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Identification of a novel prognostic ADME-related signature associated with tumor immunity for aiding therapy in head and neck squamous cell carcinoma

Cancer Gene Therapy volume 30, pages 659–670 (2023)Cite this article

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Abstract

The genes that control drug absorption, distribution, metabolism, and excretion (ADME) are also involved in carcinogenesis, cancer progression, and chemoresistance. However, no studies have systematically investigated the clinical significance and underlying functions of ADME genes in head and neck squamous cell carcinoma. Herein, we comprehensively explored the ADME genes in this disease, constructed and validated as a prognostic ADME gene signature (ADMEGS), using three ADME genes (ABCB1, ALDH1B1, and PON2) utilizing multiple datasets, including the training and test sets of The Cancer Genome Atlas and the Gene Expression Omnibus validation set. Moreover, we analyzed the relationship between the ADMEGS and clinical parameters, tumor immunity, and therapeutic response. We found that the ADMEGS was significantly correlated with the clinical, T, and N stages. Additionally, we were able to effectively differentiate tumor immune scores, immune cell infiltration statuses, and treatment responses based on the ADMEGS. As such, ADMEGS may be promising predictors for clinical outcome, tumor immunity, and treatment response.

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Fig. 1: Establishment of the ADMEGS using 3 prognostic ADME genes in HNSCC.
Fig. 2: Prognostic performance of the ADMEGS.
Fig. 3: Clinical evaluation by the ADMEGS in HNSCC patients.
Fig. 4: Function enrichment analysis in the ADMEGSlow and ADMEGShigh groups of the TCGA dataset.
Fig. 5: Estimation of tumor immune score and tumor-infiltrating immune cells by the ADMEGS.
Fig. 6: Correlation of the three ADMEGS genes with the subpopulations of T cells and B cells in the TCGA dataset.
Fig. 7: Estimation of immunotherapeutic targets by ADMEGS.

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Data availability

The HTSeq-FPKM and clinical data of HNSCC datasets can be obtained from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) and Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  2. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet (Lond, Engl). 2008;371:1695–709.

    Article  CAS  Google Scholar 

  3. Cramer JD, Burtness B, Le QT, Ferris RL. The changing therapeutic landscape of head and neck cancer. Nat Rev Clin Oncol. 2019;16:669–83.

    Article  PubMed  Google Scholar 

  4. Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer. 2018;18:269–82.

    Article  CAS  PubMed  Google Scholar 

  5. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018;81:45–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393:156–67.

    Article  CAS  PubMed  Google Scholar 

  8. Hovelson DH, Xue Z, Zawistowski M, Ehm MG, Harris EC, Stocker SL, et al. Characterization of ADME gene variation in 21 populations by exome sequencing. Pharmacogenet Genomics. 2017;27:89–100.

    Article  CAS  PubMed  Google Scholar 

  9. Klein K, Tremmel R, Winter S, Fehr S, Battke F, Scheurenbrand T, et al. A new panel-based next-generation sequencing method for ADME genes reveals novel associations of common and rare variants with expression in a human liver cohort. Front Genet. 2019;10:7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hu DG, Marri S, McKinnon RA, Mackenzie PI, Meech R. Deregulation of the genes that are involved in drug absorption, distribution, metabolism, and excretion in hepatocellular carcinoma. J Pharm Exp Ther. 2019;368:363–81.

    Article  CAS  Google Scholar 

  11. Ziniel PD, Karumudi B, Barnard AH, Fisher EM, Thatcher GR, Podust LM, et al. The Schistosoma mansoni cytochrome P450 (CYP3050A1) IS Essential for Worm Survival and Egg Development. PLoS Negl Trop Dis. 2015;9:e0004279.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Alzahrani AM, Rajendran P. The multifarious link between cytochrome P450s and cancer. Oxid Med Cell Longev. 2020;2020:3028387.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010;154:103–16.

    Article  CAS  PubMed  Google Scholar 

  14. Nigam SK. What do drug transporters really do? Nat Rev Drug Disco. 2015;14:29–44.

    Article  CAS  Google Scholar 

  15. Rees DC, Johnson E, Lewinson O. ABC transporters: the power to change. Nat Rev Mol Cell Biol. 2009;10:218–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu X. ABC family transporters. Adv Exp Med Biol. 2019;1141:13–100.

