Abstract
In the network of chemokine signaling pathways, recent reports have described the SDF-1α/CXCR4 axis and its role in cancer progression and metastasis. Interestingly, we found downregulation of CXCR4 at both transcript and protein level in cervical cancer cell lines and primary tumors. We also found CXCR4 promoter hypermethylation in cervical cancer cell lines and primary biopsy samples. DNA hypomethylating drug 5-AZA-2′-deoxycytidine and histone deacetylase inhibitor Trichostatin A treatments in cell lines reactivate both CXCR4 transcription and protein expression. Cell adhesion assay demonstrated that autocrine SDF-1α promotes the loss of cell adhesion while paracrine SDF-1α predominantly protects the normal cervical cells from loss of cell adhesion. Cervical cancer cell line C-33A having increased expression of CXCR4 after TSA treatment showed increased cell adhesion by paracrine source of SDF-1α in comparison to untreated C-33A. These findings demonstrate the first evidence that epigenetic silencing of CXCR4 makes the cells inefficient to respond to the paracrine source of SDF-1α leading to loss of cell adhesion, one of the key events in metastases and progression of the disease. Our results provide novel insight of SDF-1α/CXCR4 signaling in tumor microenvironment which may be promising to further delineate molecular mechanism of cervical carcinogenesis.
Highlights
The process of cancer progression and metastasis, driven by chemokines and its receptors, is a major cause of death in cancer patients [1, 2]
Expression profiling of CXCR4 transcript was done by semiquantitative RT-PCR in eight CC cell lines (HeLa, SiHa, ME-180, C-33A, CaSki, C-4I, MS751, and SW756), 63 (60 squamous cell carcinomas and 3 adenosquamous) primary tumor biopsies, and 30 normal cervical tissue samples
To assess the role of SDF-1α/CXCR4 signaling in SDF-1α induced cell adhesion in C-33A, we evaluated the effect of CXCR4 inhibitor AMD3100 (500 ng/mL) and SDF-1α neutralizing antibody on SDF1α induced cell adhesion
Summary
The process of cancer progression and metastasis, driven by chemokines and its receptors, is a major cause of death in cancer patients [1, 2]. Chemokine receptors are a family of seven transmembrane G protein-coupled cell surface receptors (GPCRs) and are defined by their ability to induce directional migration of cells towards a gradient of chemokine (chemotaxis). These receptors, initially identified on leukocytes, are present on many different cell types. The cross talk between cancer cells and their microenvironment has an important influence on tissue homeostasis and progression of cancers [6]. Chemokines are the major mediators of this cross talk between tumor cell and stroma [7]. The interactions between chemokine receptors and their respective chemokines help to coordinate the tumor cell growth and trafficking [8]
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