Head and neck squamous cell carcinoma (HNSCC) is the seventh leading cause of mortality among malignant tumors globally. Patients face a poor prognosis and low five-year survival rate due to late-stage diagnosis, high recurrence rate, and metastasis rate. Calcium ion channels are critically involved in tumorigenesis, development, and metastasis, participating in mechanisms such as cell proliferation, apoptosis, invasion, migration, and regulation of the tumor microenvironment. Among these channels, the transient receptor potential melastatin ion channel (TRPM) has been rapidly studied in HNSCC in recent years. Evidence suggests that TRPM channels play both promoting and suppressing roles in the progression of HNSCC, highlighting their potential as diagnostic and prognostic biomarkers, as well as therapeutic targets. This review summarizes the research findings of the TRPM family in the field of HNSCC, providing new insights into prognosis and targeted molecular therapy.
References
[1]
Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. https://doi.org/10.3322/caac.21660
[2]
Han, B., Zheng, R., Zeng, H., Wang, S., Sun, K., Chen, R., et al. (2024) Cancer Incidence and Mortality in China, 2022. Journal of the National Cancer Center, 4, 47-53. https://doi.org/10.1016/j.jncc.2024.01.006
[3]
Mody, M.D., Rocco, J.W., Yom, S.S., Haddad, R.I. and Saba, N.F. (2021) Head and Neck Cancer. The Lancet, 398, 2289-2299. https://doi.org/10.1016/s0140-6736(21)01550-6
[4]
Darvin, P., Toor, S.M., Sasidharan Nair, V. and Elkord, E. (2018) Immune Checkpoint Inhibitors: Recent Progress and Potential Biomarkers. Experimental & Molecular Medicine, 50, 1-11. https://doi.org/10.1038/s12276-018-0191-1
[5]
Shaikh, H., Karivedu, V. and Wise-Draper, T.M. (2021) Managing Recurrent Metastatic Head and Neck Cancer. Hematology/Oncology Clinics of North America, 35, 1009-1020. https://doi.org/10.1016/j.hoc.2021.05.009
[6]
Bidaud, I., Mezghrani, A., Swayne, L.A., Monteil, A. and Lory, P. (2006) Voltage-gated Calcium Channels in Genetic Diseases. Biochimica et Biophysica Acta—Molecular Cell Research, 1763, 1169-1174. https://doi.org/10.1016/j.bbamcr.2006.08.049
[7]
Santoni, G. and Farfariello, V. (2011) TRP Channels and Cancer: New Targets for Diagnosis and Chemotherapy. Endocrine, Metabolic & Immune Disorders—Drug Targets, 11, 54-67. https://doi.org/10.2174/187153011794982068
[8]
Liu, Z., Wu, H., Wei, Z., Wang, X., Shen, P., Wang, S., et al. (2016) TRPM8: A Potential Target for Cancer Treatment. Journal of Cancer Research and Clinical Oncology, 142, 1871-1881. https://doi.org/10.1007/s00432-015-2112-1
[9]
Hantute-Ghesquier, A., Haustrate, A., Prevarskaya, N. and Lehen’kyi, V. (2018) TRPM Family Channels in Cancer. Pharmaceuticals, 11, Article 58. https://doi.org/10.3390/ph11020058
[10]
Held, K., Gruss, F., Aloi, V.D., Janssens, A., Ulens, C., Voets, T., et al. (2018) Mutations in the Voltage-Sensing Domain Affect the Alternative Ion Permeation Pathway in the TRPM3 Channel. The Journal of Physiology, 596, 2413-2432. https://doi.org/10.1113/jp274124
[11]
Jiang, L.H. (2007) Subunit Interaction in Channel Assembly and Functional Regulation of Transient Receptor Potential Melastatin (TRPM) Channels. Biochemical Society Transactions, 35, 86-88. https://doi.org/10.1042/bst0350086
[12]
Liu, Q., Hu, M., Li, S., Zhang, X., Zhang, R., Lyu, H., et al. (2024) TRPM Channels in Human Cancers: Regulatory Mechanism and Therapeutic Prospects. Biomarker Research, 12, Article No. 152. https://doi.org/10.1186/s40364-024-00699-2
