The epigenetic regulation of CXCL14 plays a role in the pathobiology of oral cancers

Abstract

Background: Chemokines selectively attract and activate leukocytes and play roles in a variety of homeostatic and disease processes. Explore the biological properties of CXCL14 seems complicated due to unknown functional characteristics of CXCL14 in cancer.Methods: To study the multistep process of oral cancer development, we analyzed oral samples spanning normalcy, dysplasia and cancer from multiple perspectives, revealing a cascade of progressive changes.Results: CXCL14 protein was expressed in the cytoplasm adjacent to tumors. T classification (P<0.001), clinical stage (P=0.0013) and nodal metastasis (P=0.0035) were significantly associated with CXCL14 in relationships between CXCL14 expression levels and tumor and patient characteristics. Compared with non-tumor tissue, expression of the epidermal growth factor receptor (EGFR) gene was increased in dysplasia and was further sustained in cancer. Our data show an inverse relationship between CXCL14 and EGFR expression levels in tumor cells indicating that CXCL14 expression is beneficial for tumor suppression. To explore epigenetic regulation and the impact of CXCL14 on oral cancer, analysis of CpG islands methylation in the CXCL14 promoter region indicated that the abnormal hypermethylation of that promoter region in tumor cells and tissues is one of the mechanisms causing the reduced expression. Restoration of CXCL14 expression was induced by treatment with 5-aza-2′-deoxycytidine. Using in vivo mouse models, we demonstrate that the restoration of CXCL14 expression in irradiation-induced oral carcinoma cells induces the expression of Late Cornified Envelope (LCE) genes.Conclusions: Our data suggest that LCE genes are a novel target of CXCL14 and are likely to have a tumor suppressor function through the modulation of CXCL14 expression. In conclusion, CXCL14 might play a pivotal role in the pathobiology of oral cancer, probably by regulating DNA methylation and leukocyte migration. The level of CXCL14 expression may be a valuable adjuvant parameter to predict the prognosis of patients with oral carcinoma and may be a potential therapeutic target.

Malignant cell-specific CXCL14 promotes tumor lymphocyte infiltration in oral cavity squamous cell carcinoma

“…Furthermore, the recovery of CXCL14 expression levels has been shown to improve cetuximab-dependent tumor suppression, suggesting an inverse relationship between CXCL14 and EGFR signaling. 7 11 Additional investigation into safe and effective ways of recovering CXCL14 signaling within head and neck cancer may mature CXCL14 as a viable therapeutic target, especially for prevention of delayed regional failure in cervical nodal basins of the neck.…”

“… 2–6 In head and neck squamous cell carcinoma (HNSCC), CXCL14 expression has been demonstrated to be reduced in tumor tissues relative to adjacent normal or oral dysplasia tissues. 7 CXCL14 has also previously been associated with decreased growth in HNSCC xenograft models, 8–10 supporting its role as a tumor suppressor in HNSCC. This decreased expression has been attributed to epigenetic silencing of CXCL14 by promoter hypermethylation in tumor tissues, 7 11 and CXCL14 expression was shown to be restored by treatment with 5-azacytidine, 7 12 a demethylating agent.…”

The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses

“…These findings suggest that CXCL14 promoter hypermethylation is the key mechanism in the downregulation of CXCL14 expression in CxCa and HNC. Finally, promoter hypermethylation has been implicated in the downregulation of CXCL14 in multiple other cancers, including prostate, colorectal, gastrointestinal, liver, and oral cancers 25,28,29,31,32,37 …”

“…Finally, promoter hypermethylation has been implicated in the downregulation of CXCL14 in multiple other cancers, including prostate, colorectal, gastrointestinal, liver, and oral cancers. 25,28,29,31,32,37 An additional mechanism of CXCL14 loss was demonstrated via an atypical Rho family small GTPase, RhoBTB2. RhoBTB2 is frequently mutated, deleted, or silenced in breast and lung cancers and F I G U R E 1 An overview of the CXCL14 functions in normal squamous epithelia (left) and the tumor microenvironment of head and neck cancer (right).…”

Role of C-X-C motif chemokine ligand 14 promoter region DNA methylation and single nucleotide polymorphism in influenza A severity

“…Abnormally methylated CXCL14 mediated osteosarcoma biological behaviors and served as a major indicator in prognosis [30]. CXCL14 could also act as a tumor inhibitor in oral cancer through the modulation of DNA methylation and leukocyte activity [31]. According to Mukherjee and his colleagues, CXCL14 methylation was observed in influenza viruses, and it predicted a frustrating clinic outcome [20].…”