p-mTOR、p-S6K在鼻腔鼻窦内翻性乳头状瘤中的高表达及临床价值

doi:10.6040/j.issn.1673-3770.0.2024.393

摘要/Abstract

摘要： 目的为筛选有助于鉴别鼻息肉、鼻腔鼻窦内翻性乳头状瘤(sinonasal inverted papilloma, SNIP)的分子标志物提供方向,探讨mTOR通路抑制剂在SNIP治疗中的应用理论依据。方法通过实验分析SNIP中磷酸化哺乳动物雷帕霉素靶蛋白(p-mTOR)、磷酸化核糖体蛋白S6激酶(p-S6K)较中鼻甲黏膜表达的差异,从而为验证mTOR通路介导SNIP的发病提供实验依据。采用免疫组织化学染色方法检测实验组与对照组p-mTOR、p-S6K的表达情况,运用SPSS 23.0进性统计学分析表达差异,同时采用新鲜标本及瘤旁标本进行免疫蛋白印迹实验对结果加以验证。结果 64例SNIP石蜡包埋组织标本中p-mTOR、p-S6K的阳性表达率分别为85.94%、81.25%,对照组32例中鼻甲黏膜中p-mTOR、p-S6K的阳性表达率分别为34.38%、40.63%,两组之间经过统计学分析处理显示差异具有统计学意义(χ2=26.400,P<0.01; χ2=16.103,P<0.01);免疫蛋白印迹实验亦证实SNIP实验组与瘤旁对照标本p-mTOR、p-S6K表达存在显著差异。结论 p-mTOR、p-S6K在SNIP的发病机制中发挥重要作用,mTOR通路的过度激活是促进SNIP发病的重要机制。

关键词: 鼻腔鼻窦内翻性乳头状瘤, 免疫组织化学染色, p-mTOR, p-S6K, 蛋白表达

Abstract: Objective In order to provide directions for screening molecular markers that can help identify nasal polyps and sinonasal inverted papilloma(SNIP), and to provide a theoretical basis for exploring the application of mTOR pathway inhibitors in the treatment of SNIP. Methods The differences in the expression of phosphorylated mammalian target of rapamycin(p-mTOR)and phosphorylated ribosomal protein S6 kinase(p-S6K)in SNIP compared with that of the middle turbinate mucosa were analyzed experimentally, which provided an experimental basis for verifying that the mTOR pathway mediates the pathogenesis of SNIP. Immunohistochemical staining was used to detect the expression of p-mTOR and p-S6K in the experimental group and the control group, and the differences in expression were analyzed using SPSS23.0 progressive statistics, and the results were verified by Western blotting(WB)experiments using fresh SNIP specimens and paraneoplastic specimens. Results The positive expression rates of p-mTOR and p-S6K in paraffin-embedded tissue specimens of 64 cases of SNIP were 85.94% and 81.25%, respectively, and those of p-mTOR and p-S6K in the mucosa of 32 cases of middle turbinate in the control group were 34.38% and 40.63%, respectively, and the differences were statistically significant after the statistical analysis process(χ2=26.400, P<0.01; χ2=16.103, P<0.01); WB experiments also confirmed that there were significant differences in the expression of p-mTOR and p-S6K between the SNIP experimental group and the paraneoplastic control group. Conclusion p-mTOR and p-S6K play an important role in the pathogenesis of SNIP, and the over-activation of mTOR pathway is an important mechanism to promote the pathogenesis of SNIP.

Key words: Sinonasal inverted papilloma, Immunohistochemical staining, p-mTOR, p-S6K, Protein expression

中图分类号:

R739.62

毕恒,谢佳,龚辉成. p-mTOR、p-S6K在鼻腔鼻窦内翻性乳头状瘤中的高表达及临床价值[J]. 山东大学耳鼻喉眼学报, 2025, 39(2): 25-34.

BI Heng, XIE Jia, GONG Huicheng. Clinical value of highly expressed p-mTOR and p-S6K in sinonasal inverted papilloma[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2025, 39(2): 25-34.

