山东大学耳鼻喉眼学报 ›› 2021, Vol. 35 ›› Issue (1): 119-124.doi: 10.6040/j.issn.1673-3770.0.2020.089
王亚越1,2综述孙娟2审校
WANG Yayue1,2Overview,SUN Juan2Guidance
摘要: 在头颈恶性肿瘤中,下咽癌恶性程度高,患者生存质量较差且通常预后不良。下咽癌的治疗采用手术为主的方式,并辅助以放化疗。术后患者喉功能受损严重,寻找能够尽量保护喉功能的治疗方法是目前研究的重点。靶向治疗对下咽癌患者保护喉功能、提高生存质量意义重大。研究发现,下咽癌发生过程中涉及多种蛋白激酶介导的信号通路及基因,对可能在这一过程中有重要意义的蛋白激酶PKC-β、CDK4/6、Cdc42、Rac1、STK33、CK2和PHLPP作一综述,以期为蛋白激酶抑制剂作为下咽癌治疗的靶点提供新的方向。
中图分类号:
[1] 吴静, 刘业海. 头颈部鳞状细胞癌的靶向治疗研究进展[J]. 山东大学耳鼻喉眼学报, 2018, 32(5): 97-102. doi:10.6040/j.issn.1673-3770.0.2018.058. WU Jing, LIU Yehai. Targeted therapy for head and neck squamous cell carcinoma[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2018, 32(5): 97-102. doi:10.6040/j.issn.1673-3770.0.2018.058. [2] Vengaloor Thomas T, Nittala MR, Bhanat E, et al. Management of advanced-stage hypopharyngeal carcinoma: 25-year experience from a tertiary care medical center[J]. Cureus, 2020, 12(1): e6679. doi:10.7759/cureus.6679. [3] 周梁. 下咽癌的治疗进展[J]. 中国耳鼻咽喉颅底外科杂志, 2019, 25(4): 333-338. doi:10.11798/j.issn.1007-1520.201904001. ZHOU Liang. Progress on treatment of hypopharyngeal carcinoma[J]. Chinese Journal of Otorhinolaryngology-Skull Base Surgery, 2019, 25(4): 333-338. doi:10.11798/j.issn.1007-1520.201904001. [4] 崔晓波. 诱导化疗在局部晚期下咽癌治疗中的意义[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 10-17. doi:10.6040/j.issn.1673-3770.1.2019.027. CUI Xiaobo. Significance of induction chemotherapy in late treatment of locally advanced hypo-pharyngeal cancer[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2019, 33(4): 10-17. doi:10.6040/j.issn.1673-3770.1.2019.027. [5] Bhullar KS, Lagarón NO, McGowan EM, et al. Kinase-targeted cancer therapies: progress, challenges and future directions[J]. Mol Cancer, 2018, 17: 48. doi:10.1186/s12943-018-0804-2. [6] Ardito F, Giuliani M, Perrone D, et al. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy(Review)[J]. Int J Mol Med, 2017, 40(2): 271-280. doi:10.3892/ijmm.2017.3036. [7] Cheng HJ, Wang WW, Wang GK, et al. Silencing ras-related C3 botulinum toxin substrate 1 inhibits growth and migration of hypopharyngeal squamous cell carcinoma via the P38 mitogen-activated protein kinase signaling pathway[J]. Med Sci Monit, 2018, 24: 768-781. doi:10.12659/msm.907468. [8] Huang LY, Chen C, Zhang GD, et al. STK33 overexpression in hypopharyngeal squamous cell carcinoma: possible role in tumorigenesis[J]. BMC Cancer, 2015, 15: 13. doi:10.1186/s12885-015-1009-3. [9] Lian HW, Su M, Zhu YJ, et al. Protein kinase CK2, a potential therapeutic target in carcinoma management[J]. Asian Pac J Cancer Prev, 2019, 20(1): 23-32. doi:10.31557/apjcp.2019.20.1.23. [10] Newton AC. Protein kinase C: perfectly balanced[J]. Crit Rev Biochem Mol Biol, 2018, 53(2): 208-230. doi:10.1080/10409238.2018.1442408. [11] 黄来全, 刘大翔. BTK与PKCβ在多发性骨髓瘤中表达及调控的信号通路机制研究[J]. 