Document Type : Original Research


1 Oral and Dental Disease Research Center, Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Zahedan University of Medical Sciences, Zahedan, Iran

2 Student Research Committee, Department of Hematology and Blood Banking, School of Paramedical Sciences, Birjand University of Medical Sciences, Birjand, Iran

3 Cardiovascular Diseases Research Center, Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran


Background & Objective: CCL4 (C-C chemokine ligand4) is a chemoattractant involved in tumors' development, progression, and metastasis. The relationship between the ccl4 gene polymorphisms and the risk of OSCC has not been studied in Iran. This study aimed to identify the effect of ccl4 gene polymorphism on OSCC susceptibility in the population of Southeastern Iran.
Methods: In this case-control study, a total of 100 participants, 50 patients with OSCC who were referred to the Department of Oral Pathology, Faculty of Dentistry, Zahedan University of Medical Sciences, Iran, and 50 healthy people were included. The DNA was extracted from the tissue blocks of OSCC patients. The rs10491121 and rs1634507 in the ccl4 gene were evaluated by the tetra-ARMS (Amplification Refractory Mutation System)- PCR technique. Data were analyzed in SPSS (version 21) using the Chi-square and logistic regression test.
Results: CCL4 genotyping showed that AA+AG genotype in rs10491121 and AA+CA genotype in rs1634507 were slightly higher in control than in the case. Still, the risk of OSCC in both polymorphisms was not significantly different. The minor allele (A) in the rs10491121 and rs1634507 polymorphisms were more common in OSCC compared to the control group (OR = 1.2, 95% CI: 0.66 – 2.22, P=0.54) (OR = 1.6, 95% CI: 0.85-3.07, P=0.15). There was no association between OSCC histopathological grades and CCL4 genotypes at these two sites.
Conclusion: Our results showed no association between ccl4 gene polymorphism and the risk of oral cancer in the population of Southeastern Iran.


