Carcinomas of the oral cavity and oropharynx belong among the ten most common malignancies in the human population. The prognosis of head and neck squamous cell carcinoma (HNSCC) is determined by the degree of invasiveness of the primary tumor and by the extent of metastatic spread into regional and distant lymph nodes. Moreover, the level of the perineural invasion itself associates with tumor localization, invasion's extent, and the presence of nodal metastases. Here, we summarize the current knowledge about different aspects of epigenetic changes, which can be associated with HNSCC while focusing on perineural invasion (PNI). We review epigenetic modifications of the genes involved in the PNI process in HNSCC from the omics perspective and specific epigenetic modifications in OSCC or other neurotropic cancers associated with perineural invasion. Moreover, we summarize DNA methylation status of tumor-suppressor genes, methylation and demethylation enzymes and histone post-translational modifications associated with PNI. The influence of other epigenetic factors on the HNSCC incidence and perineural invasion such as tobacco, alcohol and oral microbiome is overviewed and HPV infection is discussed as an epigenetic factor associated with OSCC and related perineural invasion. Understanding epigenetic regulations of axon growth that lead to tumorous spread or uncovering the molecular control of axon interaction with cancer tissue can help to discover new therapeutic targets for these tumors.

Department of Clinical and Molecular Pathology and Medical Genetics Faculty of Medicine and University Hospital Ostrava Ostrava Czechia

Department of Clinical and Molecular Pathology Faculty of Medicine and University Hospital Olomouc Olomouc Czechia

Department of Experimental Biology Faculty of Science Masaryk University Brno Czechia

Department of Hematooncology University Hospital Ostrava Ostrava Czechia

Department of Histology and Embryology Medical Faculty Masaryk University Brno Czechia

Department of Maxillofacial Surgery University Hospital Ostrava Ostrava Czechia

Department of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University Baltimore MD United States

Department of Otorhinolaryngology Head and Neck Surgery University of Maryland Medical Center Baltimore MD United States

Institute for Genome Sciences University of Maryland Medical Center Baltimore MD United States

Laboratory of Molecular Morphogenesis Institute of Animal Physiology and Genetics Czech Academy of Sciences Brno Czechia

Marlene and Stewart Greenebaum Comprehensive Cancer Center University of Maryland Medical Center Baltimore MD United States

Zobrazit více v PubMed

Adhikari B. R., Uehara O., Matsuoka H., Takai R., Harada F., Utsunomiya M., et al. (2017). Immunohistochemical Evaluation of Klotho and DNA Methyltransferase 3a in Oral Squamous Cell Carcinomas. Med. Mol. Morphol. 50 (3), 155–160. 10.1007/s00795-017-0156-9 PubMed DOI

Aggarwal N., Yadav J., Thakur K., Bibban R., Chhokar A., Tripathi T., et al. (2020). Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns. Front. Cel. Infect. Microbiol. 10, 537650. 10.3389/fcimb.2020.537650 PubMed DOI PMC

Ahn H., Yang J. M., Kim H., Chung J. H., Ahn S. H., Jeong W. J., et al. (2017). Clinicopathologic Implications of the miR-197/PD-L1 axis in Oral Squamous Cell Carcinoma. Oncotarget 8 (39), 66178–66194. 10.18632/oncotarget.19842 PubMed DOI PMC

Ahn M.-Y., Yoon J.-H. (2017). Histone Deacetylase 8 as a Novel Therapeutic Target in Oral Squamous Cell Carcinoma. Oncol. Rep. 37 (1), 540–546. 10.3892/or.2016.5280 PubMed DOI

Ahn M. Y. (2018). HDAC Inhibitor Apicidin Suppresses Murine Oral Squamous Cell Carcinoma Cell Growth In Vitro and In Vivo via Inhibiting HDAC8 Expression. Oncol. Lett. 16 (5), 6552–6560. 10.3892/ol.2018.9468 PubMed DOI PMC

Al Feghali K. A., Ghanem A. I., Burmeister C., Chang S. S., Ghanem T., Keller C., et al. (2019). Impact of Smoking on Pathological Features in Oral Cavity Squamous Cell Carcinoma. J. Cancer Res. Ther. 15 (3), 582–588. 10.4103/jcrt.JCRT_641_16 PubMed DOI PMC

Aller M.-A., Arias J.-I., Arias J. (2010). Pathological Axes of Wound Repair: Gastrulation Revisited. Theor. Biol. Med. Model. 7, 37. 10.1186/1742-4682-7-37 PubMed DOI PMC

Ando M., Saito Y., Xu G., Bui N. Q., Medetgul-Ernar K., Pu M., et al. (2019). Chromatin Dysregulation and DNA Methylation at Transcription Start Sites Associated with Transcriptional Repression in Cancers. Nat. Commun. 10 (1), 2188. 10.1038/s41467-019-09937-w PubMed DOI PMC

Arantes L. M. R. B., de Carvalho A. C., Melendez M. E., Centrone C. C., Góis-Filho J. F., Toporcov T. N., et al. (2015). Validation of Methylation Markers for Diagnosis of Oral Cavity Cancer. Eur. J. Cancer 51 (5), 632–641. 10.1016/j.ejca.2015.01.060 PubMed DOI

Arif M., Vedamurthy B. M., Choudhari R., Ostwal Y. B., Mantelingu K., Kodaganur G. S., et al. (2010). Nitric Oxide-Mediated Histone Hyperacetylation in Oral Cancer: Target for a Water-Soluble HAT Inhibitor, CTK7A. Chem. Biol. 17 (8), 903–913. 10.1016/j.chembiol.2010.06.014 PubMed DOI

Augustin J. G., Lepine C., Morini A., Brunet A., Veyer D., Brochard C., et al. (2020). HPV Detection in Head and Neck Squamous Cell Carcinomas: What Is the Issue? Front. Oncol. 10, 1751. 10.3389/fonc.2020.01751 PubMed DOI PMC

Ayala G. E., Dai H., Powell M., Li R., Ding Y., Wheeler T. M., et al. (2008). Cancer-related Axonogenesis and Neurogenesis in Prostate Cancer. Clin. Cancer Res. 14 (23), 7593–7603. 10.1158/1078-0432.ccr-08-1164 PubMed DOI

Azam S. H., Pecot C. V. (2016). Cancer's Got Nerve: Schwann Cells Drive Perineural Invasion. J. Clin. Invest. 126 (4), 1242–1244. 10.1172/jci86801 PubMed DOI PMC

Baba O., Hasegawa S., Nagai H., Uchida F., Yamatoji M., Kanno N. I., et al. (2016). MicroRNA-155-5p Is Associated with Oral Squamous Cell Carcinoma Metastasis and Poor Prognosis. J. Oral Pathol. Med. 45 (4), 248–255. 10.1111/jop.12351 PubMed DOI

Bagnardi V., Blangiardo M., La Vecchia C., Corrao G. (2001). Alcohol Consumption and the Risk of Cancer: a Meta-Analysis. Alcohol. Res. Health 25 (4), 263–270. PubMed PMC

Bakst R. L., Glastonbury C. M., Parvathaneni U., Katabi N., Hu K. S., Yom S. S. (2019). Perineural Invasion and Perineural Tumor Spread in Head and Neck Cancer. Int. J. Radiat. Oncology*Biology*Physics 103 (5), 1109–1124. 10.1016/j.ijrobp.2018.12.009 PubMed DOI

Baumeister P., Welz C., Jacobi C., Reiter M. (2018). Is Perineural Invasion of Head and Neck Squamous Cell Carcinomas Linked to Tobacco Consumption? Otolaryngol. Head Neck Surg. 158 (5), 878–881. 10.1177/0194599817750354 PubMed DOI

Binmadi N. O., Basile J. R. (2011). Perineural Invasion in Oral Squamous Cell Carcinoma: a Discussion of Significance and Review of the Literature. Oral Oncol. 47 (11), 1005–1010. 10.1016/j.oraloncology.2011.08.002 PubMed DOI

Binmadi N. O., Yang Y.-H., Zhou H., Proia P., Lin Y.-L., Batista De Paula A. M., et al. (2012). RETRACTED: Plexin-B1 and Semaphorin 4D Cooperate to Promote Perineural Invasion in a RhoA/ROK-dependent Manner. Am. J. Pathol. 180 (3), 1232–1242. 10.1016/j.ajpath.2011.12.009 PubMed DOI PMC

Bockman D. E., Büchler M., Beger H. G. (1994). Interaction of Pancreatic Ductal Carcinoma with Nerves Leads to Nerve Damage. Gastroenterology 107 (1), 219–230. 10.1016/0016-5085(94)90080-9 PubMed DOI

Booth M. J., Raiber E.-A., Balasubramanian S. (2015). Chemical Methods for Decoding Cytosine Modifications in DNA. Chem. Rev., 115, 2240PMC4378238–2254. 10.1021/cr5002904 PubMed DOI PMC

Breitling L. P., Yang R., Korn B., Burwinkel B., Brenner H. (2011). Tobacco-smoking-related Differential DNA Methylation: 27K Discovery and Replication. Am. J. Hum. Genet. 88 (4), 450–457. 10.1016/j.ajhg.2011.03.003 PubMed DOI PMC

Brito B. d. L., Lourenço S. V., Damascena A. S., Kowalski L. P., Soares F. A., Coutinho-Camillo C. M. (2016). Expression of Stem Cell-Regulating miRNAs in Oral Cavity and Oropharynx Squamous Cell Carcinoma. J. Oral Pathol. Med. 45 (9), 647–654. 10.1111/jop.12424 PubMed DOI

Brunzell D. H., Stafford A. M., Dixon C. I. (2015). Nicotinic Receptor Contributions to Smoking: Insights from Human Studies and Animal Models. Curr. Addict. Rep. 2 (1), 33–46. 10.1007/s40429-015-0042-2 PubMed DOI PMC