东南大学学报(医学版), 2018, 37(4): 578-583. doi:10.3969/j.issn.1671-6264.2018.04.005. HUANG Laiquan, LIU Daxiang. Expression of BTK and PKCβin multiple myeloma and the mechanism of its regulated signaling pathway[J]. Journal of Southeast University(Medical Science Edition), 2018, 37(4): 578-583. doi:10.3969/j.issn.1671-6264.2018.04.005. [12] Zhu J, He YZ, Li J, et al. Combination of enzastaurin and ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma[J]. Blood, 2018, 132(Supplement 1): 1666. doi:10.1182/blood-2018-99-110571. [13] 李冠军, 董桂青, 李宇玥, 等. 抗肿瘤新药Enzastaurin的药理学及其临床研究进展[J]. 中国药房, 2011, 22(38): 3613-3616. [14] Tarrado-Castellarnau M, de Atauri P, Tarragó-Celada J, et al. De novo MYC addiction as an adaptive response of cancer cells to CDK 4/6 inhibition[J]. Mol Syst Biol, 2017, 13(10): 940. doi:10.15252/msb.20167321. [15] Goel S, DeCristo MJ, McAllister SS, et al. CDK4/6 inhibition in cancer: beyond cell cycle arrest[J]. Trends Cell Biol, 2018, 28(11): 911-925. doi:10.1016/j.tcb.2018.07.002. [16] 付彬, 莫春梅, 覃艳春, 等. CDK4/6抑制剂治疗恶性肿瘤研究进展[J]. 海南医学院学报, 2019, 25(21): 1676-1680. doi:10.13210/j.cnki.jhmu.20191030.001. FU Bin, MO Chunmei, QIN Yanchun, et al. Progress of CDK4/6 inhibitors in treatment of malignant tumors[J]. Journal of Hainan Medical University, 2019, 25(21): 1676-1680. doi:10.13210/j.cnki.jhmu.20191030.001. [17] Klein ME, Kovatcheva M, Davis LE, et al. CDK4/6 inhibitors: the mechanism of action may not be as simple as once thought[J]. Cancer Cell, 2018, 34(1): 9-20. doi:10.1016/j.ccell.2018.03.023. [18] Peurois F, Veyron S, Ferrandez Y, et al. Characterization of the activation of small GTPases by their GEFs on membranes using artificial membrane tethering[J]. Biochem J, 2017, 474(7): 1259-1272. doi:10.1042/bcj20170015. [19] Møller LLV, Klip A, Sylow L. Rho GTPases-emerging regulators of glucose homeostasis and metabolic health[J]. Cells, 2019, 8(5): 434. doi:10.3390/cells8050434. [20] Maldonado MDM, Dharmawardhane S. Targeting rac and Cdc42 GTPases in cancer[J]. Cancer Res, 2018. doi:10.1158/0008-5472.can-18-0619. [21] 李楠静, 刘明, 张又, 等. Rho GTP酶与肿瘤细胞耐药性的关系研究进展[J]. 山东医药, 2018, 57(7): 99-101. doi:10.3969/j.issn.1002-266X.2018.07.031. [22] 郑艳秋, 胡文良, 崔晓波, 等. CDC42抑制剂ML141对喉癌Hep-2细胞增殖的抑制作用[J]. 