Hippo信号通路及其在非小细胞肺癌中的表达和作用

doi:10.3760/cma.j.issn.1673-422X.2019.04.010

摘要/Abstract

摘要： Hippo信号通路对动物器官的生长发育以及再生发挥重要的作用。有研究表明，Yes激酶相关蛋白和转录联合激活因子PDZ结合基序组成的Hippo信号通路异常表达参与了非小细胞肺癌的发生发展，并与突变型p53有协同作用；此外，其过度表达会导致肺癌治疗耐药性发生，抑制其表达可能使癌症患者获益。了解Hippo信号通路在非小细胞肺癌中的表达和作用，有望为肺癌靶向治疗提供新的方向。

关键词: 癌, 非小细胞肺, 基因表达, Hippo信号通路, 靶向治疗

Abstract: Hippo signaling pathway plays an important role in the growth and regeneration of animal organs. Studies have shown that the misexpression of Hippo signaling pathway composed of yes-associated protein and trascriptional co-activator with PDZ-binding motif is involved in the development of non-small cell lung cancer (NSCLC) and has synergistic effect with mutant p53. In addition, its overexpression leads to drug resistance in lung cancer treatment and inhibition of its expression may benefit cancer patients. The expression and role of Hippo signaling pathway in NSCLC are described in detail, which is expected to provide a new direction for targeted therapy of lung cancer.

Key words: Carcinoma, non-small-cell lung, Gene expression, Hippo signaling pathway, Targeted therapy

王昭,王迎难,倪吉祥,朱晶. Hippo信号通路及其在非小细胞肺癌中的表达和作用[J]. 国际肿瘤学杂志, 2019, 46(4): 239-242.

Wang Zhao, Wang Yingnan, Ni Jixiang, Zhu Jing. Expression and role of Hippo signaling pathway in non-small cell lung cancer[J]. Journal of International Oncology, 2019, 46(4): 239-242.

