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摘要: 唾液是由口腔唾液腺分泌的混合生物体液，蕴含丰富的物质信息。随着唾液组学的不断发展，唾液不仅作为巨大的生物标志物储存库，唾液诊断也成为一种新型诊断技术，具有无侵袭性、易于获取、成本低等优势。但口腔环境复杂多变，标志物含量等易受影响，找到“真正的”唾液生物标志物仍然是一个挑战。本文主要关注常见肿瘤的潜在唾液标志物，包括DNA、RNA、蛋白质、代谢物和微生物等，针对目前已鉴定的或关联性标志物进行系统性总结，并指出建立多学科交叉体系开发唾液诊断技术，逐步构建唾液诊断平台，寻找更加精准的肿瘤预警标志物是未来发展方向。Abstract: Saliva, a complex mixed biological fluid secreted by the salivary glands in the oral cavity, contains a wide variety of substances and information. With the development of saliva omics, studies have shown that saliva not only serves as a huge reservoir of biomarker, but saliva diagnostics has also become a new diagnostic technology with the advantages of non-invasiveness, easy access, and low cost. However, finding "true" saliva biomarkers is still a challenge due to the complex and changeable nature of the oral environment and the high susceptibility of biomarker content to influences. Herein, mainly focusing on potential salivary biomarkers of common tumors, including DNA, RNA, proteins, metabolites and microorganisms, we gave a systematic overview of the biomarkers that had been identified so far or the associated biomarkers. We suggested that the future development direction should be the establishment of a multidisciplinary system for developing saliva diagnosis technology, the gradual construction of a saliva diagnosis platform, and the search for more precise pre-warning tumor biomarkers.
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Key words:
- Saliva /
- Salivary tumor biomarkers /
- Early diagnosis
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表 1 潜在的口腔癌唾液标志物
Table 1. Potential salivary biomarkers for oral cancer
Category Salivary tumor biomarkers Sensitivity Specificity Expression References DNA 3p, 9q, 13q, and 17p — — — [8, 16] p53, p16, p27, p63, and p73 — — — [8] p16, MGMT, DAP-K, NID2, and HOXA9 — — — [8] Cyclin D1 and Ki67 — — ↑ [8, 17] OGG1, P-Src, and Maspin — — ↓ [8, 18] mRNA IL-8, H3F3A, IL-1-β, S100P, DUSP1, OAZ1, and SAT — — ↑ [8, 14] miR-708, miR-10b, miR-19a, miR-30e, miR-26a, and miR-660 — — ↑ [2, 19-20] miR-99, miR-15a, miR-197, miR-145, and miR-150 — — ↓ [2, 19-20] Protein CD59, defensin-1, and catalase 90% 80% ↑ [2] CEA 76.4% 80.4% ↑ [13] MMP1, KNG1, ANXA2, and HSPA5 87.5% 80.5% ↑ [12] CD44, IL-8, and telomerase — — ↑ [8, 21-22] IPA, SCC-Ag 2, CA19-9, CA128, CA125, Cyfra 21-1, TPS, 8-OHdG, LDH, IgG, s-IgA, IGF, MMP-2, MMP-11, calcyclin, and RhoGDI — — — [8, 23] Clusterin — — ↓ [8, 24] Small molecule ROS, RNS, and NO — — ↑ [2, 15, 20] Microorganism Porphyromonasgingivalis, Tannerella forsythia, Candida albicans, Prevotellamelaninogenica, Streptococcus mitis, Pseudomonas aeruginosa, and Human papilloma virus — — ↑ [15, 25-26] MGMT: O6-methylguanine-DNA methyltransferase; DAP-K: death-associated protein kinase; NID2: nidogen-2; HOXA9: homeobox A9; OGG1: 8-oxoquanine DNA glycosylase; IL: interleukin; H3F3A: H3 histone, family 3A; S100P: S100 calcium binding protein P; DUSP1: dual specificity phosphatase 1; OAZ1: ornithine decarboxylase antizyme 1; SAT: spermidine/spermine N1-acetyltransferase; CD: cluster of differentiation; CEA: carcinoembryonic antigen; MMP1: matrix metalloproteinase 1; KNG1: kininogen 1; ANXA2: annexin A2; HSPA5: heat shock protein family A member 5; IPA: inhibitors of apoptosis; SCC-Ag 2: squamous cell carcinoma antigen 2; CA: cancer antigen; Cyfra 21-1: cytokeratin 19 fragment; TPS: tissue polypeptide specific antigen; 8-OHdG: 8-hydroxydeoxyguanosine; LDH: lactate dehydrogenase; Ig: immunoglobulin; IGF: insulin growth factor; RhoGDI: Rho GDP dissociation inhibitor; ROS: reactive oxygen species; RNS: reactive nitrogen species; NO: nitrogen monoxide. ↑: Upregulated genes or proteins; ↓: Downregulated genes or proteins; —: None. 
