Abstract
The transcription factor AP-2α functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2α, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. microRNAs (miRNAs) miR-200b, miR-200c and miR-429 (miR-200b/200c/429) are up-regulated in endometrial and esophageal cancers, and their overexpression correlates with resistance to cisplatin treatment. Using computational programs, we predicted that the 3′ untranslated region (UTR) of AP-2α gene contains a potential miRNA response element (MRE) for the miR-200b/200c/429 family, and the single nucleotide polymorphism (SNP) site rs1045385 (A or C allele) resided within the predicted MRE. Luciferase assays and Western blot analysis demonstrated that the miR-200b/200c/429 family recognized the MRE in the 3′ UTR of AP-2α gene and negatively regulated the expression of endogenous AP-2α proteins. SNP rs1045385 A>C variation enhanced AP-2α expression by disrupting the binding of the miR-200b/200c/429 family to the 3′ UTR of AP-2α. The effects of the two polymorphic variants on cisplatin sensitivity were determined by clonogenic assay. The overexpression of AP-2α with mutant 3′ UTR (C allele) in the endometrial cancer cell line HEC-1A, which has high levels of endogenous miR-200b/200c/429 and low levels of AP-2α protein, significantly increased cisplatin sensitivity, but overexpression of A allele of AP-2α has no significant effects, compared with mock transfection. We concluded that miR-200b/200c/429 induced cisplatin resistance by repressing AP-2α expression in endometrial cancer cells. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3′ UTR of AP-2α, which upregulated AP-2α protein expression and increased cisplatin sensitivity. Our results suggest that SNP (rs1045385) may be a potential prognostic marker for cisplatin treatment.
Highlights
The AP-2 family of transcription factors is involved in the regulation of embryonic development, cell proliferation and tumorigenesis
We demonstrated that AP-2a was directly regulated by miR-200b/200c/429 family and that the single nucleotide polymorphism (SNP) rs1045385 was located in the miR-200b/200c/429-binding site of the 39 untranslated region (UTR) of AP-2a and affected AP-2a protein expression and cisplatin resistance in endometrial cancer cells
The luciferase activity was restored using miRNA response element (MRE)-deleted 39 UTR of AP2a. These results indicate that the predicted MRE mediates the binding of the miR-200b/200c/429 family to AP-2a
Summary
The AP-2 family of transcription factors is involved in the regulation of embryonic development, cell proliferation and tumorigenesis. In addition to its roles in embryonic development, AP-2a functions as a tumor suppressor by regulating the transcription of various genes that are involved in cell proliferation and apoptosis. Several studies have shown that AP2a status is associated with the chemosensitivity of cancer cells[14,15,16]. Endogenous AP-2a protein is posttranscriptionally induced by various chemotherapeutic drugs, including cisplatin, adriamycin and taxol, and promotes chemosensitivity by enhancing therapy-induced apoptosis in colon and breast cancer cells [14]. The expression of AP-2a in the lung carcinoma cell line H460 increased the chemosensitivity to adriamycin (2.5fold) and cisplatin (5-fold)[16]
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