109
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