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表 2 潜在的肺癌唾液标志物
Table 2. Potential salivary biomarkers for lung cancer
Category Salivary tumor biomarkers Sensitivity Specificity Expression References mRNA CCNI, EGFR, FGF19, FRS2, and GREB1 93.75% 82.81% ↑ [1, 28] Protein Haptoglobin, ZAG, and calreticulin 88.5% 92.3% ↑ [1] CCNI: cyclin I; EGFR: epidermal growth factor receptor; FGF19: fibroblast growth factor 19; FRS2: fibroblast growth factor receptor substrate 2; GREB1: growth regulation by estrogen in breast cancer 1; ZAG: zinc-alpha-2-glycoprotein.
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表 3 潜在的胰腺癌唾液标志物
Table 3. Potential salivary biomarkers for pancreatic cancer
Category Salivary tumor biomarkers Sensitivity Specificity Expression References mRNA KRAS, MBD3L2, and ACRV1 90.0% 95.0% ↑ [33] DPM1 90.0% 95.0% ↓ [33] miRNA miR-17, miR-21, miR-181a, miR-181b, and miR-196a — — ↑ [38] hsa-miR-21 71.4% 100% ↑ [34] hsa-miR-23a 85.7% 100% ↑ [34] hsa-miR-23b 85.7% 100% ↑ [34] miR-29c 57% 100% ↑ [34] Protein CEA and CA125 92.31% 84.62% ↑ [32] Microorganism Neisseria elongata and Streptococcus mitis 96.4% 82.1% ↓ [35] KRAS: Kirsten rat sarcoma viral oncogene homolog; MBD3L2: methyl-CpG binding domain protein 3 like 2; ACRV1: acrosomal vesicle protein 1; DPM1: dolichol-phosphate mannosyltransferase subunit 1; CEA: carcinoembryonic antigen; CA: cancer antigen.
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表 4 潜在的乳腺癌唾液标志物
Table 4. Potential salivary biomarkers for breast cancer
Category Salivary tumor biomarkers Sensitivity Specificity Expression References mRNA CSTA, TPT1, IGF2BP1, GRM1, GRIK1, H6PD, MDM4, and S100A8 83% 97% ↑ [46] Protein CA6 — — ↑ [1] CA15-3 95.87% 88.66% ↑ [48] ER-α, VEGF, EGF, CEA, HER2, CA15-3, P53, and CA125 — — ↑ [4] Small molecule Choline, isethionate, cadavarine, N1-acetylspermidine, and spermine — — ↑ [1] CSTA: cysteine protease inhibitor A; TPT1: translationally-controlled tumor protein 1; IGF2BP1: insulin-like growth factor 2 mRNA-binding protein 1; GRM1: metabotropic glutamate receptor 1; GRIK1: glutamate receptor, ionotropic, kainate 1; H6PD: hexose-6-phosphate dehydrogenase; MDM4: murine double minute 4; S100A8: S100 calcium-binding protein A8; CA: cancer antigen; ER-α: estrogen receptor-alpha; VEGF: vascular endothelial growth factor; EGF: epidermal growth factor; CEA: carcinoembryonic antigen; HER2: human epidermal receptor 2.