    Article  CAS  PubMed  Google Scholar 

  17. Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, et al. Human sulfotransferases and their role in chemical metabolism. Toxicol Sci. 2006;90:5–22.

    Article  CAS  PubMed  Google Scholar 

  18. Hu DG, Mackenzie PI, McKinnon RA, Meech R. Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk. Drug Metab Rev. 2016;48:47–69.

    Article  CAS  PubMed  Google Scholar 

  19. Aka I, Bernal CJ, Carroll R, Maxwell-Horn A, Oshikoya KA, Van Driest SL. Clinical pharmacogenetics of Cytochrome P450-associated drugs in children. J Pers Med. 2017;7:14.

  20. Kaur G, Gupta SK, Singh P, Ali V, Kumar V, Verma M. Drug-metabolizing enzymes: role in drug resistance in cancer. Clin Transl Oncol. 2020;22:1667–80.

    Article  CAS  PubMed  Google Scholar 

  21. Pathania S, Bhatia R, Baldi A, Singh R, Rawal RK. Drug metabolizing enzymes and their inhibitors’ role in cancer resistance. Biomed Pharmacother. 2018;105:53–65.

    Article  CAS  PubMed  Google Scholar 

  22. Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007;8:118–27.

    Article  PubMed  Google Scholar 

  23. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.

    Article  PubMed  Google Scholar 

  25. Gong Y, Luo X, Yang J, Jiang Q, Liu Z. RIPK4 promoted the tumorigenicity of nasopharyngeal carcinoma cells. Biomed Pharmacother. 2018;108:1–6.

    Article  CAS  PubMed  Google Scholar 

  26. Liu ZF, Yang J, Wei SP, Luo XG, Jiang QS, Chen T, et al. Upregulated METTL3 in nasopharyngeal carcinoma enhances the motility of cancer cells. Kaohsiung J Med Sci. 2020;36:895–903.

    Article  PubMed  Google Scholar 

  27. Yang J, Gong Y, Jiang Q, Liu L, Li S, Zhou Q, et al. Circular RNA expression profiles in nasopharyngeal carcinoma by sequence analysis. Front Oncol. 2020;10:601.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shrotriya S, Agarwal R, Sclafani RA. A perspective on chemoprevention by resveratrol in head and neck squamous cell carcinoma. Adv Exp Med Biol. 2015;815:333–48.

    Article  CAS  PubMed  Google Scholar 

  29. López-Verdín S, Lavalle-Carrasco J, Carreón-Burciaga RG, Serafín-Higuera N, Molina-Frechero N, González-González R. et al. Molecular markers of anticancer drug resistance in head and neck squamous cell carcinoma: a literature review. Cancers (Basel). 2018;10:376.

  30. Shen B, Dong P, Li D, Gao S. Expression and function of ABCG2 in head and neck squamous cell carcinoma and cell lines. Exp Ther Med. 2011;2:1151–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Masood N, Kayani MA. Mutational analysis of xenobiotic metabolizing genes (CYP1A1 and GSTP1) in sporadic head and neck cancer patients. Genet Mol Biol. 2011;34:533–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lacko M, Voogd AC, Roelofs HMJ, te Morsche RHM, Oude Ophuis MB, Peters WHM, et al. Combined effect of genetic polymorphisms in phase I and II biotransformation enzymes on head and neck cancer risk. Head Neck. 2013;35:858–67.

    Article  PubMed  Google Scholar 

  33. Roh J-L, Kim EH, Park JY, Kim JW. Inhibition of glucosylceramide synthase sensitizes head and neck cancer to cisplatin. Mol Cancer Ther. 2015;14:1907–15.

    Article  CAS  PubMed  Google Scholar 

  34. Guan G-F, Zhang DEJ, Zheng Y, Wen L-J, Yu D-J, Lu Y-Q, et al. Significance of ATP-binding cassette transporter proteins in multidrug resistance of head and neck squamous cell carcinoma. Oncol Lett. 2015;10:631–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rooseboom M, Commandeur JNM, Vermeulen NPE. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev. 2004;56:53–102.

