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Oncotarget. 2016 Jul 12;7(28):43805-43819. doi: 10.18632/oncotarget.9698.

Aberrant methylation-mediated silencing of microRNAs contributes to HPV-induced anchorage independence.

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Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Department of Radiation Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.


Cervical cancer and a subset of anogenital and head-and-neck carcinomas are caused by high-risk types of the human papillomavirus (hrHPV). During hrHPV-induced malignant transformation keratinocytes become able to grow anchorage independently, a tumorigenic trait at least partly associated with inactivation of tumor suppressor genes. We used hrHPV-containing keratinocytes to investigate the role of DNA methylation-mediated silencing of microRNAs (miRNAs) in the acquisition of anchorage independence.Anchorage dependent (n=11) and independent passages (n=19) of 4 hrHPV-immortalized keratinocyte cell lines were treated with 2'-deoxy-5-azacytidine (DAC). Genome-wide miRNA expression profiles before and after treatment were compared to identify miRNAs silenced by methylation. Bisulfite sequencing and methylation-specific PCR showed increased methylation of hsa-mir-129-2/-137/-935/-3663/-3665 and -4281 in anchorage independent HPV-transformed keratinocytes and cervical cancer cell lines. Mature miRNAs derived from hsa-mir-129-2/-137/-3663 and -3665 showed functional relevance as they decreased anchorage independence in cervical cancer cell lines. Cervical (pre)cancerous lesions demonstrated increased methylation of hsa-mir-129-2/-935/-3663/-3665 and -4281, underlining the clinical relevance of our findings.In conclusion, methylation-mediated silencing of tumor suppressive miRNAs contributes to acquisition of an anchorage independent phenotype. This study further substantiates the importance of miRNAs during early stages of carcinogenesis and underlines their potential as both disease markers and therapeutic targets.


CIN lesion; DNA methylation; anoikis; cervical cancer

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Free PMC Article

Conflict of interest statement

PJFS, RDMS and CJLMM have minority stake in Self-Screen B.V., a spin-off company of VU University Medical Center Amsterdam. PJFS has been on the speaker's bureau of Roche, Abbott, Gen-Probe, Qiagen and Seegene. He is consultant for Crucell Holland B.V. CJLMM has participated in the sponsored speaker's bureau of Merck, GSK, Qiagen, Menarini, Seegene, and Roche, and served occasionally on the scientific advisory board of GSK, Qiagen, Merck, and Roche. CJLMM has occasionally been a consultant for Qiagen and Genticel and is a minority shareholder of Diassay B.V. Formerly CJLMM was a minority shareholder of Delphi Biosciences. All other authors have no conflicts of interest to declare.

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