Main Subjects

  1. Singh PK, Ahmad MK, Kumar V, Gupta R, Kohli M, Jain A, et al. Genetic polymorphism of interleukin-10 (-A592C) among oral cancer with squamous cell carcinoma. Arch Oral Biol. 2017;77:18-22. [PMID] [DOI:10.1016/j.archoralbio.2016.12.011]
  2. Attar E, Dey S, Hablas A, Seifeldin IA, Ramadan M, Rozek LS, et al. Head and neck cancer in a developing country: a population-based perspective across 8 years. Oral Oncol. 2010;46(8):591-6. [PMID] [PMCID] [DOI:10.1016/j.oraloncology.2010.05.002]
  3. Singh PK, Bogra J, Chandra G, Ahmad MK, Gupta R, Kumar V, et al. Association of TNF-α (-238 and-308) promoter polymorphisms with susceptibility of oral squamous cell carcinoma in North Indian population. Cancer Biomark. 2015; 15(2):125-31. [DOI:10.3233/CBM-140444] [PMID]
  4. Singh PK, Chandra G, Bogra J, Gupta R, Kumar V, Jain A, et al. Association of interleukin-6 genetic polymorphisms with risk of OSCC in Indian population. Meta Gene. 2015;4:142-51. [DOI:10.1016/j.mgene.2015.03.002] [PMID] [PMCID]
  5. Yang WH, Wang SJ, Chang YS, Su CM, Yang SF, Tang CH. Association of Resistin Gene Polymorphisms with Oral Squamous Cell Carcinoma Progression and Development. Biomed Res Int. 2018;2018:9531315. [DOI:10.1155/2018/9531315] [PMID] [PMCID]
  6. Liu M, Song H, Xing Z, Lu G, Li J, Chen D. Correlation between PTEN gene polymorphism and oral squamous cell carcinoma. Oncology letters. 2019;18(2):1755-60. [DOI:10.3892/ol.2019.10526] [PMID] [PMCID]
  7. Xie S, Xu H, Shan X, Liu B, Wang K, Cai Z. Clinicopathological and prognostic significance of survivin expression in patients with oral squamous cell carcinoma: evidence from a meta-analysis. PLoS One. 2015;10(2):e0116517. [DOI:10.1371/journal.pone.0116517] [PMID] [PMCID]
  8. Huang W, Song J, Jia X-W, Chen Y-X, Shi J, Jiang X. Interleukin-10 rs1800896 polymorphism is associated with increased head and neck cancer risk but not associated with its clinical stages. Oncotarget. 2017;8(23):37217. [PMID] [PMCID] [DOI:10.18632/oncotarget.16660]
  9. Lien MY, Tsai HC, Chang AC, Tsai MH, Hua CH, Wang SW, et al. Chemokine CCL4 Induces Vascular Endothelial Growth Factor C Expression and Lymphangiogenesis by miR-195-3p in Oral Squamous Cell Carcinoma. Front Immunol. 2018;9:412. [PMID] [PMCID] [DOI:10.3389/fimmu.2018.00412]
  10. Lien MY, Lin CW, Tsai HC, Chen YT, Tsai MH, Hua CH, et al. Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics. Oncotarget. 2017;8(19):31424-34. [PMID] [PMCID] [DOI:10.18632/oncotarget.15615]
  11. Menten P, Wuyts A, Van Damme J. Macrophage inflammatory protein-1. Cytokine Growth Factor Rev. 2002;13(6):455-81. [DOI:10.1016/S1359-6101(02)00045-X]
  12. Hu G-N, Tzeng H-E, Chen P-C, Wang C-Q, Zhao Y-M, Wang Y, et al. Correlation between CCL4 gene polymorphisms and clinical aspects of breast cancer. Int J Med Sci. 2018;15(11):1179. [DOI:10.7150/ijms.26771] [PMID] [PMCID]
  13. Kuo S-J, Huang C-C, Tsai C-H, Hsu H-C, Su C-M, Tang C-H. Chemokine CC motif ligand 4 gene polymorphisms associated with susceptibility to rheumatoid arthritis. BioMed Res Int. 2018;2018. [DOI:10.1155/2018/9181647] [PMID] [PMCID]
  14. Wang B, Chou YE, Lien MY, Su CM, Yang SF, Tang CH. Impacts of CCL4 gene polymorphisms on hepatocellular carcinoma susceptibility and development. Int J Med Sci. 2017;14(9):880-4. [DOI:10.7150/ijms.19620] [PMID] [PMCID]
  15. Modi WS, Lautenberger J, An P, Scott K, Goedert JJ, Kirk GD, et al. Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. Am J Hum Genet. 2006;79(1):120-8. [DOI:10.1086/505331] [PMID] [PMCID]
  16. Sadeghi M, Lahdou I, Oweira H, Daniel V, Terness P, Schmidt J, et al. Serum levels of chemokines CCL4 and CCL5 in cirrhotic patients indicate the presence of hepatocellular carcinoma. Br J Cancer. 2015;113(5):756-62. [DOI:10.1038/bjc.2015.227] [PMID] [PMCID]
  17. Zhang Z, Feng J, Mao A, Le K, La Placa D, Wu X, et al. SNPs in inflammatory genes CCL11, CCL4 and MEFV in a fibromyalgia family study. PLoS One. 2018;13(6):e0198625. [PMCID] [DOI:10.1371/journal.pone.0198625] [PMID]
  18. Bharuthram A. The role of CCL4/Mip-1b in HIV infection.
  19. Barnes L, Eveson J, Reichart P, Sidransky D. World Health Organization classifications tumours. Pathology and genetics of head and neck tumours. Lyon: IARC. 2005.
  20. Sim YC, Hwang J-H, Ahn K-M. Overall and disease-specific survival outcomes following primary surgery for oral squamous cell carcinoma: analysis of consecutive 67 patients. J Korean Assoc Oral Maxillofac Surg. 2019; 45 (2):83-90. [DOI:10.5125/jkaoms.2019.45.2.83] [PMID] [PMCID]
  21. Kademani D, Bell RB, Bagheri S, Holmgren E, Dierks E, Potter B, et al. Prognostic factors in intraoral squamous cell carcinoma: the influence of histologic grade. J Oral Maxillofac Surg. 2005; 63(11):1599-605. [DOI:10.1016/j.joms.2005.07.011] [PMID]
  22. Rogers SN, Brown JS, Woolgar JA, Lowe D, Magennis P, Shaw RJ, et al. Survival following primary surgery for oral cancer. Oral Oncol. 2009;45(3):201-11. [DOI:10.1016/j.oraloncology.2008.05.008] [PMID]
  23. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. [DOI:10.3322/caac.21492] [PMID]
  24. MMS-V KR-R, Aponte-Colón DA, Forestier-Román IS, Quintero-Aguiló ME, Martínez-Ferrer M. CCL-4 enhances prostate cancer migration and invasion by modulating integrin expression. Int J Clin Exp Med. 2016;9(3):5426-38.
  25. Liu J, Li F, Wang L, Chen X, Wang D, Cao L, et al. CTL-vs T reg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma. British journal of cancer. 2015;113(5):747-55. [DOI:10.1038/bjc.2015.290] [PMID] [PMCID]
  26. Li L, Liu YD, Zhan YT, Zhu YH, Li Y, Xie D, et al. High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma. Thorac Cancer. 2018;9(7):775-84. [DOI:10.1111/1759-7714.12643] [PMID] [PMCID]
  27. Lien M-Y. CCL4 promotes oral squamous cell carcinoma angiogenesis by targeting the angiopoietin-2 signal pathway. AACR; 2020. [DOI:10.1158/1538-7445.AM2020-1480]
  28. Hu W, Chien S-Y, Ying P, Liu P-I, Su C-M, Tang C-H. Impact of CCL4 gene polymorphisms upon the progression of lung cancer in a Han Chinese cohort. Medicine. 2020;99(3). [DOI:10.1097/MD.0000000000018906] [PMID] [PMCID]
  29. Hua F, Tian Y. CCL4 promotes the cell proliferation, invasion and migration of endometrial carcinoma by targeting the VEGF-A signal pathway. Int J Clin Exp Pathol. 2017;10 (11):11288-99.
  30. De la Fuente López M, Landskron G, Parada D, Dubois-Camacho K, Simian D, Martinez M, et al. The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvir-onment and tumor-associated macrophage markers in colorectal cancer. Tumor Biol. 2018;40(11):1010428318810059. [DOI:10.1177/1010428318810059] [PMID]