参考文献

［1］ Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492. ［2］ Torre LA, Siegel RL, Jemal A. Lung cancer statistics［J］. Adv Exp Med Biol, 2016, 893: 1-19. DOI: 10.1007/978-3-319-242231_1. ［3］ Pedersen JH, Ashraf H. Implementation and organization of lung cancer screening［J］. Ann Transl Med, 2016, 4(8): 152. DOI: 10.21037/atm.2016.03.59. ［4］ Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer［J］. Nat Rev Cancer, 2015, 15(2): 73-79. DOI: 10.1038/nrc3876. ［5］ Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer［J］. Cancer Cell, 2016, 29(6): 783-803. DOI: 10.1016/j.ccell.2016.05.005. ［6］ Panciera T, Azzolin L, Cordenonsi M, et al. Mechanobiology of YAP and TAZ in physiology and disease［J］. Nat Rev Mol Cell Biol, 2017, 18(12): 758-770. DOI: 10.1038/nrm.2017.87. ［7］ Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation［J］. Genes Dev, 2016, 30(1): 1-17. DOI: 10.1101/gad.274027.115. ［8］ Piccolo S, Dupont S, Cordenonsi M. The biology of YAP/TAZ: hippo signaling and beyond［J］. Physiol Rev, 2014, 94(4): 1287-1312. DOI: 10.1152/physrev.00005.2014. ［9］ Chen Q, Zhang N, Xie R, et al. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP［J］. Genes Dev, 2015, 29(12): 1285-1297. DOI: 10.1101/gad.264234.115. ［10］ Meng Z, Moroishi T, MottierPavie V, et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway［J］. Nat Commun, 2015, 6: 8357. DOI: 10.1038/ncomms9357. ［11］ Oudhoff MJ, Freeman SA, Couzens AL, et al. Control of the hippo pathway by Set7-dependent methylation of Yap［J］. Dev Cell, 2013, 26(2): 188-194. DOI: 10.1016/j.devcel.2013.05.025. ［12］ Kohli P, Bartram MP, Habbig S, et al. Label-free quantitative proteomic analysis of the YAP/TAZ interactome［J］. Am J Physiol Cell Physiol, 2014, 306(9): C805-C818. DOI: 10.1152/ajpcell.00339.2013. ［13］ Hansen CG, Moroishi T, Guan KL. YAP and TAZ: a nexus for Hippo signaling and beyond［J］. Trends Cell Biol, 2015, 25(9): 499-513. DOI: 10.1016/j.tcb.2015.05.002. ［14］ Dai Y, Jablons D, You L. Hippo pathway in lung development［J］. J Thorac Dis, 2017, 9(8): 2246-2250. DOI: 10.21037/jtd.2017.07.18. ［15］ Elbediwy A, Vincent-Mistiaen ZI, Spencer-Dene B, et al. Integrin signalling regulates YAP and TAZ to control skin homeostasis［J］. Development, 2016, 143(10): 1674-1687. DOI: 10.1242/dev.133728. ［16］ Szymaniak AD, Mahoney JE, Cardoso WV, et al. Crumbs3-mediated polarity directs airway epithelial cell fate through the Hippo pathway effector Yap［J］. Dev Cell, 2015, 34(3): 283-296. DOI: 10.1016/j.devcel.2015.06.020. ［17］ Malik SA, Khan MS, Dar M, et al. TAZ is an independent prognostic factor in non-small cell lung carcinoma: elucidation at protein level［J］. Cancer Biomark, 2017, 18(4): 389-395. DOI: 10.3233/CBM-160263. ［18］ Chen HY, Yu SL, Ho BC, et al. R331W missense mutation of oncogene YAP1 is a germline risk allele for lung adenocarcinoma with medical actionability［J］. J Clin Oncol, 2015, 33(20): 2303-2310. DOI: 10.1200/JCO.2014.59.3590. ［19］ Noto A, De Vitis C, Pisanu ME, et al. Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ［J］. Oncogene, 2017, 36(32): 4573-4584. DOI: 10.1038/onc.2017.75. ［20］ Zhang W, Gao Y, Li F, et al. YAP promotes malignant progression of Lkb1-deficient lung adenocarcinoma through downstream regulation of survivin［J］. Cancer Res, 2015, 75(21): 4450-4457. DOI: 10.1158/0008-5472.CAN-14-3396. ［21］ Noguchi S, Saito A, Horie M, et al. An integrative analysis of the tumorigenic role of TAZ in human non-small cell lung cancer［J］. Clin Cancer Res, 2014, 20(17): 4660-4672. DOI: 10.1158/1078-0432.CCR-13-3328. ［22］ Guo J, Wu Y, Yang L, et al. Repression of YAP by NCTD disrupts NSCLC progression［J］. Oncotarget, 2017, 8(2): 2307-2319. DOI: 10.18632/oncotarget.13668. ［23］ Lau AN, Curtis SJ, Fillmore CM, et al. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis［J］. EMBO J, 2014, 33(5): 468-481. DOI: 10.1002/embj.201386082. ［24］ Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types［J］. Nature, 2013, 502(7471): 333-339. DOI: 10.1038/nature12634. ［25］ Zhang J, Xu Z, Yu L, et al. Assessment of the potential diagnostic value of serum p53 antibody for cancer: a meta-analysis［J］. PLoS One, 2014, 9(6): e99255. DOI: 10.1371/journal.pone.0099255. ［26］ Mattioni M, Soddu S, Prodosmo A, et al. Prognostic role of serum p53 antibodies in lung cancer［J］. BMC Cancer, 2015, 15: 148. DOI: 10.1186/s12885-015-1174-4. ［27］ Di Agostino S, Sorrentino G, Ingallina E, et al. YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins［J］. EMBO Rep, 2016, 17(2): 188-201. DOI: 10.15252/embr.201540488. ［28］ Ettinger DS, Aisner DL, Wood DE, et al. NCCN guidelines insights: non-small cell lung cancer, version 5.2018［J］. J Natl Compr Canc Netw, 2018, 16(7): 807-821. DOI: 10.6004/jnccn.2018.0062. ［29］ Zhao Z, Zheng N, Wang L, et al. Rottlerin exhibits antitumor activity via down-regulation of TAZ in non-small cell lung cancer［J］. Oncotarget, 2017, 8(5): 7827-7838. DOI: 10.18632/oncotarget.13974. ［30］ Nguyen HB, Babcock JT, Wells CD, et al. LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap［J］. Oncogene, 2013, 32(35): 4100-4109. DOI: 10.1038/onc.2012.431. ［31］ Hsu YL, Hung JY, Chou SH, et al. Angiomotin decreases lung cancer progression by sequestering oncogenic YAP/TAZ and decreasing Cyr61 expression［J］. Oncogene, 2015, 34(31): 4056-4068. DOI: 10.1038/onc.2014.333. ［32］ Xu CM, Liu WW, Liu CJ, et al. Mst1 overexpression inhibited the growth of human non-small cell lung cancer in vitro and in vivo［J］. Cancer Gene Ther, 2013, 20(8): 453-460. DOI: 10.1038/cgt.2013.40. ［33］ Zhang W, Gao Y, Li P, et al. VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex［J］. Cell Res, 2014, 24(3): 331-343. DOI: 10.1038/cr.2014.10. ［34］ Xie M, Wu X, Zhang J, et al. Ski regulates Smads and TAZ signaling to suppress lung cancer progression［J］. Mol Carcinog, 2017, 56(10): 2178-2189. DOI: 10.1002/mc.22661. ［35］ McGowan M, Kleinberg L, Halvorsen AR, et al. NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors［J］. Genes Cancer, 2017, 8(3-4): 497-504. DOI: 10.18632/genesandcancer.136. ［36］ Cheng H, Zhang Z, RodriguezBarrueco R, et al. Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells［J］. Oncotarget, 2016, 7(20): 28976-28988. DOI: 10.18632/oncotarget.6721. ［37］ Hsu PC, You B, Yang YL, et al. YAP promotes erlotinib resistance in human nonsmall cell lung cancer cells［J］. Oncotarget, 2016, 7(32): 51922-51933. DOI: 10.18632/oncotarget.10458. ［38］ Willers H, Azzoli CG, Santivasi WL, et al. Basic mechanisms of therapeutic resistance to radiation and chemotherapy in lung cancer［J］. Cancer J, 2013, 19(3): 200-207. DOI: 10.1097/PPO.0b013e318292e4e3. ［39］ Tian Y, Zhang Z, Miao L, et al. Anexelekto (AXL) increases resistance to EGFR-TKI and activation of AKT and ERK1/2 in non-small cell lung cancer cells［J］. Oncol Res, 2016, 24(5): 295-303. DOI: 10.3727/096504016X14648701447814. ［40］ Cianfrocca R, Rosanò L, Tocci P, et al. Blocking endothelin-1-receptor/β-catenin circuit sensitizes to chemotherapy in colorectal cancer［J］. Cell Death Differ, 2017, 24(10): 1811-1820. DOI: 10.1038/cdd.2017.121. ［41］ Azzolin L, Panciera T, Soligo S, et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response［J］. Cell, 2014, 158(1): 157-170. DOI: 10.1016/j.cell.2014.06.013. ［42］ Deng F, Peng L, Li Z, et al. YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal,regeneration and tumorigenesis after DSS-induced injury［J］. Cell Death Dis, 2018, 9(2): 153. DOI: 10.1038/s41419-017-0244-8.