Bur A. M., Lin A., Weinstein G. S. (2016). Adjuvant Radiotherapy for Early Head and Neck Squamous Cell Carcinoma with Perineural Invasion: A Systematic Review. Head Neck 38 Suppl 1 (Suppl. 1), E2350–E2357. 10.1002/hed.24295 PubMed DOI

Caldemeyer K. S., Mathews V. P., Righi P. D., Smith R. R. (1998). Imaging Features and Clinical Significance of Perineural Spread or Extension of Head and Neck Tumors. Radiographics 18 (1), 97–110. 10.1148/radiographics.18.1.9460111 PubMed DOI

Cao W., Feng Z., Cui Z., Zhang C., Sun Z., Mao L., et al. (2012). Up-regulation of Enhancer of Zeste Homolog 2 Is Associated Positively with Cyclin D1 Overexpression and Poor Clinical Outcome in Head and Neck Squamous Cell Carcinoma. Cancer 118 (11), 2858–2871. 10.1002/cncr.26575 PubMed DOI

Celentano A., Yap T., Paolini R., Yiannis C., Mirams M., Koo K., et al. (2021). Inhibition of Matrix Metalloproteinase‐2 Modulates Malignant Behaviour of Oral Squamous Cell Carcinoma Cells. J. Oral Pathol. Med. 50 (3), 323–332. 10.1111/jop.12992 PubMed DOI

Centers for Disease Control and Prevention (2010). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention. PubMed

Chang H.-H., Chiang C.-P., Hung H.-C., Lin C.-Y., Deng Y.-T., Kuo M. Y.-P. (2009). Histone Deacetylase 2 Expression Predicts Poorer Prognosis in Oral Cancer Patients. Oral Oncol. 45 (7), 610–614. 10.1016/j.oraloncology.2008.08.011 PubMed DOI

Chattopadhyay I., Verma M., Panda M. (2019). Role of Oral Microbiome Signatures in Diagnosis and Prognosis of Oral Cancer. Technol. Cancer Res. Treat. 18 (1), 1533033819867354–19. 10.1177/1533033819867354 PubMed DOI PMC

Chatzistefanou I., Lubek J., Markou K., Ord R. A. (2017). The Role of Perineural Invasion in Treatment Decisions for Oral Cancer Patients: A Review of the Literature. J. Craniomaxillofac. Surg. 45 (6), 821–825. 10.1016/j.jcms.2017.02.022 PubMed DOI

Chen F., Qi S., Zhang X., Wu J., Yang X., Wang R. (2019). lncRNA PLAC2 Activated by H3K27 Acetylation Promotes Cell Proliferation and Invasion via the Activation of Wnt/β-catenin P-athway in O-ral S-quamous C-ell C-arcinoma. Int. J. Oncol. 54 (4), 1183–1194. 10.3892/ijo.2019.4707 PubMed DOI PMC

Chen L.-H., Hsu W.-L., Tseng Y.-J., Liu D.-W., Weng C.-F. (2016). Involvement of DNMT 3B Promotes Epithelial-Mesenchymal Transition and Gene Expression Profile of Invasive Head and Neck Squamous Cell Carcinomas Cell Lines. BMC Cancer 16, 431. 10.1186/s12885-016-2468-x PubMed DOI PMC

Chen W., Zhang H.-L., Shao X.-J., Jiang Y.-G., Zhao X.-G., Gao X., et al. (2007). Gene Expression Profile of Salivary Adenoid Cystic Carcinoma Associated with Perineural Invasion. Tohoku J. Exp. Med. 212 (3), 319–334. 10.1620/tjem.212.319 PubMed DOI

Chen Y.-W., Kao S.-Y., Wang H.-J., Yang M.-H. (2013). Histone Modification Patterns Correlate with Patient Outcome in Oral Squamous Cell Carcinoma. Cancer 119 (24), 4259–4267. 10.1002/cncr.28356 PubMed DOI

Chen Y. L., Hu C. M., Hsu J. T., Chang C. C., Huang T. Y., Chiang P. H., et al. (2018). Cellular 5-hydroxylmethylcytosine Content Determines Tumorigenic Potential and Prognosis of Pancreatic Ductal Adenocarcinoma. Am. J. Cancer Res. 8 (12), 2548–2563. PubMed PMC

Chernov A. V., Sounni N. E., Remacle A. G., Strongin A. Y. (2009). Epigenetic Control of the Invasion-Promoting MT1-MMP/MMP-2/TIMP-2 axis in Cancer Cells. J. Biol. Chem. 284 (19), 12727–12734. 10.1074/jbc.m900273200 PubMed DOI PMC

Chou S.-T., Peng H.-Y., Mo K.-C., Hsu Y.-M., Wu G.-H., Hsiao J.-R., et al. (2019). MicroRNA-486-3p Functions as a Tumor Suppressor in Oral Cancer by Targeting DDR1. J. Exp. Clin. Cancer Res. 38 (1), 281. 10.1186/s13046-019-1283-z PubMed DOI PMC

Choukrallah M.-A., Sierro N., Martin F., Baumer K., Thomas J., Ouadi S., et al. (2019). Tobacco Heating System 2.2 Has a Limited Impact on DNA Methylation of Candidate Enhancers in Mouse Lung Compared with Cigarette Smoke. Food Chem. Toxicol. 123, 501–510. 10.1016/j.fct.2018.11.020 PubMed DOI

Clarke T. L., Tang R., Chakraborty D., Van Rechem C., Ji F., Mishra S., et al. (2020). Histone Lysine Methylation Dynamics ControlEGFRDNA Copy-Number Amplification. Cancer Discov. 10 (2), 306–325. 10.1158/2159-8290.cd-19-0463 PubMed DOI PMC

Colacino J. A., Dolinoy D. C., Duffy S. A., Sartor M. A., Chepeha D. B., Bradford C. R., et al. (2013). Comprehensive Analysis of DNA Methylation in Head and Neck Squamous Cell Carcinoma Indicates Differences by Survival and Clinicopathologic Characteristics. PLoS One 8 (1), e54742. 10.1371/journal.pone.0054742 PubMed DOI PMC

Coppedè F., Lopomo A., Spisni R., Migliore L. (2014). Genetic and Epigenetic Biomarkers for Diagnosis, Prognosis and Treatment of Colorectal Cancer. Wjg 20 (4), 943–56. 10.3748/wjg.v20.i4.943 PubMed DOI PMC

D'Addario C., Johansson S., Candeletti S., Romualdi P., Ögren S. O., Terenius L., et al. (2011). Ethanol and Acetaldehyde Exposure Induces Specific Epigenetic Modifications in the Prodynorphin Gene Promoter in a Human Neuroblastoma Cell Line. FASEB j. 25 (3), 1069–1075. 10.1096/fj.10-168534 PubMed DOI

Dauksa A., Gulbinas A., Barauskas G., Pundzius J., Oldenburg J., El-Maarri O. (2012). Whole Blood DNA Aberrant Methylation in Pancreatic Adenocarcinoma Shows Association with the Course of the Disease: a Pilot Study. PLoS One 7 (5), e37509. 10.1371/journal.pone.0037509 PubMed DOI PMC

de Abreu P. M., Có A. C. G., Azevedo P. L., do Valle I. B., de Oliveira K. G., Gouvea S. A., et al. (2018). Frequency of HPV in Oral Cavity Squamous Cell Carcinoma. BMC Cancer 18 (1), 324. 10.1186/s12885-018-4247-3 PubMed DOI PMC

Deborde S., Wong R. J. (2017). How Schwann Cells Facilitate Cancer Progression in Nerves. Cell. Mol. Life Sci. 74 (24), 4405–4420. 10.1007/s00018-017-2578-x PubMed DOI PMC

Deepak Roshan V. G., Sinto M. S., Vargees B. T., Kannan S. (2019). Loss of CDKN2A and CDKN2B Expression Is Associated with Disease Recurrence in Oral Cancer. J. Oral Maxillofac. Pathol. 23 (1), 82–89. 10.4103/jomfp.JOMFP_184_18 PubMed DOI PMC

Degli Esposti D., Sklias A., Lima S. C., Beghelli-de la Forest Divonne S., Cahais V., Fernandez-Jimenez N., et al. (2017). Unique DNA Methylation Signature in HPV-Positive Head and Neck Squamous Cell Carcinomas. Genome Med. 9 (1), 33. 10.1186/s13073-017-0419-z PubMed DOI PMC

Fagan J. J., Collins B., Barnes L., D'Amico F., Myers E. N., Johnson J. T. (1998). Perineural Invasion in Squamous Cell Carcinoma of the Head and Neck. Arch. Otolaryngol. Head Neck Surg. 124, 637–40. 10.1001/archotol.124.6.637 PubMed DOI

Faraji F., Schubert A. D., Kagohara L. T., Tan M., Xu Y., Zaidi M., et al. (2018). “The Genome-wide Molecular Landscape of HPV-Driven and HPV-Negative Head and Neck Squamous Cell Carcinoma,” in Molecular Determinants of Head and Neck Cancer. 2018. Current Cancer Research. Editors Burtness B., Golemis E. (Cham: Humana Press; ).