  36. Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302:1429–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mizushima T, Tirador KA, Miyamoto H. Androgen receptor activation: a prospective therapeutic target for bladder cancer? Expert Opin Ther Targets. 2017;21:249–57.

    Article  CAS  PubMed  Google Scholar 

  38. Bélanger A, Pelletier G, Labrie F, Barbier O, Chouinard S. Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans. Trends Endocrinol Metab. 2003;14:473–9.

    Article  PubMed  Google Scholar 

  39. Samson JM, Ravindran Menon D, Smith DE, Baird E, Kitano T, Gao D, et al. Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes. Chem Biol Interact. 2019;314:108822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Szafarowski T, Sierdziński J, Ludwig N, Głuszko A, Filipowska A, Szczepański MJ. Assessment of cancer stem cell marker expression in primary head and neck squamous cell carcinoma shows prognostic value for aldehyde dehydrogenase (ALDH1A1). Eur J Pharm. 2020;867:172837.

    Article  CAS  Google Scholar 

  41. da Silva LP, Lopes MLDDS, Sarmento ASC, de Albuquerque Borges M, de Moura SRS, Sobral APV, et al. Increased expression of ALDH-1 is associated with clinical parameters of salivary glands neoplasms. Exp Mol Pathol. 2020;117:104552.

    Article  PubMed  Google Scholar 

  42. Köy Y, Dirilenoglu F, Tetikkurt Ü, Muhammedoğlu A, Çelik A. Aldehyde dehydrogenase-1 positivity is associated with ER negativity in patients with invasive ductal carcinoma of the breast. Pol J Pathol. 2020;71:254–60.

    Article  PubMed  Google Scholar 

  43. Bearrood TE, Aguirre-Figueroa G, Chan J. Rational design of a red fluorescent sensor for ALDH1A1 displaying enhanced cellular uptake and reactivity. Bioconjug Chem. 2020;31:224–8.

    Article  CAS  PubMed  Google Scholar 

  44. Wang W, He S, Zhang R, Peng J, Guo D, Zhang J, et al. ALDH1A1 maintains the cancer stem-like cells properties of esophageal squamous cell carcinoma by activating the AKT signal pathway and interacting with β-catenin. Biomed Pharmacother. 2020;125:109940.

    Article  CAS  PubMed  Google Scholar 

  45. Nie S, Qian X, Shi M, Li H, Peng C, Ding X, et al. ALDH1A3 accelerates pancreatic cancer metastasis by promoting glucose metabolism. Front Oncol. 2020;10:915.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Rebollido-Rios R, Venton G, Sánchez-Redondo S, Iglesias I, Felip C, Fournet G, et al. Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer. Oncogene. 2020;39:2756–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Golla JP, Kandyliari A, Tan WY, Chen Y, Orlicky DJ, Thompson DC, et al. Interplay between APC and ALDH1B1 in a newly developed mouse model of colorectal cancer. Chem Biol Interact. 2020;331:109274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Singh S, Arcaroli J, Chen Y, Thompson DC, Messersmith W, Jimeno A, et al. ALDH1B1 is crucial for colon tumorigenesis by modulating Wnt/β-catenin, Notch and PI3K/Akt signaling pathways. PLoS ONE. 2015;10:e0121648.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Witte I, Altenhöfer S, Wilgenbus P, Amort J, Clement AM, Pautz A, et al. Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells. Cell Death Dis. 2011;2:e112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Altenhöfer S, Witte I, Teiber JF, Wilgenbus P, Pautz A, Li H, et al. One enzyme, two functions: PON2 prevents mitochondrial superoxide formation and apoptosis independent from its lactonase activity. J Biol Chem. 2010;285:24398–403.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Krüger M, Pabst AM, Al-Nawas B, Horke S, Moergel M. Paraoxonase-2 (PON2) protects oral squamous cell cancer cells against irradiation-induced apoptosis. J Cancer Res Clin Oncol. 2015;141:1757–66.

    Article  PubMed  Google Scholar 

  52. Edemir B. Identification of prognostic organic cation and anion transporters in different cancer entities by in silico analysis. Int J Mol Sci. 2020;21:4491.