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[1] WANG X, KACZOR-URBANOWICZ K E, WONG D T. Salivary biomarkers in cancer detection. Med Oncol,2017,34(1): 7. doi: 10.1007/s12032-016-0863-4 [2] GOPAL S K, RAVI P. Salivary biomarkers--a modern approach to diagnosis. J Pharm Sci Res,2021,13(11): 677–680. [3] DEVARAJ S D. Salivary biomarkers--a review. J Pharm Sci Res,2013,5(10): 210. [4] LAIDI F, ZAOUI F. Saliva diagnostic and cancer monitoring: overview. J Intern Dent Med Res,2015,8(2): 94–97. [5] SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin,2021,71(3): 209–249. doi: 10.3322/caac.21660 [6] CROSBY D, BHATIA S, BRINDLE K M, et al. Early detection of cancer. Science,2022,375(6586): eaay9040. doi: 10.1126/science.aay9040 [7] ZHANG A, SUN H, WANG X. Saliva metabolomics opens door to biomarker discovery, disease diagnosis, and treatment. Appl Biochem Biotechnol,2012,168(6): 1718–1727. doi: 10.1007/s12010-012-9891-5 [8] SAXENA S, SANKHLA B, SUNDARAGIRI K S, et al. A review of salivary biomarker: a tool for early oral cancer diagnosis. Adv Biomed Res,2017,6: 90. doi: 10.4103/2277-9175.211801 [9] FAN T, WANG X, ZHANG S, et al. NUPR1 promotes the proliferation and metastasis of oral squamous cell carcinoma cells by activating TFE3-dependent autophagy. Signal Transduct Target Ther,2022,7(1): 1–11. doi: 10.1038/s41392-022-00939-7 [10] WARNAKULASURIYA S, KERR A R. Oral cancer screening: past, present, and future. J Dent Res,2021,100(12): 1313–1320. doi: 10.1177/00220345211014795 [11] LIAO P H, CHANG Y C, HUANG M F, et al. Mutation of p53 gene codon 63 in saliva as a molecular marker for oral squamous cell carcinomas. Oral Oncol,2000,36(3): 272–276. doi: 10.1016/S1368-8375(00)00005-1 [12] YAO Z, AN W, TUERDI M, et al. Identification of novel prognostic indicators for oral squamous cell carcinoma based on proteomics and metabolomics. Transl Oncol,2016,33: 101672. doi: 10.1016/j.tranon.2023.101672 [13] KAUR J, JACOBS R, HUANG Y, et al. Salivary biomarkers for oral cancer and pre-cancer screening: a review. Clin Oral Investig,2018,22(2): 633–640. doi: 10.1007/s00784-018-2337-x [14] LI Y, JOHN M A S, ZHOU X, et al. Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res,2004,10(24): 8442–8450. doi: 10.1158/1078-0432.ccr-04-1167 [15] KAKABADZE M Z, PARESISHVILI T, KARALASHVILI L, et al. Oral microbiota and oral cancer: review. Oncol Rev,2020,14(2): 476. doi: 10.4081/oncol.2020.476 [16] CALIFANO J, Van Der RIET P, WESTRA W, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res,1996,56(11): 2488–2492. doi: 10.1016/S0194-5998(96)80631-0 [17] VIELBA R, BILBAO J, ISPIZUA A, et al. p53 and cyclin D1 as prognostic factors in squamous cell carcinoma of the larynx. Laryngoscope,2003,113(1): 167–172. doi: 10.1097/00005537-200301000-00031 [18] SHPITZER T, HAMZANY Y, BAHAR G, et al. Salivary analysis of oral cancer biomarkers. Br J Cancer,2009,101(7): 1194–1198. doi: 10.1038/sj.bjc.6605290 [19] POORNIMA G, KUMAR T S M. Genomic alphabets of saliva as a biomarker in oral cancer. J Indian Acad Oral