Feng B., Wang K., Herpel E., Plath M., Weichert W., Freier K., et al. (2021). Prognostic Gene Signature for Squamous Cell Carcinoma with a Higher Risk for Treatment Failure and Accelerated MEK-ERK Pathway Activity. Cancers 13 (20), 5182. 10.3390/cancers13205182 PubMed DOI PMC

Feng Y.-H., Tsao C.-J. (2016). Emerging Role of microRNA-21 in Cancer. Biomed. Rep. 5 (4), 395–402. 10.3892/br.2016.747 PubMed DOI PMC

Franz M., Wolheim A., Richter P., Umbreit C., Dahse R., Driemel O., et al. (2010). Stromal Laminin Chain Distribution in normal, Hyperplastic and Malignant Oral Mucosa: Relation to Myofibroblast Occurrence and Vessel Formation. J. Oral Pathol. Med. 39 (4), 290–8. 10.1111/j.1600-0714.2009.00840.x PubMed DOI

Fujimoto M., Kitazawa R., Maeda S., Kitazawa S. (2005). Methylation Adjacent to Negatively Regulating AP-1 Site Reactivates TrkA Gene Expression during Cancer Progression. Oncogene 24 (32), 5108–5118. 10.1038/sj.onc.1208697 PubMed DOI

Fukada M., Matsuhashi N., Takahashi T., Sugito N., Heishima K., Akao Y., et al. (2020). Tumor Tissue MIR92a and Plasma MIRs21 and 29a as Predictive Biomarkers Associated with Clinicopathological Features and Surgical Resection in a Prospective Study on Colorectal Cancer Patients. Jcm 9 (8), 2509. 10.3390/jcm9082509 PubMed DOI PMC

Gao F., Griffin N., Faulkner S., Rowe C. W., Williams L., Roselli S., et al. (2018). The Neurotrophic Tyrosine Kinase Receptor TrkA and its Ligand NGF Are Increased in Squamous Cell Carcinomas of the Lung. Sci. Rep. 8 (1), 8135. 10.1038/s41598-018-26408-2 PubMed DOI PMC

Gao F., Huang C., Lin M., Wang Z., Shen J., Zhang H., et al. (2009). Frequent Inactivation of RUNX3 by Promoter Hypermethylation and Protein Mislocalization in Oral Squamous Cell Carcinomas. J. Cancer Res. Clin. Oncol. 135 (5), 739–747. 10.1007/s00432-008-0508-x PubMed DOI

Gao W. Y., Yang G., Wang J., He J. M., Wang P. (2020). CSN6 Promotes Malignant Progression of Oral Squamous Cell Carcinoma by Down-Regulating TIMP-2. Eur. Rev. Med. Pharmacol. Sci. 24 (10), 5419–5428. 10.26355/eurrev_202005_21326 PubMed DOI

Gaździcka J., Gołąbek K., Strzelczyk J. K., Ostrowska Z. (2020). Epigenetic Modifications in Head and Neck Cancer. Biochem. Genet. 58 (2), 213–244. 10.1007/s10528-019-09941-1 PubMed DOI PMC

Ge M. H., Chen C., Xu J. J., Ling Z. Q. (2011). Unfavorable Clinical Implications for Hypermethylation of RUNX3 in Patients with Salivary Gland Adenoid Cystic Carcinoma. Oncol. Rep. 26 (2), 349–57. 10.3892/or.2011.1282 PubMed DOI

Gentilini F., Capitani O., Tinto D., Rigillo A., Sabattini S., Bettini G., et al. (2020). Assessment of PDGFRβ Promoter Methylation in Canine Osteosarcoma Using Methylation‐sensitive High‐resolution Melting Analysis. Vet. Comp. Oncol. 18 (4), 484–493. 10.1111/vco.12567 PubMed DOI

Geybels M. S., Fang M., Wright J. L., Qu X., Bibikova M., Klotzle B., et al. (2017). PTEN Loss Is Associated with Prostate Cancer Recurrence and Alterations in Tumor DNA Methylation Profiles. Oncotarget 8 (48), 84338–84348. 10.18632/oncotarget.20940 PubMed DOI PMC

Ghantous Y., Schussel J. L., Brait M. (2018). Tobacco and Alcohol-Induced Epigenetic Changes in Oral Carcinoma. Curr. Opin. Oncol. 30 (3), 152–158. 10.1097/cco.0000000000000444 PubMed DOI PMC

Gil Z., Carlson D. L., Gupta A., Lee N., Hoppe B., Shah J. P., et al. (2009). Patterns and Incidence of Neural Invasion in Patients with Cancers of the Paranasal Sinuses. Arch. Otolaryngol. Head Neck Surg. 135 (2), 173–9. 10.1001/archoto.2008.525 PubMed DOI

Gil Z., Cavel O., Kelly K., Brader P., Rein A., Gao S. P., et al. (2010). Paracrine Regulation of Pancreatic Cancer Cell Invasion by Peripheral Nerves. J. Natl. Cancer Inst. 102 (2), 107–118. 10.1093/jnci/djp456 PubMed DOI PMC

Gillison M. L., Akagi K., Xiao W., Jiang B., Pickard R. K. L., Li J., et al. (2019). Human Papillomavirus and the Landscape of Secondary Genetic Alterations in Oral Cancers. Genome Res. 29 (1), 1–17. 10.1101/gr.241141.118 PubMed DOI PMC

Guerrero-Preston R., Soudry E., Acero J., Orera M., Moreno-López L., Macía-Colón G., et al. (2011). NID2 and HOXA9 Promoter Hypermethylation as Biomarkers for Prevention and Early Detection in Oral Cavity Squamous Cell Carcinoma Tissues and Saliva. Cancer Prev. Res. 4 (7), 1061–1072. 10.1158/1940-6207.capr-11-0006 PubMed DOI PMC

Guida F., Sandanger T. M., Castagné R., Campanella G., Polidoro S., Palli D., et al. (2015). Dynamics of Smoking-Induced Genome-wide Methylation Changes with Time since Smoking Cessation. Hum. Mol. Genet. 24 (8), 2349–2359. 10.1093/hmg/ddu751 PubMed DOI PMC

Guo M., Peng Y., Gao A., Du C., Herman J. G. (2019). Epigenetic Heterogeneity in Cancer. Biomark Res. 7, 23. 10.1186/s40364-019-0174-y PubMed DOI PMC

Guo Q., Song Y., Zhang H., Wu X., Xia P., Dang C. (2013). Detection of Hypermethylated Fibrillin-1 in the Stool Samples of Colorectal Cancer Patients. Med. Oncol. 30 (4), 695. 10.1007/s12032-013-0695-4 PubMed DOI

Guo Q., Wu Y., Guo X., Cao L., Xu F., Zhao H., et al. (2021). The RNA-Binding Protein CELF2 Inhibits Ovarian Cancer Progression by Stabilizing FAM198B. Mol. Ther. - Nucleic Acids 23, 169–184. 10.1016/j.omtn.2020.10.011 PubMed DOI PMC

Guo T., Sakai A., Afsari B., Considine M., Danilova L., Favorov A. V., et al. (2017). A Novel Functional Splice Variant of AKT3 Defined by Analysis of Alternative Splice Expression in HPV-Positive Oropharyngeal Cancers. Cancer Res. 77 (19), 5248–5258. 10.1158/0008-5472.can-16-3106 PubMed DOI PMC

Guo T., Zambo K. D. A., Zamuner F. T., Ou T., Hopkins C., Kelley D. Z., et al. (2020). Chromatin Structure Regulates Cancer-specific Alternative Splicing Events in Primary HPV-Related Oropharyngeal Squamous Cell Carcinoma. Epigenetics 15 (9), 959–971. 10.1080/15592294.2020.1741757 PubMed DOI PMC

Hadley M., Noonepalle S., Banik D., Villagra A. (2019). “Functional Analysis of HDACs in Tumorigenesis,” in Protein Acetylatio Methods in Molecular Biology. Editor BroshJr. R. (New York, NY: Humana; ), 1983. 10.1007/978-1-4939-9434-2_17 PubMed DOI

Hedbäck N., Jensen D. H., Specht L., Fiehn A.-M. K., Therkildsen M. H., Friis-Hansen L., et al. (2014). MiR-21 Expression in the Tumor Stroma of Oral Squamous Cell Carcinoma: an Independent Biomarker of Disease Free Survival. PLoS One 9 (4), e95193. 10.1371/journal.pone.0095193 PubMed DOI PMC

Hema K., Smitha T., Sheethal H., Mirnalini S. (2017). Epigenetics in Oral Squamous Cell Carcinoma. J. Oral Maxillofac. Pathol. 21 (2), 252–259. 10.4103/jomfp.jomfp_150_17 PubMed DOI PMC

Hervás-Marín D., Higgins F., Sanmartín O., López-Guerrero J. A., Bañó M. C., Igual J. C., et al. (2019). Genome Wide DNA Methylation Profiling Identifies Specific Epigenetic Features in High-Risk Cutaneous Squamous Cell Carcinoma. PLoS One 14 (12), e0223341. 10.1371/journal.pone.0223341 PubMed DOI PMC

Hu S., Wang H., Yan D. (2018a) Loss of miR-16 Contributes to Tumor Progression by Activation of Tousled-like Kinase 1 in Oral Squamous Cell Carcinoma. Cell Cycle 17:2284–2295.10.1080/15384101.2018.1526601 PubMed DOI PMC

Huang S. F., Cheng S. D., Chien H. T., Liao C. T., Chen I. H., Wang H. M., et al. (2012). Relationship between Epidermal Growth Factor Receptor Gene Copy Number and Protein Expression in Oral Cavity Squamous Cell Carcinoma. Oral Oncol. 48 (1), 67–72. 10.1016/j.oraloncology.2011.06.511 PubMed DOI

Huang W., Li G., Wang Z., Zhou L., Yin X., Yang T., et al. (2021). A Ten-N6-Methyladenosine (m6A)-Modified Gene Signature Based on a Risk Score System Predicts Patient Prognosis in Rectum Adenocarcinoma. Front. Oncol. 10, 567931. 10.3389/fonc.2020.567931 PubMed DOI PMC

Hübbers C. U., Akgül B. (2015). HPV and Cancer of the Oral Cavity. Virulence 6 (3), 244–8. 10.1080/21505594.2014.999570 PubMed DOI PMC

