Genetic and Epigenetic Determinants of Endometrial LIF Expression and the Potential Role of Human Papillomavirus E6-Mediated p53 Degradation

Our review develops a mechanistic hypothesis and does not describe an established pathway. The empirical premise on which it rests, that HPV E6 is expressed in endometrial tissue and degrades p53 at that site, has not been demonstrated in humans. Endometrial expression of leukaemia inhibitory factor (LIF) is required for blastocyst implantation, and in the mouse it is transcribed under the control of p53 acting at a response element in intron 1 that is conserved in the human gene. Human support for the same relationship is genetic rather than biochemical. The TP53 codon 72 polymorphism rs1042522 alters LIF transactivation and has been associated with implantation failure in several cohorts while showing no effect in the largest. Variation in LIF itself at rs929271, and in MDM2, MDM4 and USP7, has been associated with implantation and with later pregnancy maintenance. High-risk human papillomavirus brings a second genome into the same regulatory problem. The E6 oncoprotein recruits the E6-associated protein ubiquitin ligase and directs p53 to proteasomal degradation, and the efficiency of that reaction varies by more than two orders of magnitude across high-risk genotypes and again between natural sequence variants of HPV16 E6. Loss of p53 also raises DNMT1 and removes p53-dependent microRNAs, which places the axis inside the epigenetic programme of the cycling endometrium.