  53. Li Q, Shu Y. Role of solute carriers in response to anticancer drugs. Mol Cell Ther. 2014;2:15.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer. 2018;18:452–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Choi C-H. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int. 2005;5:30.

    Article  PubMed  PubMed Central  Google Scholar 

  56. van den Broek GB, Wildeman M, Rasch CRN, Armstrong N, Schuuring E, Begg AC, et al. Molecular markers predict outcome in squamous cell carcinoma of the head and neck after concomitant cisplatin-based chemoradiation. Int J Cancer. 2009;124:2643–50.

    Article  PubMed  Google Scholar 

  57. Lu Z, Kleeff J, Shrikhande S, Zimmermann T, Korc M, Friess H, et al. Expression of the multidrug-resistance 1 (MDR1) gene and prognosis in human pancreatic cancer. Pancreas. 2000;21:240–7.

    Article  CAS  PubMed  Google Scholar 

  58. Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357:eaan2507.

  59. Cao QT, Aguiar JA, Tremblay BJM, Abbas N, Tiessen N, Revill S, et al. ABCF1 regulates dsDNA-induced immune responses in human airway epithelial cells. Front Cell Infect Microbiol. 2020;10:487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lai L, Azzam KM, Lin W-C, Rai P, Lowe JM, Gabor KA, et al. MicroRNA-33 regulates the innate immune response via ATP binding cassette transporter-mediated remodeling of membrane microdomains. J Biol Chem. 2016;291:19651–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Westerterp M, Gautier EL, Ganda A, Molusky MM, Wang W, Fotakis P, et al. Cholesterol accumulation in dendritic cells links the inflammasome to acquired immunity. Cell Metab. 2017;25:1294–1304.e6.

  62. Seyffer F, Tampé R. ABC transporters in adaptive immunity. Biochim Biophys Acta. 2015;1850:449–60.

    Article  CAS  PubMed  Google Scholar 

  63. Eggensperger S, Tampé R. The transporter associated with antigen processing: a key player in adaptive immunity. Biol Chem. 2015;396:1059–72.

    Article  CAS  PubMed  Google Scholar 

  64. Abele R, Tampé R. Moving the cellular peptidome by transporters. Front Cell Dev Biol. 2018;6:43.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81974424, 81772903), the National Key Research and Development Project of China (Nos. 2020YFC1316900, 2020YFC1316901), the Hunan provincial Health and Family Planning Commission (Nos. B202307019501, 202103030223, 20201947, B20180186), the Hunan Provincial Natural Science Foundation of China (Nos. 2021JJ40502, 2019JJ50547), and the Hunan Province Science and Technology Department (No. 2017Sk50206).

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Authors and Affiliations

  1. The First Affiliated Hospital, Department of Otorhinolaryngology, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, People’s Republic of China

    Zhifeng Liu

  2. Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, People’s Republic of China

    Zhifeng Liu, Xin Zhang & Juncheng Wang

  3. Otolaryngolgy Major Disease Research Key of Hunan Province, 410008, Changsha, Hunan, People’s Republic of China

    Zhifeng Liu, Xin Zhang & Juncheng Wang

  4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 410008, Changsha, Hunan, People’s Republic of China

    Zhifeng Liu, Yuxi Tian, Xin Zhang & Juncheng Wang

  5. Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, People’s Republic of China

    Yuxi Tian

  6. The First Affiliated Hospital, Department of Gastroenterology, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, People’s Republic of China

    Jing Yang

  7. Cancer Research Institute, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, University of South China, 421001, Hengyang, Hunan, People’s Republic of China

    Jing Yang

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ZL and XZ designed the study and approved the manuscript; JW contributed to the data analysis and experiment execution; JW and JY wrote the manuscript; YT conducted data interpretations and depicted the figures.

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Correspondence to Juncheng Wang or Jing Yang.

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Liu, Z., Tian, Y., Zhang, X. et al. Identification of a novel prognostic ADME-related signature associated with tumor immunity for aiding therapy in head and neck squamous cell carcinoma. Cancer Gene Ther 30, 659–670 (2023). https://doi.org/10.1038/s41417-022-00557-z

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