Irimie A. I., Ciocan C., Gulei D., Mehterov N., Atanasov A. G., Dudea D., et al. (2018). Current Insights into Oral Cancer Epigenetics. Int. J. Mol. Sci. 19 (3), 670. 10.3390/ijms19030670 PubMed DOI PMC

Ito S., Shen L., Dai Q., Wu S. C., Collins L. B., Swenberg J. A., et al. (2011). Tet Proteins Can Convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333 (6047), 1300–3. 10.1126/science.1210597 PubMed DOI PMC

Iwahashi N., Nagasaka T., Tezel G., Iwashita T., Asai N., Murakumo Y., et al. (2002). Expression of Glial Cell Line-Derived Neurotrophic Factor Correlates with Perineural Invasion of Bile Duct Carcinoma. Cancer 94 (1), 167–74. 10.1002/cncr.10169 PubMed DOI

Jaber M. A., Porter S. R., Gilthorpe M. S., Bedi R., Scully C. (1999). Risk Factors for Oral Epithelial Dysplasia-Tthe Role of Smoking and Alcohol. Oral Oncol. 35 (2), 151–6. 10.1016/s1368-8375(98)00106-7 PubMed DOI

Jardim J. F., Francisco A. L., Gondak R., Damascena A., Kowalski L. P. (2015). Prognostic Impact of Perineural Invasion and Lymphovascular Invasion in Advanced Stage Oral Squamous Cell Carcinoma. Int. J. Oral Maxillofac. Surg. 44 (1), 23–8. 10.1016/j.ijom.2014.10.006 PubMed DOI

Jäwert F., Hasséus B., Kjeller G., Magnusson B., Sand L., Larsson L. (2013). Loss of 5-hydroxymethylcytosine and TET2 in Oral Squamous Cell Carcinoma. Anticancer Res. 33 (10), 4325–8. PubMed

Jha M., Aggarwal R., Jha A. K., Shrivastava A. (2015). Natural Compounds: DNA Methyltransferase Inhibitors in Oral Squamous Cell Carcinoma. Appl. Biochem. Biotechnol. 177 (3), 577–94. 10.1007/s12010-015-1768-y PubMed DOI

Jiang C., Liu F., Xiao S., He L., Wu W., Zhao Q. (2021). miR-29a-3p Enhances the Radiosensitivity of Oral Squamous Cell Carcinoma Cells by Inhibiting ADAM12. Eur. J. Histochem. 65 (3), 3295. 10.4081/ejh.2021.3295 PubMed DOI PMC

Jiang X., Wu J., Wang J., Huang R. (2019). Tobacco and Oral Squamous Cell Carcinoma: A Review of Carcinogenic Pathways. Tob. Induc Dis. 17, 29. 10.18332/tid/105844 PubMed DOI PMC

Jithesh P. V., Risk J. M., Schache A. G., Dhanda J., Lane B., Liloglou T., et al. (2013). The Epigenetic Landscape of Oral Squamous Cell Carcinoma. Br. J. Cancer 108, 370–379. 10.1038/bjc.2012.568 PubMed DOI PMC

Johnson N. W., Jayasekara P., Amarasinghe A. A. (2011). Squamous Cell Carcinoma and Precursor Lesions of the Oral Cavity: Epidemiology and Aetiology. Periodontol 57 (1), 19–37. 10.1111/j.1600-0757.2011.00401.x PubMed DOI

Jonas S., Izaurralde E. (2015). Towards a Molecular Understanding of microRNA-Mediated Gene Silencing. Nat. Rev. Genet. 16 (7), 421–33. 10.1038/nrg3965 PubMed DOI

Kartha V. K., Stawski L., Han R., Haines P., Gallagher G., Noonan V., et al. (2016). PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas. PLoS One 11 (4), e0154645. 10.1371/journal.pone.0154645 PubMed DOI PMC

Kelley D. Z., Flam E. L., Izumchenko E., Danilova L. V., Wulf H. A., Guo T., et al. (2017). Integrated Analysis of Whole-Genome ChIP-Seq and RNA-Seq Data of Primary Head and Neck Tumor Samples Associates HPV Integration Sites with Open Chromatin Marks. Cancer Res. 77 (23), 6538–6550. 10.1158/0008-5472.can-17-0833 PubMed DOI PMC

Kim S. H., Kim S. H., Joung J. Y., Lee G. K., Hong E. K., Kang K. M., et al. (2015). Overexpression of ERG and Wild-type PTEN Are Associated with Favorable Clinical Prognosis and Low Biochemical Recurrence in Prostate Cancer. PLoS One 10 (4), e0122498. 10.1371/journal.pone.0122498 PubMed DOI PMC

Kim S. Y., Han Y. K., Song J. M., Lee C. H., Kang K., Yi J. M., et al. (2019). Aberrantly Hypermethylated Tumor Suppressor Genes Were Identified in Oral Squamous Cell Carcinoma (OSCC). Clin. Epigenetics 11 (1), 116. 10.1186/s13148-019-0715-0 PubMed DOI PMC

Kinross J., Mirnezami R., Alexander J., Brown R., Scott A., Galea D., et al. (2017). A Prospective Analysis of Mucosal Microbiome-Metabonome Interactions in Colorectal Cancer Using a Combined MAS 1HNMR and Metataxonomic Strategy. Sci. Rep. 7 (1), 8979. 10.1038/s41598-017-08150-3 PubMed DOI PMC

Klussmann J. P., Mooren J. J., Lehnen M., Claessen S. M., Stenner M., Huebbers C. U., et al. (2009). Genetic Signatures of HPV-Related and Unrelated Oropharyngeal Carcinoma and Their Prognostic Implications. Clin. Cancer Res. 15 (5), 1779–86. 10.1158/1078-0432.ccr-08-1463 PubMed DOI

Ko M., An J., Pastor W. A., Koralov S. B., Rajewsky K., Rao A. (2015). TET Proteins and 5-methylcytosine Oxidation in Hematological Cancers. Immunol. Rev. 263 (1), 6–21. 10.1111/imr.12239 PubMed DOI PMC

Kolenda T., Guglas K., Teresiak A., Bliźniak R., Lamperska K. (2019). Low Let-7d and High miR-205 Expression Levels Positively Influence HNSCC Patient Outcome. J. Biomed. Sci. 26 (1), 17. 10.1186/s12929-019-0511-3 PubMed DOI PMC

Koo K., Mouradov D., Angel C. M., Iseli T. A., Wiesenfeld D., McCullough M. J., et al. (2021). Genomic Signature of Oral Squamous Cell Carcinomas from Non-smoking Non-drinking Patients. Cancers (Basel). 13 (5), 1029. 10.3390/cancers13051029 PubMed DOI PMC

Kreimer A. R., Chaturvedi A. K., Alemany L., Anantharaman D., Bray F., Carrington M., et al. (2020). Summary from an International Cancer Seminar Focused on Human Papillomavirus (HPV)-positive Oropharynx Cancer, Convened by Scientists at IARC and NCI. Oral Oncol. 108, 104736. 10.1016/j.oraloncology.2020.104736 PubMed DOI PMC

Kumar R., Rai A. K., Das D., Das R., Kumar R. S., Sarma A., et al. (2015). Alcohol and Tobacco Increases Risk of High Risk HPV Infection in Head and Neck Cancer Patients: Study from North-East Region of India. PLoS One 10 (10), e0140700. 10.1371/journal.pone.0140700 PubMed DOI PMC

Kumari K., Das B., Adhya A. K., Rath A. K., Mishra S. K. (2019). Genome-wide Expression Analysis Reveals Six Contravened Targets of EZH2 Associated with Breast Cancer Patient Survival. Scientific Rep. 9, 1974. 10.1038/s41598-019-39122-4 PubMed DOI PMC

Kurtz K. A., Hoffman H. T., Zimmerman M. B., Robinson R. A. (2005). Perineural and Vascular Invasion in Oral Cavity Squamous Carcinoma: Increased Incidence on Re-review of Slides and by Using Immunohistochemical Enhancement. Arch. Pathol. Lab. Med. 129 (3), 354–9. 10.5858/2005-129-354-paviio PubMed DOI

La Rosa G. R. M., Gattuso G., Pedullà E., Rapisarda E., Nicolosi D., Salmeri M. (2020). Association of Oral Dysbiosis with Oral Cancer Development. Oncol. Lett. 19 (4), 3045–3058. 10.3892/ol.2020.11441 PubMed DOI PMC

Larsen S. R., Johansen J., Sørensen J. A., Krogdahl A. (2009). The Prognostic Significance of Histological Features in Oral Squamous Cell Carcinoma. J. Oral Pathol. Med. 38 (8), 657–62. 10.1111/j.1600-0714.2009.00797.x PubMed DOI

Lee K. W., Pausova Z. (2013). Cigarette Smoking and DNA Methylation. Front. Genet. 4, 132. 10.3389/fgene.2013.00132 PubMed DOI PMC

Lee L. Y., De Paz D., Lin C. Y., Fan K. H., Wang H. M., Hsieh C. H., et al. (2019). Prognostic Impact of Extratumoral Perineural Invasion in Patients with Oral Cavity Squamous Cell Carcinoma. Cancer Med. 8 (14), 6185–6194. 10.1002/cam4.2392 PubMed DOI PMC

Lenz B., Klafki H. W., Hillemacher T., Killisch N., Schaller G., Frieling H., et al. (2010). Smoking Behaviour Is Associated with Expression and Phosphorylation of CREB in Human Buffy Coat. Int. J. Neuropsychopharmacol. 13 (2), 207–15. 10.1017/S1461145709991052 PubMed DOI

