Hypermethylation of Single CpG Dinucleotides at the Promoter of CXCL13 Gene Promoting Cell Migration in Cervical Cancer
Background:
Chemokine 13 (CXCL13) and its chemokine receptor 5 (CXCR5) are involved
in the onset of various types of cancer. However, their role in cervical cancer (CC) remains
unknown.
Objective:
To investigate the role of chemokine 13 (CXCL13) and its receptor in CC.
Methods:
The expression of CXCL13/CXCR5 and the infiltration of CXCR5+CD8+ T cells in CC,
cervical intraepithelial neoplasia (CIN), normal cervical epithelial (NCE) tissues, and in CC cell
lines were analysed and the associated clinical significance was determined. In vitro, CXCL13 overexpression
and DNA methyltransferase inhibition (through S110) were used to investigate the biological
function and the underlying mechanism that regulates CXCL13 expression. Tumor growth
and liver metastasis were also evaluated in the xenogenous subcutaneously implant model.
Results:
CXCL13/CXCR5 expression levels and the infiltration of CXCR5+CD8+ T cells were significantly
decreased in CC tissues compared with CIN and NCE tissues. CXCL13 downregulation
was significantly correlated with the FIGO stages, lymph node metastasis, interstitial infiltration
depth, and pathological grade. The overexpression of CXCL13 suppressed CC cell migration.
CXCL13 downregulation was associated with hypermethylation in CC cell lines, and primary tumor
biopsies. Furthermore, a CpG dinucleotide at the HIF-1a transcription factor motifs in the promoter
element of CXCL13 was consistently methylated in CC cells and associated with HIF-1a. CXCL13
overexpression and S110 treatment dramatically repressed tumor growth and liver metastasis in the
xenograft model; whereas it’s low expression increased the risk of death in CC patients.
Conclusion:
DNA methylation-dependent CXCL13 downregulation may promote cervical carcinogenesis
and progression.