Med Radiol,2017,29(4): 300. doi: 10.4103/jiaomr.JIAOMR_90_16 [20] YANG Y, LI Y X, YANG X, et al. Progress risk assessment of oral premalignant lesions with saliva miRNA analysis. BMC Cancer,2013,13(1): 1–8. doi: 10.1186/1471-2407-13-129 [21] FRANZMANN E J, REATEGUI E P, PEDROSO F, et al. Soluble CD44 is a potential marker for the early detection of head and neck cancer. Cancer Epidemiol Biomarkers Prev,2007,16(7): 1348–1355. doi: 10.1158/1055-9965.EPI-06-0011 [22] JOHN M A S, LI Y, ZHOU X, et al. Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg,2004,130(8): 929–935. doi: 10.1001/archotol.130.8.929 [23] MARKOPOULOS A K, MICHAILIDOU E Z, TZIMAGIORGIS G. Salivary markers for oral cancer detection. Open Dent J,2010,4: 172–178. doi: 10.2174/1874210601004010172 [24] HU S, ARELLANO M, BOONTHEUNG P, et al. Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res,2008,14(19): 6246–6252. doi: 10.1158/1078-0432.CCR-07-5037 [25] KANG M S, OH J S, KIM H J, et al. Prevalence of oral microbes in the saliva of oncological patients. J Bacteriol Virol,2009,39(4): 277–285. doi: 10.4167/jbv.2009.39.4.277 [26] MAGER D, HAFFAJEE A, DEVLIN P, et al. The salivary microbiota as a diagnostic indicator of oral cancer: a descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. J Transl Med,2005,3: 27. doi: 10.1186/1479-5876-3-27 [27] HIRSCH F R, SCAGLIOTTI G V, MULSHINE J L, et al. Lung cancer: current therapies and new targeted treatments. Lancet,2017,389(10066): 299–311. doi: 10.1016/S0140-6736(16)30958-8 [28] ZHANG L, XIAO H, ZHOU H, et al. Development of transcriptomic biomarker signature in human saliva to detect lung cancer. Cell Mol Life Sci,2012,69(19): 3341–3350. doi: 10.1007/s00018-012-1027-0 [29] QIAN K, WANG Y, HUA L, et al. New method of lung cancer detection by saliva test using surface-enhanced Raman spectroscopy. Thoracic Cancer,2018,9(11): 1556–1561. doi: 10.1111/1759-7714.12837 [30] 李晓舟, 杨天月, 丁建华. 唾液表面增强拉曼光谱用于肺癌的诊断. 光谱学与光谱分析,2012,32(2): 391–393. doi: 10.3964/j.issn.1000-0593(2012)02-0391-03 [31] 高明, 徐钧, 杨文慧. 胰腺癌早期诊断的肿瘤标志物研究进展. 肿瘤研究与临床,2020,32(12): 881–884. doi: 10.3760/cma.j.cn115355-20191021-00482 [32] 赵治锋, 谢荣理, 沈东杰, 等. 唾液肿瘤标志物诊断胰腺癌的研究. 外科理论与实践,2019,24(2): 149–154. doi: 10.16139/j.1007-9610.2019.02.013 [33] ZHANG L, FARRELL J J, ZHOU H, et al. Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer. Gastroenterology,2010,138(3): 949–957.e947. doi: 10.1053/j.gastro.2009.11.010 [34] HUMEAU M, VIGNOLLE-VIDONI A, SICARD F, et al. Salivary microRNA in pancreatic cancer patients. PLoS One,2015,10(6): e0130996. doi: 10.1371/journal.pone.0130996 [35] FARRELL J J, ZHANG L, ZHOU H, et al. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut,2012,61(4): 582–588. doi: 10.1136/gutjnl-2011-300784 [36] TORRES P J, FLETCHER E M, GIBBONS S M, et al. Characterization of the salivary microbiome in patients with pancreatic cancer. Peerj,2015,3: e1373. doi: 10.7717/peerj.1373 [37] LAU C, KIM Y, CHIA D, et al. Role of pancreatic cancer-derived exosomes in salivary biomarker development. J Biol Chem,2013,288(37): 26888–26897. doi: 10.1074/jbc.M113.452458 [38] GAO S, CHEN L Y, WANG P, et al. MicroRNA expression in salivary supernatant of patients with pancreatic cancer and its relationship with ZHENG. Biomed Res Int,2014,2014: 756347. doi: 10.1155/2014/756347 [39] XIAO H, ZHANG Y, KIM Y, et al. Differential proteomic analysis of human saliva using tandem mass tags quantification for gastric cancer detection. Sci Rep,2016,6: 22165. doi: 10.1038/srep22165 [40] LI F, YOSHIZAWA J M, KIM K M, et al. Discovery and validation of salivary extracellular RNA biomarkers for noninvasive detection of gastric cancer. Clin Chem,2018,64(10): 1513–1521. doi: 10.1373/clinchem.2018.290569 [41] RÖCKEN C. Predictive biomarkers in gastric cancer. J Cancer Res Clin Oncol,2023,149(1): 467–481. doi: 10.1007/s00432-022-04408-0 [42] USUI Y, TANIYAMA Y, ENDO M, et al. Helicobacter pylori, homologous-recombination genes, and gastric cancer. N Engl J Med,2023,388(13): 1181–1190. doi: 10.1056/NEJMoa2211807 [43] 杨锴毓, 李雨庆, 周学东. 口腔幽门螺杆菌与胃幽门螺杆菌感染关系的研究进展. 华西口腔医学杂志,2014,32(3): 314–318. doi: 10.7518/hxkq.2014.03.025 [44] SUN Y S, ZHAO Z, YANG Z N, et al. Risk factors and preventions of breast cancer. Int J Biol Sci,2017,13(11): 1387–1397. doi: 10.7150/ijbs.21635 [45] YARDIM-AKAYDIN S, KARAHALIL B, BAYTAS S N. New therapy strategies in the management of breast cancer. Drug Discov Today,2022,27(6): 1755–1762. doi: 10.1016/j.drudis.2022.03.014 [46] ZHANG L, XIAO H, KARLAN S, et al. Discovery and preclinical validation of salivary transcriptomic and proteomic biomarkers for the non-invasive detection of breast cancer. PLoS One,2010,5(12): e15573. doi: 10.1371/journal.pone.0015573 [47] FÜZÉRY A K, LEVIN J, CHAN M M, et al. Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges. Clin Proteomics,2013,10(1): 1–14. doi: 10.1186/1559-0275-10-13 [48] WU W, GONG H, LIU M, et al. Noninvasive breast tumors detection based on saliva protein surface enhanced Raman spectroscopy and regularized multinomial regression//Proceedings of the 2015 8th International Conference on Biomedical Engineering and Informatics (BMEI). Shenyang: IEEE, 2015: 214-218. doi: 10.1109/BMEI.2015.7401503. [49] 李艺, 祝洪澜, 昌晓红, 等. 初诊晚期上皮性卵巢癌的规范化治疗. 现代妇产科进展,2020,29(10): 778–782. doi: 10.13283/j.cnki.xdfckjz.2020.10.011 [50] CHEN D X, SCHWARTZ P E, LI F Q. Saliva and serum CA 125 assays for detecting malignant ovarian tumors. Obstet Gynecol,1990,75(4): 701–704. [51] SCHAPHER M, WENDLER O, GRÖSCHL M, et al. Salivary leptin as a candidate diagnostic marker in salivary gland tumors. Clin Chem,2009,55(5): 914–922. doi: 10.1373/clinchem.2008.116939 [52] WANG N, FANG J Y. Fusobacterium nucleatum, a key pathogenic factor and microbial biomarker for colorectal cancer. Trends Microbiol,2023,31(2): 159–172. doi: 10.1016/j.tim.2022.08.010 [53] SAZANOV A A, KISELYOVA E V, ZAKHARENKO A A, et al. Plasma and saliva miR-21 expression in colorectal cancer patients. J Appl Genet,2017,58(2): 231–237. doi: 10.1007/s13353-016-0379-9 -
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