Li D., Bai Y., Feng Z., Li W., Yang C., Guo Y., et al. (2019). Study of Promoter Methylation Patterns of HOXA2, HOXA5, and HOXA6 and its Clinicopathological Characteristics in Colorectal Cancer. Front. Oncol. 9, 394. 10.3389/fonc.2019.00394 PubMed DOI PMC

Li E., Zhang Y. (2014). DNA Methylation in Mammals. Cold Spring Harb Perspect. Biol. 6 (5), a019133. 10.1101/cshperspect.a019133 PubMed DOI PMC

Li G., Li X., Yang M., Xu L., Deng S., Ran L. (2017). Prediction of Biomarkers of Oral Squamous Cell Carcinoma Using Microarray Technology. Sci. Rep. 7, 42105. 10.1038/srep42105 PubMed DOI PMC

Li H., Wang X., Zhang M., Wang M., Zhang J., Ma S. (2021). Identification of HOXA1 as a Novel Biomarker in Prognosis of Head and Neck Squamous Cell Carcinoma. Front. Mol. Biosci. 7, 602068. 10.3389/fmolb.2020.602068 PubMed DOI PMC

Li Y., Mao Y., Zhang Y., Cai S., Chen G., Ding Y., et al. (2014). Alcohol Drinking and Upper Aerodigestive Tract Cancer Mortality: A Systematic Review and Meta-Analysis. Oral Oncol. 10.1016/j.oraloncology.2013.12.015 PubMed DOI

Liebig C., Ayala G., Wilks J., Verstovsek G., Liu H., Agarwal N., et al. (2009a). Perineural Invasion Is an Independent Predictor of Outcome in Colorectal Cancer. J. Clin. Oncol. 27 (31), 5131–7. 10.1200/jco.2009.22.4949 PubMed DOI PMC

Liebig C., Ayala G., Wilks J. A., Berger D. H., Albo D. (2009b). Perineural Invasion in Cancer: a Review of the Literature. Cancer 115 (15), 3379–91. 10.1002/cncr.24396 PubMed DOI

Lin L. H., Lin J. S., Yang C. C., Cheng H. W., Chang K. W., Liu C. J. (2020a). Overexpression of Platelet-Derived Growth Factor and its Receptor Are Correlated with Oral Tumorigenesis and Poor Prognosis in Oral Squamous Cell Carcinoma. Int. J. Mol. Sci. 21 (7), 2360. 10.3390/ijms21072360 PubMed DOI PMC

Lin .P, Tian P., Pang J., Lai L., He G., Song Y., et al. (2020b). Clinical Significance of COL1A1 and COL1A2 Expression Levels in Hypopharyngeal Squamous Cell Carcinoma. Oncol Lett 20 (1), 803–809. 10.3892/ol.2020.11594 PubMed DOI PMC

Liu D., Song L., Dai Z., Guan H., Kang H., Zhang Y., et al. (2018). MiR-429 Suppresses Neurotrophin-3 to Alleviate Perineural Invasion of Pancreatic Cancer. Biochem. Biophys. Res. Commun. 505 (4), 1077–1083. 10.1016/j.bbrc.2018.09.147 PubMed DOI

Liu S., de Medeiros M. C., Fernandez E. M., Zarins K. R., Cavalcante R. G., Qin T., et al. (2020). 5-Hydroxymethylation Highlights the Heterogeneity in Keratinization and Cell Junctions in Head and Neck Cancers. Clin. Epigenetics 12 (1), 175. 10.1186/s13148-020-00965-8 PubMed DOI PMC

Liu Y., Chen H., Sun Z., Chen X. (2015). Molecular Mechanisms of Ethanol-Associated Oro-Esophageal Squamous Cell Carcinoma. Cancer Lett. 361 (2), 164–73. 10.1016/j.canlet.2015.03.006 PubMed DOI PMC

Lleras R. A., Smith R. V., Adrien L. R., Schlecht N. F., Burk R. D., Harris T. M., et al. (2013). Unique DNA Methylation Loci Distinguish Anatomic Site and HPV Status in Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res. 19 (19), 5444–55. 10.1158/1078-0432.ccr-12-3280 PubMed DOI PMC

Llewelyn J., Smoking Mitchell. R. (1994). Alcohol and Oral Cancer in South East Scotland: a 10-year Experience. Br. J. Oral Maxillofac. Surg. 32 (3), 146–152. 10.1016/0266-4356(94)90098-1 PubMed DOI

Ma K. H., Hung H. A., Svaren J. (2016). Epigenomic Regulation of Schwann Cell Reprogramming in Peripheral Nerve Injury. J. Neurosci. 36 (35), 9135–47. 10.1523/jneurosci.1370-16.2016 PubMed DOI PMC

Mahmood N., Hanif M., Ahmed A., Jamal Q., Mushtaq S., Khan A., et al. (2019). Circulating miR-21 as a Prognostic and Predictive Biomarker in Oral Squamous Cell Carcinoma. Pak J. Med. Sci. 35 (5), 1408–1412. 10.12669/pjms.35.5.331 PubMed DOI PMC

Marques A. E. M., do Nascimento Filho C. H. V., Marinho Bezerra T. M., Guerra E. N. S., Castilho R. M., Squarize C. H. (2020). Entinostat Is a Novel Therapeutic Agent to Treat Oral Squamous Cell Carcinoma. J. Oral Pathol. Med. 49 (8), 771–779. 10.1111/jop.13039 PubMed DOI

Mascolo M., Siano M., Ilardi G., Russo D., Merolla F., De Rosa G., et al. (2012). Epigenetic Disregulation in Oral Cancer. Int. J. Mol. Sci. 13 (2), 2331–53. 10.3390/ijms13022331 PubMed DOI PMC

Mello F. W., Melo G., Pasetto J. J., Silva C. A. B., Warnakulasuriya S., Rivero E. R. C. (2019). The Synergistic Effect of Tobacco and Alcohol Consumption on Oral Squamous Cell Carcinoma: a Systematic Review and Meta-Analysis. Clin. Oral Investig. 23 (7), 2849–2859. 10.1007/s00784-019-02958-1 PubMed DOI

Menbari M. N., Rahimi K., Ahmadi A., Mohammadi-Yegane S., Elyasi A., Darvishi N., et al. (2020). Association of HDAC8 Expression with Pathological Findings in Triple Negative and Non-triple Negative Breast Cancer: Implications for Diagnosis. Iran Biomed. J. 24 (5), 288–94. 10.29252/ibj.24.5.283 PubMed DOI PMC

Mendaza S., Ulazia-Garmendia A., Monreal-Santesteban I., Córdoba A., Azúa Y. R., Aguiar B., et al. (2020). ADAM12 Is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 21 (3), 903. 10.3390/ijms21030903 PubMed DOI PMC

Miller C. S., Johnstone B. M. (2001). Human Papillomavirus as a Risk Factor for Oral Squamous Cell Carcinoma: a Meta-Analysis, 1982-1997. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 91 (6), 622–35. 10.1067/moe.2001.115392 PubMed DOI

Misawa K., Imai A., Mochizuki D., Mima M., Endo S., Misawa Y., et al. (2018). Association of TET3 Epigenetic Inactivation with Head and Neck Cancer. Oncotarget 9 (36), 24480–24493. 10.18632/oncotarget.25333 PubMed DOI PMC

Misawa K., Kanazawa T., Misawa Y., Imai A., Endo S., Hakamada K., et al. (2011-2012). Hypermethylation of Collagen α2 (I) Gene (COL1A2) Is an Independent Predictor of Survival in Head and Neck Cancer. Cancer Biomark 10 (3-4), 135–44. 10.3233/CBM-2012-0242 PubMed DOI

Misawa K., Mochizuki D., Imai A., Endo S., Mima M., Misawa Y., et al. (2016). Prognostic Value of Aberrant Promoter Hypermethylation of Tumor-Related Genes in Early-Stage Head and Neck Cancer. Oncotarget 7 (18), 26087–98. 10.18632/oncotarget.8317 PubMed DOI PMC

Morse D. E., Psoter W. J., Cleveland D., Cohen D., Mohit-Tabatabai M., Kosis D. L., et al. (2007). Smoking and Drinking in Relation to Oral Cancer and Oral Epithelial Dysplasia. Cancer Causes Control 18, 919–929. 10.1007/s10552-007-9026-4 PubMed DOI PMC

Narasimhan N. S., Narasimhan N. M. (2018). The Emerging Role of MicroRNA21 in Oral Cancer. Biomed. Pharmacol. J. 11 (4). 10.13005/bpj/1569 DOI

O'Brien C. J., Lahr C. J., Soong S. J., Gandour M. J., Jones J. M., Urist M. M., et al. (1986). Surgical Treatment of Early-Stage Carcinoma of the Oral Tongue-Wwound Adjuvant Treatment Be Beneficial? Head Neck Surg. 8 (6), 401–8. 10.1002/hed.2890080603 PubMed DOI

Ondruschka C., Buhtz P., Motsch C., Freigang B., Schneider-Stock R., Roessner A., et al. (2002). Prognostic Value of MMP-2, -9 and TIMP-1,-2 Immunoreactive Protein at the Invasive Front in Advanced Head and Neck Squamous Cell Carcinomas. Pathol. Res. Pract. 198 (8), 509–15. 10.1078/s0344-0338(04)70292-7 PubMed DOI

Otálora-Otálora B. A., Henríquez B., López-Kleine L., Rojas A. (2019). RUNX Family: Oncogenes or Tumor Suppressors (Review). Oncol. Rep. 42 (1), 3–19. 10.3892/or.2019.7149 PubMed DOI PMC

Park J. S., Park Y. N., Lee K. Y., Kim J. K., Yoon D. S. (2013). P16 Hypermethylation Predicts Surgical Outcome Following Curative Resection of Mid/distal Bile Duct Cancer. Ann. Surg. Oncol. 20 (8), 2511–7. 10.1245/s10434-013-2908-7 PubMed DOI