参考文献

[1] 李芊颖, 陈合新. 鼻内翻性乳头状瘤发生发展机制的研究进展[J]. 中国耳鼻咽喉颅底外科杂志, 2021, 27(2): 237-242. doi:10.11798/j.issn.1007-1520.202103075 LI Qianying, CHEN Hexin. Advances in research on mechanism of development of nasal inverted papilloma[J]. Chinese Journal of Otorhinolaryngology-Skull Base Surgery, 2021, 27(2): 237-242. doi:10.11798/j.issn.1007-1520.202103075
[2] Vrabec DP. The inverted Schneiderian papilloma: a 25-year study[J]. Laryngoscope, 1994, 104(5 Pt 1): 582-605. doi:10.1002/lary.5541040513
[3] Minovi A, Kollert M, Draf W, et al. Inverted papilloma: feasibility of endonasal surgery and long-term results of 87 cases[J]. Rhinology, 2006, 44(3): 205-210.
[4] 于焕新, 刘钢. 鼻内翻性乳头状瘤恶变32例临床分析[J]. 中华耳鼻咽喉头颈外科杂志, 2013, 48(12): 1002-1005. doi:10.3760/cma.j.issn.1673-0860.2013.12.007 YU Huanxin, LIU Gang. Malignant transformation of sinonasal inverted papilloma: retrospective analysis of 32 cases[J]. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 2013, 48(12): 1002-1005. doi:10.3760/cma.j.issn.1673-0860.2013.12.007
[5] von Buchwald C, Bradley PJ. Risks of malignancy in inverted papilloma of the nose and paranasal sinuses[J]. Curr Opin Otolaryngol Head Neck Surg, 2007, 15(2): 95-98. doi:10.1097/MOO.0b013e3280803d9b
[6] Wu HH, Zafar S, Huan YM, et al. Fascin over expression is associated with dysplastic changes in sinonasal inverted papillomas: a study of 47 cases[J]. Head Neck Pathol, 2009, 3(3): 212-216. doi:10.1007/s12105-009-0133-2
[7] 王明婕, 侯丽珍, 周兵, 等. 鼻腔鼻窦内翻性乳头状瘤恶变的相关危险因素分析[J]. 临床耳鼻咽喉头颈外科杂志, 2021, 35(7): 627-632. doi:10.13201/j.issn.2096-7993.2021.07.011 WANG Mingjie, HOU Lizhen, ZHOU Bing, et al. Risk factors of malignant transformation of sinonasal inverted papilloma[J]. Journal of Clinical Otorhinolaryngology Head and Neck Surgery, 2021, 35(7): 627-632. doi:10.13201/j.issn.2096-7993.2021.07.011
[8] Lu JM, Zang HJ, Zheng HM, et al. Overexpression of p-Akt, p-mTOR and p-eIF4E proteins associates with metastasis and unfavorable prognosis in non-small cell lung cancer[J]. PLoS One, 2020, 15(2): e0227768. doi:10.1371/journal.pone.0227768
[9] 陈业刚, 杨拓, 刘鹏, 等. p-mTOR、p-p70S6K蛋白在膀胱尿路上皮癌中的表达[J]. 中国中西医结合外科杂志, 2013, 19(6): 639-642. doi:10.3969/j.issn.1007-6948.2013.06.009 CHEN Yegang, YANG Tuo, LIU Peng, et al. Expression of p-mTOR and p-p70S6K in urothelial bladder cancer[J]. Chinese Journal of Surgery of Integrated Traditional and Western Medicine, 2013, 19(6): 639-642. doi:10.3969/j.issn.1007-6948.2013.06.009
[10] 《免疫组织化学检测技术共识》编写组. 免疫组织化学检测技术共识[J]. 中华病理学杂志, 2019, 48(2): 87-91. doi:10.3760/cma.j.issn.0529-5807.2019.02.002
[11] Pradhan P, Mishra A, Preetam C, et al. Exclusive endoscopic approach in the management of sinonasal inverted Papilloma[J]. Indian J Otolaryngol Head Neck Surg, 2023, 75(Suppl 1): 785-792. doi:10.1007/s12070-022-03332-6
[12] Yeom S, Lee DH, Lim SC. Clinical outcomes of sinonasal inverted papilloma: a retrospective analysis of 139 cases[J]. J Laryngol Otol, 2023, 137(10): 1154-1157. doi:10.1017/S0022215123000361