[13]
Ciaglia, T., Vestuto, V., Bertamino, A., González-Muñiz, R. and Gómez-Monterrey, I. (2023) On the Modulation of TRPM Channels: Current Perspectives and Anticancer Therapeutic Implications. Frontiers in Oncology, 12, Article 1065935. https://doi.org/10.3389/fonc.2022.1065935
[14]
Qin, F., Lao, L., Huang, M., Tan, H., Jin, X., Ma, X., et al. (2020) Evaluation of the TRPM Protein Family as Potential Biomarkers for Various Types of Human Cancer Using Public Database Analyses. Experimental and Therapeutic Medicine, 20, 770-785. https://doi.org/10.3892/etm.2020.8739
[15]
Chu, T.H., Yang, C.C., Liu, C.J., Lui, M.T., Lin, S.C. and Chang, K.W. (2013) miR-211 Promotes the Progression of Head and Neck Carcinomas by Targeting TGFβRII. CancerLetters, 337, 115-124. https://doi.org/10.1016/j.canlet.2013.05.032
[16]
Hossain, M.Z., Ando, H., Unno, S., Masuda, Y. and Kitagawa, J. (2018) Activation of TRPV1 and TRPM8 Channels in the Larynx and Associated Laryngopharyngeal Regions Facilitates the Swallowing Reflex. International Journal of Molecular Sciences, 19, Article 4113. https://doi.org/10.3390/ijms19124113
[17]
Fu, W., Wang, J., Li, T., Qiao, Y., Zhang, Z., Zhang, X., et al. (2025) Persistent Activation of TRPM4 Triggers Necrotic Cell Death Characterized by Sodium Overload. Nature Chemical Biology, 21, 1238-1249. https://doi.org/10.1038/s41589-025-01841-3
[18]
Dai, Y., Wang, H., Wang, W. and Zhuang, X. (2025) Multidimensional Pan Cancer Analysis of the Sodium Induced Cell Death Gene TRPM4. Scientific Reports, 15, Article No. 29768. https://doi.org/10.1038/s41598-025-15082-w
[19]
Qiao, W., Lan, X.M., Ma, H.X., Chan, J.Y.K., Lui, V.W.Y., Yeung, K.W.K., et al. (2019) Effects of Salivary Mg on Head and Neck Carcinoma via TRPM7. JournalofDentalResearch, 98, 304-312. https://doi.org/10.1177/0022034518813359
[20]
Chen, T.M., Huang, C.M., Hsieh, M.S., Lin, C.S., Lee, W.H., Yeh, C.T. and Liu, S.C. (2022) TRPM7 via Calcineurin/NFAT Pathway Mediates Metastasis and Chemotherapeutic Resistance in Head and Neck Squamous Cell Carcinoma. Aging, 14, 5250-5270. https://doi.org/10.18632/aging.204154
[21]
Lin, N.C., Vu Nguyen, T.H., Shih, Y.H., Chen, Y.H., Shen, Y.W., et al. (2024) Association of Higher Transient Receptor Potential Melastatin 8 Expression with Higher Tumor Histologic Grades, Lymph Node Metastasis, Risk Factors, and Worse Survival in Patients with Head and Neck Squamous Cell Carcinoma. JournalofDentalSciences, 19, 492-501. https://doi.org/10.1016/j.jds.2023.09.007
[22]
Tan, Y., Wang, Z., Xu, M., Li, B., Huang, Z., Qin, S., et al. (2023) Oral Squamous Cell Carcinomas: State of the Field and Emerging Directions. InternationalJournalofOralScience, 15, Article No. 44. https://doi.org/10.1038/s41368-023-00249-w
Zhu, F., Cai, X., Yang, X., He, J., Wang, C., Wang, M., et al. (2020) TRPM2 Expression Levels Are Associated with Histological Grading in Patients with Tongue Squamous Cell Carcinoma. MolecularMedicineReports, 22, 3566-3574. https://doi.org/10.3892/mmr.2020.11417
[25]
Wang, Y.Y., Wang, W.C., Su, C.W., Hsu, C.W., Yuan, S.S. and Chen, Y.K. (2023) Overexpression of Transient Receptor Potential Melastatin 6 during Human Oral Squamous Cell Carcinogenesis. JournalofDentalSciences, 18, 382-391. https://doi.org/10.1016/j.jds.2022.11.002
[26]
Okamoto, Y., Ohkubo, T., Ikebe, T. and Yamazaki, J. (2012) Blockade of TRPM8 Activity Reduces the Invasion Potential of Oral Squamous Carcinoma Cell Lines. International Journal of Oncology, 40, 1431-1440.