Peng S. Y., Tu H. F., Yang C. C., Wu C. H., Liu C. J., Chang K. W., et al. (2018). miR-134 Targets PDCD7 to Reduce E-Cadherin Expression and Enhance Oral Cancer Progression. Int. J. Cancer 143 (11), 2892–2904. 10.1002/ijc.31638 PubMed DOI

Piqué L., Martinez de Paz A., Piñeyro D., Martínez-Cardús A., Castro de Moura M., Llinàs-Arias P., et al. (2019). Epigenetic Inactivation of the Splicing RNA-Binding Protein CELF2 in Human Breast Cancer. Oncogene 38 (45), 7106–7112. 10.1038/s41388-019-0936-x PubMed DOI

Prueitt R. L., Yi M., Hudson R. S., Wallace T. A., Howe T. M., Yfantis H. G., et al. (2008). Expression of microRNAs and Protein-Coding Genes Associated with Perineural Invasion in Prostate Cancer. Prostate 68 (11), 1152–64. 10.1002/pros.20786 PubMed DOI PMC

Pulukuri S. M., Patibandla S., Patel J., Estes N., Rao J. S. (2007). Epigenetic Inactivation of the Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) Gene in Human Prostate Tumors. Oncogene 26 (36), 5229–37. 10.1038/sj.onc.1210329 PubMed DOI PMC

Puram S. V., Tirosh I., Parikh A. S., Patel A. P., Yizhak K., Gillespie S., et al. (2017). Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell 171 (7), 1611–1624.e24. 10.1016/j.cell.2017.10.044 PubMed DOI PMC

Rahima B., Shingaki S., Nagata M., Saito C. (2004). Prognostic Significance of Perineural Invasion in Oral and Oropharyngeal Carcinoma. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 97 (4), 423–31. 10.1016/j.tripleo.2003.10.014 PubMed DOI

Rajan C., Roshan V. G. D., Khan I., Manasa V. G., Himal I., Kattoor J., et al. (2021). MiRNA Expression Profiling and Emergence of New Prognostic Signature for Oral Squamous Cell Carcinoma. Sci. Rep. 11 (1), 7298. 10.1038/s41598-021-86316-w PubMed DOI PMC

Ramzan F., Vickers M. H., Mithen R. F. (2021). Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review. Int. J. Mol. Sci. 22 (9), 5047. 10.3390/ijms22095047 PubMed DOI PMC

Rasmussen K. D., Helin K. (2016). Role of TET Enzymes in DNA Methylation, Development, and Cancer. Genes Dev. 30 (7), 733–750. 10.1101/gad.276568.115 PubMed DOI PMC

Rastogi B., Raut S. K., Panda N. K., Rattan V., Radotra B. D., Khullar M. (2016). Overexpression of HDAC9 Promotes Oral Squamous Cell Carcinoma Growth, Regulates Cell Cycle Progression, and Inhibits Apoptosis. Mol. Cell Biochem 415 (1-2), 183–96. 10.1007/s11010-016-2690-5 PubMed DOI

Rather M. I., Nagashri M. N., Swamy S. S., Gopinath K. S., Kumar A. (2013). Oncogenic microRNA-155 Down-Regulates Tumor Suppressor CDC73 and Promotes Oral Squamous Cell Carcinoma Cell Proliferation: Implications for Cancer Therapeutics. J. Biol. Chem. 288 (1), 608–18. 10.1074/jbc.m112.425736 PubMed DOI PMC

Reis P. P., Tomenson M., Cervigne N. K., Machado J., Jurisica I., Pintilie M., et al. (2010). Programmed Cell Death 4 Loss Increases Tumor Cell Invasion and Is Regulated by miR-21 in Oral Squamous Cell Carcinoma. Mol. Cancer 9, 238. 10.1186/1476-4598-9-238 PubMed DOI PMC

Ren S., Gaykalova D., Wang J., Guo T., Danilova L., Favorov A., et al. (2018). Discovery and Development of Differentially Methylated Regions in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma. Int. J. Cancer 143 (10), 2425–2436. 10.1002/ijc.31778 PubMed DOI

Renjie W., Haiqian L. (2015). MiR-132, miR-15a and miR-16 Synergistically Inhibit Pituitary Tumor Cell Proliferation, Invasion and Migration by Targeting Sox5. Cancer Lett. 356, 568–78. 10.1016/j.canlet.2014.10.003 PubMed DOI

Roh J., Muelleman T., Tawfik O., Thomas S. M. (2015). Perineural Growth in Head and Neck Squamous Cell Carcinoma: a Review. Oral Oncol. 51 (1), 16–23. 10.1016/j.oraloncology.2014.10.004 PubMed DOI PMC

Ross G. L., Soutar D. S., MacDonald D. G., Shoaib T., Camilleri I. G., Robertson A. G. (2004). Improved Staging of Cervical Metastases in Clinically Node-Negative Patients with Head and Neck Squamous Cell Carcinoma. Ann. Surg. Oncol. 11 (2), 213–8. 10.1245/aso.2004.03.057 PubMed DOI

Ruokolainen H., Pääkkö P., Turpeenniemi-Hujanen T. (2006). Tissue and Circulating Immunoreactive Protein for MMP-2 and TIMP-2 in Head and Neck Squamous Cell Carcinoma-Ttissue Immunoreactivity Predicts Aggressive Clinical Course. Mod. Pathol. 19 (2), 208–17. 10.1038/modpathol.3800506 PubMed DOI

Russo D., Merolla F., Varricchio S., Salzano G., Zarrilli G., Mascolo M., et al. (2020). Erratum: Epigenetics of Oral and Oropharyngeal Cancers (Review). Biomed. Rep. 12 (5), 290. 10.3892/br.2020.1290 PubMed DOI PMC

Saad M. A., Kuo S. Z., Rahimy E., Zou A. E., Korrapati A., Rahimy M., et al. (2015). Alcohol-dysregulated miR-30a and miR-934 in Head and Neck Squamous Cell Carcinoma. Mol. Cancer 14, 181. 10.1186/s12943-015-0452-8 PubMed DOI PMC

Saito Y., Liang G., Egger G., Friedman J. M., Chuang J. C., Coetzee G. A., et al. (2006). Specific Activation of Microrna-127 with Downregulation of the Proto-Oncogene Bcl6 by Chromatin-Modifying Drugs in Human Cancer Cells. Cancer Cell 9, 435–443. 10.1016/j.ccr.2006.04.020 PubMed DOI

Sakuma T., Uzawa K., Onda T., Shiiba M., Yokoe H., Shibahara T., et al. (2006). Aberrant Expression of Histone Deacetylase 6 in Oral Squamous Cell Carcinoma. Int. J. Oncol. 29 (1), 117–24. 10.3892/ijo.29.1.117 PubMed DOI

Salaspuro M. P. (2003). Acetaldehyde, Microbes, and Cancer of the Digestive Tract. Crit. Rev. Clin. Lab. Sci. 40, 183–208. 10.1080/713609333 PubMed DOI

Sartor M. A., Dolinoy D. C., Jones T. R., Colacino J. A., Prince M. E., Carey T. E., et al. (2011). Genome-wide Methylation and Expression Differences in HPV(+) and HPV(-) Squamous Cell Carcinoma Cell Lines Are Consistent with Divergent Mechanisms of Carcinogenesis. Epigenetics 6 (6), 777–87. 10.4161/epi.6.6.16216 PubMed DOI PMC

Sato T., Suzuki M., Sato Y., Echigo S., Rikiishi H. (2006). Sequence-dependent Interaction between Cisplatin and Histone Deacetylase Inhibitors in Human Oral Squamous Cell Carcinoma Cells. Int. J. Oncol. 28, 1233–1241. 10.3892/ijo.28.5.1233 PubMed DOI

Scanlon C. S., Banerjee R., Inglehart R. C., Liu M., Russo N., Hariharan A., et al. (2015). Galanin Modulates the Neural Niche to Favour Perineural Invasion in Head and Neck Cancer. Nat. Commun. 6, 6885. 10.1038/ncomms7885 PubMed DOI PMC

Scott A. J., Alexander J. L., Merrifield C. A., Cunningham D., Jobin C., Brown R., et al. (2019). International Cancer Microbiome Consortium Consensus Statement on the Role of the Human Microbiome in Carcinogenesis. Gut 68 (9), 1624–1632. 10.1136/gutjnl-2019-318556 PubMed DOI PMC

Seitz H. K., Stickel F., Homann N. (2004). Pathogenetic Mechanisms of Upper Aerodigestive Tract Cancer in Alcoholics. Int. J. Cancer 108 (4), 483–7. 10.1002/ijc.11600 PubMed DOI

Seitz H. K., Stickel F. (2007). Molecular Mechanisms of Alcohol-Mediated Carcinogenesis. Nat. Rev. Cancer 7, 599–612. 10.1038/nrc2191 PubMed DOI

Shrestha B., Bajracharya D., Byatnal A. A., Kamath A., Radhakrishnan R. (2017). May High MMP-2 and TIMP-2 Expressions Increase or Decrease the Aggressivity of Oral Cancer? Pathol. Oncol. Res. 23 (1), 197–206. 10.1007/s12253-016-0149-3 PubMed DOI

Shukla S. D., Lee Y. J., Park P. H., Aroor A. R. (2007). Acetaldehyde Alters MAP Kinase Signalling and Epigenetic Histone Modifications in Hepatocytes. Novartis Found. Symp. 285, 217–24. 10.1002/9780470511848.ch16 PubMed DOI

Sierko E., Wojtukiewicz M. Z., Kisiel W. (2007). The Role of Tissue Factor Pathway Inhibitor-2 in Cancer Biology. Semin. Thromb. Hemost. 33 (7), 653–9. 10.1055/s-2007-991532 PubMed DOI