[13] Sbrana MF, Borges RFR, Pinna FR, et al. Sinonasal inverted papilloma: rate of recurrence and malignant transformation in 44 operated patients[J]. Braz J Otorhinolaryngol, 2021, 87(1): 80-84. doi:10.1016/j.bjorl.2019.07.003
[14] Upadhya IB, Rao K. Sinonasal inverted Papilloma: a narrative review[J]. Indian J Otolaryngol Head Neck Surg, 2022, 74(2): 1017-1022. doi:10.1007/s12070-020-02089-0
[15] Tong CCL, Palmer JN. Updates in the cause of sinonasal inverted papilloma and malignant transformation to squamous cell carcinoma[J]. Curr Opin Otolaryngol Head Neck Surg, 2021, 29(1): 59-64. doi:10.1097/MOO.0000000000000692
[16] Ferreli F, Di Bari M, Moya-Plana A, et al. Association between human papillomavirus infection and malignant transformation of sinonasal inverted papilloma: a systematic review and meta-analysis[J]. Am J Otolaryngol,2022,43(6):103614. doi: 10.1016/j.amjoto.2022.103614
[17] 吴迪, 王成硕, 张罗. 人乳头状瘤病毒感染与鼻内翻性乳头状瘤[J]. 临床耳鼻咽喉头颈外科杂志, 2018, 32(10): 798-802. doi:10.13201/j.issn.1001-1781.2018.10.018 WU Di, WANG Chengshuo, ZHANG Luo. Human papillomavirus infection and sinonasal inverted papilloma[J]. Journal of Clinical Otorhinolaryngology Head and Neck Surgery, 2018, 32(10): 798-802. doi:10.13201/j.issn.1001-1781.2018.10.018
[18] 胡滢洁, 王雅丽. 老年鼻腔-鼻窦内翻性乳头状瘤术后复发危险因素及预测模型建立[J]. 中国老年学杂志, 2022, 42(11): 2673-2676. doi:10.3969/j.issn.1005-9202.2022.11.021
[19] Wang H, Li HB, Hu L, et al. EGFR and KRAS mutations in Chinese patients with sinonasal inverted papilloma and oncocytic papilloma[J]. Histopathology, 2019, 75(2): 274-281. doi:10.1111/his.13868
[20] 范宗宪, 白洁, 杨琳红, 等. Pin1和NF-κB p65在鼻内翻性乳头状瘤组织中表达及意义[J]. 中国医药导刊, 2017, 19(2): 186-187, 192. doi:10.3969/j.issn.1009-0959.2017.02.036 FAN Zongxian, BAI Jie, YANG Linhong, et al. Expression and significance of Pin1 and NF-κB p65 in nasal inverted Papilloma tissues[J]. Chinese Journal of Medicinal Guide, 2017, 19(2): 186-187, 192. doi:10.3969/j.issn.1009-0959.2017.02.036
[21] Battaglioni S, Benjamin D, Wälchli M, et al. mTOR substrate phosphorylation in growth control[J]. Cell, 2022, 185(11): 1814-1836. doi:10.1016/j.cell.2022.04.013
[22] Tavares MR, Pavan ICB, Amaral CL, et al. The S6K protein family in health and disease[J]. Life Sci, 2015, 131: 1-10. doi:10.1016/j.lfs.2015.03.001
[23] Martina JA, Chen Y, Gucek M, et al. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB[J]. Autophagy, 2012, 8(6): 903-914. doi:10.4161/auto.19653
[24] Guertin DA, Stevens DM, Thoreen CC, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1[J]. Dev Cell, 2006, 11(6): 859-871. doi:10.1016/j.devcel.2006.10.007
[25] 李钰,刘皓,王敏,等.mTOR通路在耳蜗中的研究进展[J].山东大学耳鼻喉眼学报, 2024, 38(5): 112-118. doi:10.6040/j.issn.1673-3770.0.2023.448 LI Yu, LIU Hao, WANG Min, et al. Progress of mTOR pathway in the cochlea[J]. Journal of Otorhinolaryngology and Ophthalmology of Shandong University, 2024, 38(5): 112-118. doi: 10.6040/j.issn.1673-3770.0.2023.448
[26] Surviladze Z, Sterk RT, DeHaro SA, et al. Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway and inhibition of autophagy[J]. J Virol, 2013, 87(5): 2508-2517. doi:10.1128/JVI.02319-12
