Crosstalk between cell fate and survival pathways during uterine cervical carcinoma progression: a molecular and clinical perspective

Abstract

The development of uterine cervical cancer is primarily attributed to infection by high-risk human papillomaviruses (HR-HPVs). E5, E6 and E7, the three early oncoproteins of HR-HPVs, have been implicated in initiation and progression of cervical cancer. The intricate molecular mechanisms that orchestrate aberrant cellular transformations to establish carcinoma of the cervical epithelium following viral infections are poorly understood. Here, we discuss how deregulation of three major cell fate regulatory pathways, Hedgehog, Wnt and Notch, and cell survival strategies involving EGFR signaling and G1/S checkpoint contribute towards cervical cancer development and progression. Further exploration of protein interaction database has revealed several genes that are involved in cervical cancer initiation and progression, and the two crucial "driver” genes, MYC and CTNNB1 (β-catenin), have been identified as major players in protein-protein interaction network. GSK3β emerged as the key mediator of crosstalk between Hedgehog, Wnt and Notch signaling pathways. GSK3β regulates cytoplasmic stabilization and nuclear translocation of β-catenin, which further impacts the expression of MYC, critical for cell cycle progression. Collectively, our analyses suggest that combinatorial therapeutic targeting of these proteins may be more effective in blocking cervical cancer initiation and progression.

Keywords

Uterine cervical cancer / hedgehog / Notch / Wnt / G1/S checkpoint / GSK3β / β-catenin / MYC

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