Silverman B. R., Shi J. (2016). Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications. Int. J. Mol. Sci. 17 (12), 2138. 10.3390/ijms17122138 PubMed DOI PMC

Sim J., Kim Y., Kim H., Bang S., Jee S., Park S., et al. (2020). Loss of MTUS1 Expression Is Associated with Poor Prognosis in Patients with Gallbladder Carcinoma. Vivo 34 (1), 125–132. 10.21873/invivo.11753 PubMed DOI PMC

Soo K. C., Carter R. L., O'Brien C. J., Barr L., Bliss J. M., Shaw H. J. (1986). Prognostic Implications of Perineural Spread in Squamous Carcinomas of the Head and Neck. Laryngoscope 96 (10), 1145–8. 10.1288/00005537-198610000-00015 PubMed DOI

Sousa L. O., Sobral L. M., Matsumoto C. S., Saggioro F. P., López R. V., Panepucci R. A., et al. (2016). Lymph Node or Perineural Invasion Is Associated with Low miR-15a, miR-34c and miR-199b Levels in Head and Neck Squamous Cell Carcinoma. BBA Clin. 6, 159–164. 10.1016/j.bbacli.2016.11.001 PubMed DOI PMC

Speight P. M., Barrett A. W. (2009). Prognostic Factors in Malignant Tumours of the Salivary Glands. Br. J. Oral Maxillofac. Surg. 47 (8), 587–93. 10.1016/j.bjoms.2009.03.017 PubMed DOI

Staibano S., Mignogna C., Lo Muzio L., Mascolo M., Salvatore G., Di Benedetto M., et al. (2007). Chromatin Assembly Factor-1 (CAF-1)-Mediated Regulation of Cell Proliferation and DNA Repair: a Link with the Biological Behaviour of Squamous Cell Carcinoma of the Tongue? Histopathology 50 (7), 911–9. 10.1111/j.1365-2559.2007.02698.x PubMed DOI

Stornetta A., Guidolin V., Balbo S. (2018). Alcohol-Derived Acetaldehyde Exposure in the Oral Cavity. Cancers (Basel) 10 (1), 20. 10.3390/cancers10010020 PubMed DOI PMC

Stott F. J., Bates S., James M. C., McConnell B. B., Starborg M., Brookes S., et al. (1998). The Alternative Product from the Human CDKN2A Locus, p14(ARF), Participates in a Regulatory Feedback Loop with P53 and MDM2. EMBO J. 17 (17), 5001–14. 10.1093/emboj/17.17.5001 PubMed DOI PMC

Su Mun L., Wye Lum S., Kong Yuiin Sze G., Hock Yoong C., Ching Yung K., Kah Lok L., et al. (2021). Association of Microbiome with Oral Squamous Cell Carcinoma: A Systematic Review of the Metagenomic Studies. Int. J. Environ. Res. Public Health 18 (14), 7224. 10.3390/ijerph18147224 PubMed DOI PMC

Sullivan L. M., Smee R. (2006). Leptomeningeal Carcinomatosis from Perineural Invasion of a Lip Squamous Cell Carcinoma. Australas. Radiol. 50 (3), 262–6. 10.1111/j.1440-1673.2006.01577.x PubMed DOI

Supic G., Kozomara R., Brankovic-Magic M., Jovic N., Magic Z. (2009). Gene Hypermethylation in Tumor Tissue of Advanced Oral Squamous Cell Carcinoma Patients. Oral Oncol. 45 (12), 1051–7. PubMed

Supic G., Kozomara R., Jovic N., Zeljic K., Magic Z. (2011). Hypermethylation of RUNX3 but Not WIF1 Gene and its Association with Stage and Nodal Status of Tongue Cancers. Oral Dis. 17 (8), 794–800. 10.1111/j.1601-0825.2011.01838.x PubMed DOI

Supic G., Kozomara R., Zeljic K., Jovic N., Magic Z. (2017). Prognostic Value of the DNMTs mRNA Expression and Genetic Polymorphisms on the Clinical Outcome in Oral Cancer Patients. Clin. Oral Investig. 21 (1), 173–182. 10.1007/s00784-016-1772-9 PubMed DOI

Sutton D. N., Brown J. S., Rogers S. N., Vaughan E. D., Woolgar J. A. (2003). The Prognostic Implications of the Surgical Margin in Oral Squamous Cell Carcinoma. Int. J. Oral Maxillofac. Surg. 32 (1), 30–4. 10.1054/ijom.2002.0313 PubMed DOI

Suzuki M., Shinohara F., Endo M., Sugazaki M., Echigo S., Rikiishi H. (2009). Zebularine Suppresses the Apoptotic Potential of 5-fluorouracil via cAMP/PKA/CREB Pathway against Human Oral Squamous Cell Carcinoma Cells. Cancer Chemother. Pharmacol. 64 (2), 223–32. 10.1007/s00280-008-0833-4 PubMed DOI

Szabo A., Gurlich R., Liberko M., Soumarova R., Vernerova Z., Mandys V., et al. (2020). Expression of Selected microRNAs in Pancreatic Ductal Adenocarcinoma: Is There a Relation to Tumor Morphology, Progression and Patient's Outcome? Neoplasma 67 (5), 1170–1181. 10.4149/neo_2020_200123N87 PubMed DOI

Tan L., Shi Y. G. (2012). Tet Family Proteins and 5-hydroxymethylcytosine in Development and Disease. Development 139 (11), 1895–902. 10.1242/dev.070771 PubMed DOI PMC

Tang K. L., Tang H. Y., Du Y., Tian T., Xiong S. J. (2019). MiR-638 Suppresses the Progression of Oral Squamous Cell Carcinoma through Wnt/β-Catenin Pathway by Targeting Phospholipase D1. Artif. Cell Nanomed Biotechnol 47 (1), 3278–3285. 10.1080/21691401.2019.1647222 PubMed DOI

Tasoulas J., Giaginis C., Patsouris E., Manolis E., Theocharis S. (2015). Histone Deacetylase Inhibitors in Oral Squamous Cell Carcinoma Treatment. Expert Opin. Investig. Drugs 24 (1), 69–78. 10.1517/13543784.2014.952368 PubMed DOI

Thienpont B., Steinbacher J., Zhao H., D'Anna F., Kuchnio A., Ploumakis A., et al. (2016). Tumour Hypoxia Causes DNA Hypermethylation by Reducing TET Activity. Nature 537 (7618), 63–68. 10.1038/nature19081 PubMed DOI PMC

Torre L. A., Bray F., Siegel R. L., Ferlay J., Lortet-Tieulent J., Jemal A. (2015). Global Cancer Statistics. CA Cancer J. Clin. 65 (2), 87–108. 10.3322/caac.21262 PubMed DOI

Uehara E., Shiiba M., Shinozuka K., Saito K., Kouzu Y., Koike H., et al. (2012). Upregulated Expression of ADAM12 Is Associated with Progression of Oral Squamous Cell Carcinoma. Int. J. Oncol. 40 (5), 1414–22. 10.3892/ijo.2012.1339 PubMed DOI

Urvalek A. M., Osei-Sarfo K., Tang X. H., Zhang T., Scognamiglio T., Gudas L. J. (2015). Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers during Oral Cavity Carcinogenesis. Alcohol. Clin. Exp. Res. 39 (8), 1360–72. 10.1111/acer.12772 PubMed DOI PMC

Verdoodt B., Sommerer F., Palisaar R. J., Noldus J., Vogt M., Nambiar S., et al. (2011). Inverse Association of P16 INK4a and P14 ARF Methylation of the CDKN2a Locus in Different Gleason Scores of Prostate Cancer. Prostate Cancer Prostatic Dis. 14 (4), 295–301. 10.1038/pcan.2011.45 PubMed DOI

Viet C. T., Schmidt B. L. (2008). Methylation Array Analysis of Preoperative and Postoperative Saliva DNA in Oral Cancer Patients. Cancer Epidemiol. Biomarkers Prev. 17 (12), 3603–11. 10.1158/1055-9965.epi-08-0507 PubMed DOI

Virani S., Bellile E., Bradford C. R., Carey T. E., Chepeha D. B., Colacino J. A., et al. (2015). NDN and CD1A Are Novel Prognostic Methylation Markers in Patients with Head and Neck Squamous Carcinomas. BMC Cancer 15, 825. 10.1186/s12885-015-1806-8 PubMed DOI PMC

Waddington C. H. (1942). The Epigenotype. Endeavor (1), 18–20.

