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Generation of Organotypic Raft Cultures from Primary Human Keratinocytes
Published on: February 22, 2012
HPV16 E5 and KGFR/FGFR2b interplay in differentiating epithelial cells.
Valeria Purpura1, Francesca Belleudi, Silvia Caputo
1Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Italy.
Oncotarget
|April 3, 2013
Summary
Human papillomavirus type 16 E5 protein disrupts keratinocyte differentiation by downregulating keratinocyte growth factor receptor (KGFR). Restoring KGFR signaling counteracts this effect, highlighting KGFR's tumor-suppressive role in HPV16-associated carcinogenesis.
Area of Science:
- Oncology
- Cell Biology
- Virology
Background:
- Human papillomavirus type 16 E5 (HPV16 E5) protein contributes to epithelial transformation by altering differentiating suprabasal cell behavior.
- HPV16 E5 dysregulates receptor tyrosine kinases, including keratinocyte growth factor receptor (KGFR/FGFR2b), affecting its signaling and trafficking in undifferentiated keratinocytes.
- KGFR is a key mediator of epithelial homeostasis and a potential target of HPV16 E5 in differentiated cells.
Purpose of the Study:
- To investigate the interaction between HPV16 E5 and KGFR/FGFR2b in human keratinocytes committed to differentiation.
- To elucidate the role of KGFR in HPV16 E5-induced impairment of keratinocyte differentiation.
Main Methods:
- Utilized an in vitro model of forced KGFR overexpression or depletion in E5-expressing human keratinocytes undergoing synchronous differentiation.
- Employed quantitative RT-PCR, biochemical assays, and immunofluorescence analysis to assess KGFR levels, differentiation markers, and signaling pathways.
- Investigated the effect of KGFR on p63 expression and the involvement of PI3K/Akt signaling.
Main Results:
- Down-modulation of KGFR by HPV16 E5 led to a decrease in the early differentiation marker K1.
- Re-expression of KGFR and activation of its signaling pathway effectively counteracted the differentiation defect.
- KGFR induced a ligand-dependent decrease in p63 via a miR-203-independent mechanism, blocked by PI3K/Akt inhibition.
- HPV16 E5-induced keratinocyte differentiation impairment involves alterations in the KGFR/p63 crosstalk.
Conclusions:
- KGFR plays a tumor-suppressive role in HPV16 E5-mediated carcinogenesis by maintaining keratinocyte differentiation.
- Alterations in KGFR/p63 crosstalk contribute to the differentiation defects observed in HPV16 E5-expressing keratinocytes.
- Both the tumor-suppressive action of KGFR and the oncogenic role of HPV16 E5 may involve the p63 pathway.
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