[27]
Su, T., Chen, Y.H., Wu, K.K. and Xu, X.H. (2024) Anti-Cancer Agent Piperlongumine Is an Inhibitor of Transient Receptor Potential Melastatin 7 Channel in Oral Squamous Cell Carcinoma. JournalofOralBiosciences, 66, 430-438. https://doi.org/10.1016/j.job.2024.03.002
[28]
Chang, E.T. and Adami, H.O. (2006) The Enigmatic Epidemiology of Nasopharyngeal Carcinoma. CancerEpidemiology, Biomarkers&Prevention, 15, 1765-1777. https://doi.org/10.1158/1055-9965.epi-06-0353
[29]
Chen, J.P., Luan, Y., You, C.X., Chen, X.H., Luo, R.C. and Li, R. (2010) TRPM7 Regulates the Migration of Human Nasopharyngeal Carcinoma Cell by Mediating Ca2+ Influx. CellCalcium, 47, 425-432. https://doi.org/10.1016/j.ceca.2010.03.003
[30]
Chen, J.P., Wang, J., Luan, Y., Wang, C.X., Li, W.H., Zhang, J.B., et al. (2015) TRPM7 Promotes the Metastatic Process in Human Nasopharyngeal Carcinoma. CancerLetters, 356, 483-490. https://doi.org/10.1016/j.canlet.2014.09.032
[31]
Qin, Y., Liao, Z.W., Luo, J.Y., Wu, W.Z., Lu, A.S., et al. (2016) Functional Characterization of TRPM7 in Nasopharyngeal Carcinoma and Its Knockdown Effects on Tumorigenesis. TumorBiology, 37, 9273-9283. https://doi.org/10.1007/s13277-015-4636-z
[32]
Bozec, A., Poissonnet, G., Dassonville, O. and Culié, D. (2023) Current Therapeutic Strategies for Patients with Hypopharyngeal Carcinoma: Oncologic and Functional Outcomes. Journal of Clinical Medicine, 12, Article 1237. https://doi.org/10.3390/jcm12031237
[33]
Dou, Y., Li, Y., Chen, J., Wu, S., Xiao, X., Xie, S., et al. (2013) Inhibition of Cancer Cell Proliferation by Midazolam by Targeting Transient Receptor Potential Melastatin 7. Oncology Letters, 5, 1010-1016. https://doi.org/10.3892/ol.2013.1129
[34]
Jiao, J., Wang, Y., Sun, X. and Jiang, X. (2017) Insights into the Roles of Midazolam in Cancer Therapy. Evidence-Based Complementary and Alternative Medicine, 2017, Article 3826506. https://doi.org/10.1155/2017/3826506
[35]
Liberale, C., Soloperto, D., Marchioni, A., Monzani, D. and Sacchetto, L. (2023) Updates on Larynx Cancer: Risk Factors and Oncogenesis. International Journal of Molecular Sciences, 24, Article 12913. https://doi.org/10.3390/ijms241612913
[36]
Zhang, Y., Tian, K., Zhou, E., Xue, X., Yan, S., Chen, Y., et al. (2021) Hsa_circ_0023305 Enhances Laryngeal Squamous Cell Carcinoma Progression and Modulates TRPM7 via miR-218-5p Sponging. BioMed Research International, 2021, Article 9968499. https://doi.org/10.1155/2021/9968499
[37]
Yazgan, Y. and Cinar, R. (2025) Gallic Acid Enhances Cisplatin-Induced Death of Human Laryngeal Cancer Cells by Activating the TRPM2 Channel. Doklady Biochemistry and Biophysics, 521, 221-231. https://doi.org/10.1134/s1607672924601276
[38]
Yağcı, T., Çınar, R., Altıner, H.İ., Dündar, R. and Yıldızhan, K. (2025) The Role of TRPM2 Channel in Doxorubicin-Induced Cell Damage in Laryngeal Squamous Cancer Cells. Doklady Biochemistry and Biophysics, 520, 123-129. https://doi.org/10.1134/s1607672924601070
[39]
Pan, F., Wang, K., Zheng, M., Ren, Y., Hao, W. and Yan, J. (2022) A TRP Family Based Signature for Prognosis Prediction in Head and Neck Squamous Cell Carcinoma. Journal of Oncology, 2022, 1-13. https://doi.org/10.1155/2022/8757656
[40]
Izquierdo, C., Martín-Martínez, M., Gómez-Monterrey, I. and González-Muñiz, R. (2021) TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. International Journal of Molecular Sciences, 22, Article 8502. https://doi.org/10.3390/ijms22168502