[1]	钱晓涛, 石子宜, 胡格, 吴晓维. Ⅲ~ⅣA期食管鳞状细胞癌放化疗后行巩固化疗的疗效：一项真实世界临床研究[J]. 国际肿瘤学杂志, 2024, 51(6): 326-331.
[2]	郭泽浩, 张俊旺. PFDN及其亚基在肿瘤发生发展中的作用[J]. 国际肿瘤学杂志, 2024, 51(6): 350-353.
[3]	王盈, 刘楠, 郭兵. 抗体药物偶联物在转移性乳腺癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 364-369.
[4]	王丽, 刘志华, 杨伟洪, 蒋凤莲, 李全泳, 宋浩杰, 鞠文东. ROS1突变肺腺鳞癌合并脑梗死为主要表现的Trousseau综合征1例[J]. 国际肿瘤学杂志, 2024, 51(6): 382-384.
[5]	范志鹏, 余静, 胡静, 廖正凯, 徐禹, 欧阳雯, 谢丛华. 炎症标志物的变化趋势对一线接受免疫联合化疗的晚期非小细胞肺癌患者预后的预测价值[J]. 国际肿瘤学杂志, 2024, 51(5): 257-266.
[6]	王俊毅, 洪楷彬, 纪荣佳, 陈大朝. 癌结节对结直肠癌根治性切除术后肝转移的影响[J]. 国际肿瘤学杂志, 2024, 51(5): 280-285.
[7]	顾芳萌, 徐晨阳, 雷大鹏. 人工智能辅助电子喉镜检查在喉癌及喉癌前病变诊治中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(5): 303-307.
[8]	王培鑫, 赵军, 徐世红, 姜朝阳, 王小强, 杨红娟. 铁死亡相关机制在骨肉瘤中的应用进展[J]. 国际肿瘤学杂志, 2024, 51(5): 308-311.
[9]	张文馨, 夏泠, 彭晋, 周福祥. 甲胎蛋白升高型胃肝样腺癌1例并文献复习[J]. 国际肿瘤学杂志, 2024, 51(5): 312-315.
[10]	王昆, 周中新, 臧其威. 血清TGF-β1、VEGF水平对非小细胞肺癌患者单孔胸腔镜根治术后复发的预测价值[J]. 国际肿瘤学杂志, 2024, 51(4): 198-203.
[11]	杨毫, 施贵冬, 张程城, 张跃, 张力文, 付茂勇. 信迪利单抗与替雷利珠单抗在进展期食管鳞状细胞癌新辅助治疗中的疗效及安全性对比[J]. 国际肿瘤学杂志, 2024, 51(4): 210-216.
[12]	姚益新, 沈煜霖. 血清SOCS3、TXNIP水平对肝细胞癌TACE治疗预后的预测价值[J]. 国际肿瘤学杂志, 2024, 51(4): 217-222.
[13]	胡婷婷, 王越华. 电子鼻与线虫鼻——新型早期癌症筛查工具[J]. 国际肿瘤学杂志, 2024, 51(4): 223-226.
[14]	杨智, 陆以乔, 顾花艳, 丁佳玲, 郭贵龙. 肿瘤微环境介导乳腺癌靶向治疗耐药的研究进展[J]. 国际肿瘤学杂志, 2024, 51(4): 235-238.
[15]	张栋岩, 王品, 魏秋亚, 邓成伍, 魏相相, 高远飞, 王琛. 索凡替尼靶向联合卡培他滨和奥沙利铂治疗肝内胆管癌术后患者1例及文献复习[J]. 国际肿瘤学杂志, 2024, 51(4): 249-253.