The small splice variant of HPV16 E6, E6⁎, reduces tumor formation in cervical carcinoma xenografts

•The small splice isoform of E6, E6⁎, acts in an anti-oncogenic manner in vivo.•E6⁎ expression reduces tumor formation in both HPV+ (SiHa) and HPV− (C33A) cells.•E6⁎-mediated tumor inhibition is greater in HPV+ SiHa cells than in HPV− C33A cells.

High-risk types of human papillomavirus (HPV) cause nearly all cases of cervical cancer. The E6 oncoprotein is produced as a full-length variant (E6) as well as several shorter isoforms (E6⁎). E6⁎ inhibits certain oncogenic activities of E6, suggesting that it might play an anti-oncogenic role in vivo. To test this, we created E6⁎-expressing SiHa (HPV+) and C33A (HPV−) cells, then examined the ability of both the parental and E6⁎-expressing cells to form tumors in nude mice. We found that over-expression of E6⁎ indeed decreased the growth of tumors derived from both SiHa and C33A cells, with the reduction greatest in tumors derived from E6⁎-expressing SiHa cells. These findings point to multiple anti-oncogenic characteristics of E6⁎, some of which likely involve down-regulation of the full-length isoform, and others that are independent of HPV. These data represent the first demonstration of biologically-relevant E6⁎ activities distinct from those of the full-length isoform in vivo.