Wallwork B. D., Anderson S. R., Coman W. B. (2007). Squamous Cell Carcinoma of the Floor of the Mouth: Tumour Thickness and the Rate of Cervical Metastasis. ANZ J. Surg. 77 (9), 761–4. 10.1111/j.1445-2197.2007.04219.x PubMed DOI

Wang V., Wu W. (2009). MicroRNA-based Therapeutics for Cancer. BioDrugs 23 (1), 15–23. 10.2165/00063030-200923010-00002 PubMed DOI

Wang W., Gao J., Man X. H., Li Z. S., Gong Y. F. (2009). Significance of DNA Methyltransferase-1 and Histone Deacetylase-1 in Pancreatic Cancer. Oncol. Rep. 21 (6), 1439–47. 10.3892/or_00000372 PubMed DOI

Wang X., Li G. H. (2018). MicroRNA-16 Functions as a Tumor-Suppressor Gene in Oral Squamous Cell Carcinoma by Targeting AKT3 and BCL2L2. J. Cell Physiol 233 (12), 9447–9457. 10.1002/jcp.26833 PubMed DOI PMC

Wang X., Li H., Shi J. (2019). LncRNA HOXA11-AS Promotes Proliferation and Cisplatin Resistance of Oral Squamous Cell Carcinoma by Suppression of miR-214-3p Expression. Biomed. Res. Int. 2019, 8645153. 10.1155/2019/8645153 PubMed DOI PMC

Wang Y., Hu H., Wang Q., Li Z., Zhu Y., Zhang W., et al. (2017). The Level and Clinical Significance of 5-hydroxymethylcytosine in Oral Squamous Cell Carcinoma: An Immunohistochemical Study in 95 Patients. Pathol. Res. Pract. 213 (8), 969–974. 10.1016/j.prp.2017.04.016 PubMed DOI

Watanabe T., Morinaga S., Akaike M., Numata M., Tamagawa H., Yamamoto N., et al. (2012). The Cellular Level of Histone H3 Lysine 4 Dimethylation Correlates with Response to Adjuvant Gemcitabine in Japanese Pancreatic Cancer Patients Treated with Surgery. Eur. J. Surg. Oncol. 38 (11), 1051–7. 10.1016/j.ejso.2012.08.008 PubMed DOI

Woolgar J. A. (2006). Histopathological Prognosticators in Oral and Oropharyngeal Squamous Cell Carcinoma. Oral Oncol. 42 (3), 229–39. 10.1016/j.oraloncology.2005.05.008 PubMed DOI

Woolgar J. A., Scott J. (1995). Prediction of Cervical Lymph Node Metastasis in Squamous Cell Carcinoma of the Tongue/floor of Mouth. Head Neck 17 (6), 463–72. 10.1002/hed.2880170603 PubMed DOI

Wu J., Liu J., Wei X., Yu Q., Niu X., Tang S., et al. (2019). A Feature-Based Analysis Identifies COL1A2 as a Regulator in Pancreatic Cancer. J. Enzyme Inhib. Med. Chem. 34 (1), 420–428. 10.1080/14756366.2018.1484734 PubMed DOI PMC

Yamamoto T., Hirosue A., Nakamoto M., Yoshida R., Sakata J., Matsuoka Y., et al. (2020). BRD4 Promotes Metastatic Potential in Oral Squamous Cell Carcinoma through the Epigenetic Regulation of the MMP2 Gene. Br. J. Cancer 123 (4), 580–590. 10.1038/s41416-020-0907-6 PubMed DOI PMC

Yang X., Han B., Zhang R., Su Y., Hosseini D. K., Wu H., et al. (2021). Development and Validation of a RNA Binding Protein-Associated Prognostic Model for Head and Neck Squamous Cell Carcinoma. Aging (Albany NY) 13 (6), 7975–7997. 10.18632/aging.202848 PubMed DOI PMC

Yang Y., Deng X., Chen X., Chen S., Song L., Meng M., et al. (2020). Landscape of Active Enhancers Developed De Novo in Cirrhosis and Conserved in Hepatocellular Carcinoma. Am. J. Cancer Res. 10 (10), 3157–3178. PubMed PMC

Yao Q., Chen Y., Zhou X. (2019). The Roles of microRNAs in Epigenetic Regulation. Curr. Opin. Chem. Biol. 51, 11–17. 10.1016/j.cbpa.2019.01.024 PubMed DOI

Yi X., Guo J., Guo J., Sun S., Yang P., Wang J., et al. (2017). EZH2-mediated Epigenetic Silencing of TIMP2 Promotes Ovarian Cancer Migration and Invasion. Scientific Rep. 7, 3568. 10.1038/s41598-017-03362-z PubMed DOI PMC

Yorioka C. W., Coletta R. D., Alves F., Nishimoto I. N., Kowalski L. P., Graner E. (2002). Matrix Metalloproteinase-2 and -9 Activities Correlate with the Disease-free Survival of Oral Squamous Cell Carcinoma Patients. Int. J. Oncol. 20 (1), 189–94. 10.3892/ijo.20.1.189 PubMed DOI

Yoshizaki T., Maruyama Y., Sato H., Furukawa M. (2001). Expression of Tissue Inhibitor of Matrix Metalloproteinase-2 Correlates with Activation of Matrix Metalloproteinase-2 and Predicts Poor Prognosis in Tongue Squamous Cell Carcinoma. Int. J. Cancer 95 (1), 44–50. 10.1002/1097-0215(20010120)95:1<44::aid-ijc1008>3.0.co;2-m PubMed DOI

Yu E. H., Tu H. F., Wu C. H., Yang C. C., Chang K. W. (2017). MicroRNA-21 Promotes Perineural Invasion and Impacts Survival in Patients with Oral Carcinoma. J. Chin. Med. Assoc. 80 (6), 383–388. 10.1016/j.jcma.2017.01.003 PubMed DOI

Yu S. Y., Wang Y. P., Chang J. Y., Shen W. R., Chen H. M., Chiang C. P. (2014). Increased Expression of MCM5 Is Significantly Associated with Aggressive Progression and Poor Prognosis of Oral Squamous Cell Carcinoma. J. Oral Pathol. Med. 43 (5), 344–9. 10.1111/jop.12134 PubMed DOI

Yu V., Singh P., Rahimy E., Zheng H., Kuo S. Z., Kim E., et al. (2016). RNA-seq Analysis Identifies Key Long Non-coding RNAs Connected to the Pathogenesis of Alcohol-Associated Head and Neck Squamous Cell Carcinoma. Oncol. Lett. 12 (4), 2846–2853. 10.3892/ol.2016.4972 PubMed DOI PMC

Zebolsky A. L., George E., Gulati A., Wai K. C., Carpenter P., Van Zante A., et al. (2021). Risk of Pathologic Extranodal Extension and Other Adverse Features after Transoral Robotic Surgery in Patients with HPV-Positive Oropharynx Cancer. JAMA Otolaryngol. Head Neck Surg., e212777. 10.1001/jamaoto.2021.2777 PubMed DOI PMC

Zhai L. L., Wu Y., Cai C. Y., Tang Z. G. (2015). Upregulated Matrix Metalloproteinase-2 and Downregulated Tissue Factor Pathway Inhibitor-2 Are Risk Factors for Lymph Node Metastasis and Perineural Invasion in Pancreatic Carcinoma. Onco Targets Ther. 8, 2827–34. 10.2147/ott.s90599 PubMed DOI PMC

Zhang C. Y., Mao L., Li L., Tian Z., Zhou X. J., Zhang Z. Y., et al. (2007). Promoter Methylation as a Common Mechanism for Inactivating E-Cadherin in Human Salivary Gland Adenoid Cystic Carcinoma. Cancer 110 (1), 87–95. 10.1002/cncr.22758 PubMed DOI

Zhang J., Fu X., Liu D., Yang M., Yang J., Huo Y., et al. (2020). Molecular Markers Associated with Perineural Invasion in Pancreatic Ductal Adenocarcinoma. Oncol. Lett. 20 (4), 5. 10.3892/ol.2020.11866 PubMed DOI PMC

Zhang M., Xian H. C., Dai L., Tang Y. L., Liang X. H. (2021). MicroRNAs: Emerging Driver of Cancer Perineural Invasion. Cell Biosci 11 (1), 117. 10.1186/s13578-021-00630-4 PubMed DOI PMC

Zhang R., Qi F., Zhao F., Li G., Shao S., Zhang X., et al. (2019). Cancer-associated Fibroblasts Enhance Tumor-Associated Macrophages Enrichment and Suppress NK Cells Function in Colorectal Cancer. Cell Death Dis 10 (4), 273. 10.1038/s41419-019-1435-2 PubMed DOI PMC

Zhao L., Yu Y., Wu J., Bai J., Zhao Y., Li C., et al. (2014). Role of EZH2 in Oral Squamous Cell Carcinoma Carcinogenesis. Gene 537 (2), 197–202. 10.1016/j.gene.2014.01.006 PubMed DOI

Zheng B., Qu J., Ohuchida K., Feng H., Chong S. J. F., Yan Z., et al. (2020b). LAMA4 Upregulation Is Associated with High Liver Metastasis Potential and Poor Survival Outcome of Pancreatic Cancer. Theranostics 10, 10274–10289. 10.7150/thno.47001 PubMed DOI PMC

Zheng J., Wang J., Jia Y., Liu T., Duan Y., Liang X., et al. (2019b). microRNA-211 Promotes Proliferation, Migration, and Invasion Ability of Oral Squamous Cell Carcinoma Cells via Targeting the Bridging Integrator 1 Protein. J. Cell Biochem 120 (3), 4644–4653. 10.1002/jcb.27753 PubMed DOI PMC

Zheng Q., Maksimovic I., Upad A., David Y. (2020a). Non-enzymatic Covalent Modifications: a New Link between Metabolism and Epigenetics. Protein Cell 11 (6), 401–416. 10.1007/s13238-020-00722-w PubMed DOI PMC

Zheng Q., Prescott N. A., Maksimovic I., David Y. (2019a). (De) Toxifying the Epigenetic Code. Chem. Res. Toxicol. 32 (5), 796–807. 10.1021/acs.chemrestox.9b00013 PubMed DOI PMC

Zhou W. N., Du Y. F., Bai J., Song X. M., Zheng Y., Yuan H., et al. (2017). RUNX3 Plays a Tumor Suppressor Role by Inhibiting Cell Migration, Invasion and Angiogenesis in Oral Squamous Cell Carcinoma. Oncol. Rep. 38 (4), 2378–2386. 10.3892/or.2017.5857 PubMed DOI

Zhu Z., Friess H., diMola F. F., Zimmermann A., Graber H. U., Korc M., et al. (1999). Nerve Growth Factor Expression Correlates with Perineural Invasion and Pain in Human Pancreatic Cancer. J. Clin. Oncol. 17 (8), 2419–28. 10.1200/jco.1999.17.8.2419 PubMed DOI