现代生物医学进展, 2016, 16(4): 644-646, 651. doi:10.13241/j.cnki.pmb.2016.04.010. ZHENG Yanqiu, HU Wenliang, CUI Xiaobo, et al. CDC42 inhibitor ML141 suppresses laryngeal cancer hep-2 cell proliferation[J]. Progress in Modern Biomedicine, 2016, 16(4): 644-646, 651. doi:10.13241/j.cnki.pmb.2016.04.010. [23] Chen C, Huang LY, Zhang GD, et al. STK33 potentiates the malignancy of hypopharyngeal squamous carcinoma: Possible relation to calcium[J]. Cancer Biol Ther, 2016, 17(9): 976-984. doi:10.1080/15384047.2016.1210739. [24] Chua M, Ortega C, Sheikh A, et al. CK2 in cancer: cellular and biochemical mechanisms and potential therapeutic target[J]. Pharmaceuticals, 2017, 10(4): 18. doi:10.3390/ph10010018. [25] Zhang F, Yang B, Shi SL, et al. RNA interference(RNAi)mediated stable knockdown of protein casein kinase 2-alpha(CK2α)inhibits migration and invasion and enhances cisplatin-induced apoptosis in HEp-2 laryngeal carcinoma cells[J]. Acta Histochem, 2014, 116(6): 1000-1006. doi:10.1016/j.acthis.2014.04.001. [26] Ortega CE, Seidner Y, Dominguez I. Mining CK2 in cancer[J]. PLoS One, 2014, 9(12): e115609. doi:10.1371/journal.pone.0115609. [27] Grzechnik AT, Newton AC. PHLPPing through history: a decade in the life of PHLPP phosphatases[J]. Biochem Soc Trans, 2016, 44(6): 1675-1682. doi:10.1042/bst20160170. [28] Qiu YH, Li XY, Yi B, et al. Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting Survivin phosphorylation and nuclear export in gallbladder cancer[J]. Oncotarget, 2015, 6(22): 19148-19162. doi:10.18632/oncotarget.3721. [29] Zhou JY, Yu XM, Wang J, et al. Aberrant expression of PHLPP1 and PHLPP2 correlates with poor prognosis in patients with hypopharyngeal squamous cell carcinoma[J]. PLoS One, 2015, 10(3): e0119405. doi:10.1371/journal.pone.0119405. [30] Gao TY, Furnari F, Newton AC. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth[J]. Mol Cell, 2005, 18(1): 13-24. doi:10.1016/j.molcel.2005.03.008. [31] Qiao M, Wang YQ, Xu XE, et al. Mst1 is an interacting protein that mediates PHLPPs' induced apoptosis[J]. Mol Cell, 2010, 38(4): 512-523. doi:10.1016/j.molcel.2010.03.017. [32] 胡文良, 郑艳秋, 崔晓波, 等. 下咽癌中差异表达的蛋白激酶及其抑制剂的生物信息学筛选[J]. 山东大学耳鼻喉眼学报, 2016, 30(3): 24-28, 36. doi: 10.6040/j.issn.1673-3770.0.2015.340. HU Wenliang, ZHENG Yanqiu, CUI Xiaobo, et al. Bioinformatic screening of differentially expressed protein kinases and their inhibitors in hypopharyngeal cancer[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2016, 30(3): 24-28, 36. doi: 10.6040/j.issn.1673-3770.0.2015.340. [33] Marei H, Malliri A. Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms[J]. Small Gtpases, 2017, 8(3): 139-163. doi:10.1080/21541248.2016.1211398. [34] Michaelis M, Rothweiler F, Löschmann N, et al. Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status[J]. Oncotarget, 2015, 6(19): 17605-17620. doi:10.18632/oncotarget.2889. [35] Spring LM, Zangardi ML, Moy B, et al. Clinical management of potential toxicities and drug interactions related to cyclin-dependent kinase 4/6 inhibitors in breast cancer: practical considerations and recommendations[J]. Oncol, 2017, 22(9): 1039-1048. doi:10.1634/theoncologist.2017-0142. [36] Ku BM, Yi SY, Koh J, et al. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma[J]. Oncotarget, 2016, 7(12): 14803-14813. doi:10.18632/oncotarget.7543. [37] 徐永茹, 徐平, 徐锋, 等. CDC42与癌症[J]. 军事医学, 2016, 40(3): 256-260. doi:10.7644/j.issn.1674-9960.2016.03.023. XU Yongru, XU Ping, XU Feng, et al. The role of CDC42 in cancer[J]. Military Medical Sciences, 2016, 40(3): 256-260. doi:10.7644/j.issn.1674-9960.2016.03.023. [38] Schnitzler A, Gratz A, Bollacke A, et al. A π-halogen bond of dibenzofuranones with the gatekeeper Phe113 in human protein kinase CK2 leads to potent tight binding inhibitors[J]. Pharmaceuticals, 2018, 11(1): 23. doi:10.3390/ph11010023. |
[1] | 陈东彦,钱晔,魏东敏,李文明,夏同良,雷大鹏,潘新良. 高频超声诊断下咽鳞癌淋巴结转移的临床研究[J]. 山东大学耳鼻喉眼学报, 2022, 36(5): 18-23. |
[2] | 张钰曲毅. 眼弓形体病的发病机制及防治研究进展[J]. 山东大学耳鼻喉眼学报, 2022, 36(5): 70-76. |
[3] | 宋晴 宋西成. 安罗替尼联合治疗在肿瘤治疗中的研究进展[J]. 山东大学耳鼻喉眼学报, 2022, 36(5): 106-112. |
[4] | 黄扬周,傅丽华,吴巧莲,黄霞,林隽,叶青. 乳突结节性筋膜炎误诊1例[J]. 山东大学耳鼻喉眼学报, 2022, 36(5): 119-121. |
[5] | 姜超,周炫辰,韩杰,岳志勇. IVc期下咽癌特征分析及列线图预后模型构建[J]. 山东大学耳鼻喉眼学报, 2022, 36(4): 49-54. |
[6] | 龚霄阳,李旺,陈曦. 原发性咽旁间隙肿瘤67例回顾性分析[J]. 山东大学耳鼻喉眼学报, 2022, 36(4): 60-65. |
[7] | 张礼俊, 胥然, 罗继芳, 刘国旗, 何千, 李玮, 蒋振华. 头颈肿瘤游离皮瓣修复术后皮瓣坏死及皮瓣相关并发症影响因素分析[J]. 山东大学耳鼻喉眼学报, 2022, 36(4): 86-90. |
[8] | 毛泽凡陈曦,程雷. 喉神经内分泌癌的研究进展[J]. 山东大学耳鼻喉眼学报, 2022, 36(4): 114-119. |
[9] | 王媚 李志海. 喉癌干细胞:克服多药耐药性的潜在治疗靶点[J]. 山东大学耳鼻喉眼学报, 2022, 36(4): 120-128. |
[10] | 陈家宏,王琳,姜彦,于龙刚,张继生,张志勇,孔静文. 原发性鼻腔鼻窦骨外尤文肉瘤/外周原始神经外胚层肿瘤2例并文献复习[J]. 山东大学耳鼻喉眼学报, 2022, 36(3): 290-296. |
[11] | 赵笑冰,张大为,陈仁杰. 中耳间变性大T细胞淋巴瘤1例并文献复习[J]. 山东大学耳鼻喉眼学报, 2022, 36(2): 7-14. |
[12] | 程瑶,张震,杨吉,冯成敏,邓启成,张西,赵锐,朱鑫,吴俊志,刘海,邓世山. CIP2A在下咽癌中的表达及临床意义[J]. 山东大学耳鼻喉眼学报, 2022, 36(2): 40-44. |
[13] | 姚周周,张革化,常利红. 汉防己甲素调控肿瘤细胞自噬的研究进展[J]. 山东大学耳鼻喉眼学报, 2022, 36(2): 139-143. |
[14] | 李玲,李聪,孙岩,陈良. 婴儿中耳胚胎型横纹肌肉瘤1例并文献复习[J]. 山东大学耳鼻喉眼学报, 2022, 36(1): 55-59. |
[15] | 陈坤,陆慧,黄琦,李磊,孟国珍,杨军,侯东明. 小儿先天性鼻腔鼻窦肿物的临床诊疗观察[J]. 山东大学耳鼻喉眼学报, 2022, 36(1): 81-85. |
|