[27] Aguayo F, Perez-Dominguez F, Osorio JC, et al. PI3K/AKT/mTOR signaling pathway in HPV-driven head and neck carcinogenesis: therapeutic implications[J]. Biology, 2023, 12(5): 672. doi:10.3390/biology12050672
[28] Guo Z, Li K, Liu P, et al. Targeted therapy for head and neck squamous cell carcinoma microenvironment[J]. Front Med(Lausanne), 2023, 30(10): 1257898. doi: 10.3389/fmed.2023.1257898
[29] 刘磊, 向中正, 李一, 等. 头颈部鳞癌免疫检查点抑制剂治疗专家共识[J]. 华西口腔医学杂志, 2022, 40(6): 619-628. doi:10.7518/hxkq.2022.06.001 LIU Lei, XIANG Zhongzheng, LI Yi, et al. The immune checkpoint inhibitors treatment of head and neck squamous cell carcinoma: an expert consensus[J]. West China Journal of Stomatology, 2022, 40(6): 619-628. doi:10.7518/hxkq.2022.06.001
[30] 刘清华, 林丽珠. 肿瘤分子靶向药物的药理与临床[J]. 临床药物治疗杂志, 2008, 6(5): 50-54. doi:10.3969/j.issn.1672-3384.2008.05.014 LIU Qinghua, LIN Lizhu. The pharmacology and clinical use of tumor molecular target drugs[J]. Clinical Medication Journal, 2008, 6(5): 50-54. doi:10.3969/j.issn.1672-3384.2008.05.014
[31] 陈晓晗, 陆静钰, 陆海军. 头颈部鳞状细胞癌靶向治疗进展[J]. 现代肿瘤医学, 2021, 29(9): 1632-1635. doi:10.3969/j.issn.1672-4992.2021.09.036 CHEN Xiaohan, LU Jingyu, LU Haijun. Advances in targeted therapy for head and neck squamous cell carcinoma[J]. Journal of Modern Oncology, 2021, 29(9): 1632-1635. doi:10.3969/j.issn.1672-4992.2021.09.036
[32] Dunn LA, Fury MG, Xiao H, et al. A phase II study of temsirolimus added to low-dose weekly carboplatin and paclitaxel for patients with recurrent and/or metastatic(R/M)head and neck squamous cell carcinoma(HNSCC)[J]. Ann Oncol, 2018, 29(7): 1606. doi:10.1093/annonc/mdx801
[33] Grünwald V, Keilholz U, Boehm A, et al. TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck(SCCHN)of the German SCCHN Group(AIO)[J]. Ann Oncol, 2015, 26(3): 561-567. doi:10.1093/annonc/mdu571
[34] Krouse JH. Development of a staging system for inverted Papilloma[J]. Laryngoscope, 2000, 110(6): 965-968. doi:10.1097/00005537-200006000-00015
[35] Meng YF, Fang GL, Wang XD, et al. Origin site-based staging system of sinonasal inverted papilloma for application to endoscopic sinus surgery[J]. Head Neck, 2019, 41(2): 440-447. doi:10.1002/hed.25435
[36] 李化静, 戴皓, 任婉丽, 等. 鼻内镜联合低温等离子刀手术治疗鼻内翻性乳头状瘤的疗效观察[J]. 现代肿瘤医学, 2018, 26(24): 3943-3946. doi:10.3969/j.issn.1672-4992.2018.24.013 LI Huajing, DAI Hao, REN Wanli, et al. Observation of the curative effect of the nasal inverted papilloma treated by nasal endoscopic and low-temperature plasma[J]. Journal of Modern Oncology, 2018, 26(24): 3943-3946. doi:10.3969/j.issn.1672-4992.2018.24.013
[37] 王胜国, 陈志太, 周本忠, 等. 鼻内镜下联合低温等离子刀切除鼻腔鼻窦内翻性乳头状瘤37例[J]. 山东大学耳鼻喉眼学报, 2021, 35(2): 67-70. doi:10.6040/j.issn.1673-3770.1.2020.090 WANG Shengguo, CHEN Zhitai, ZHOU Benzhong, et al. Thirty-seven cases of inverted papillomas in the nasal cavity and the nasal sinus treated by low-temperature plasma under nasal endoscope[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2021, 35(2): 67-70. doi:10.6040/j.issn.1673-3770.1.2020.090

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed