NELL2-Robo3 signaling promotes keratinocyte proliferation and inhibits keratinocyte apoptosis in condyloma acuminatum through autocrine and paracrine mechanisms.

Background: Condyloma acuminatum (CA) is caused by low-risk HPV infection and characterized by benign epithelial proliferation. NELL2, as a secreted glycoprotein, is strongly linked to dermatosis, but its function in CA remains unknown.

Objective: To investigate the expression, function and mechanism of NELL2 in CA.

Methods: The expression of NELL2 was detected in CA and normal skin tissues. HaCaT cells stably expressing HPV11-E7 (HPV11-E7-HaCaT) and control group (Vector-HaCaT) were constructed to explore the relationship between HPV infection and NELL2 expression. We downregulated NELL2 expression in HPV11-E7-HaCaT cells and added recombinant human NELL2 to medium of Vector-HaCaT and HPV11-E7-HaCaT cells to examine the effects of NELL2 on cell proliferation and apoptosis. The activation of MAPK pathway and the role of Robo3 were evaluated to explore the mechanisms underlying these effects.

Results: NELL2 was overexpressed in CA, and increased NELL2 expression was positively associated with high HPV copy number and high Ki67 expression. HPV11-E7 induced the expression of NELL2 in HaCaT cells. In addition, NELL2 promoted proliferation and inhibited apoptosis in HPV11-E7-HaCaT and Vector-HaCaT cells through autocrine and paracrine mechanisms. NELL2 treatment activated the ERK pathway, and ERK inhibition by U0126 confirmed that ERK pathway was essential for the function of NELL2 in CA. Moreover, Robo3 acts as the NELL2 receptor in CA.

Conclusion: NELL2 binds Robo3 to promote keratinocyte proliferation and inhibit keratinocyte apoptosis in CA through autocrine and paracrine mechanisms. NELL2-Robo3 signaling may be regarded as a potential target for CA treatment in the future.