Oncogenic E6 and/or E7 proteins drive proliferation and invasion of human papilloma virus-positive head and neck squamous cell cancer through upregulation of Ror2 expression

Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)-positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV-related cancers. However, the function of Ror2 in HPV-positive HNSCC is currently unknown. Here, we first examined the expression levels of Ror2 in clinical specimens from patients with HPV-negative and HPV-positive oropharyngeal squamous cell cancer (OPSCC) via immunohistochemical analysis. We found that Ror2 was expressed in both HPV-negative and HPV-positive OPSCC tissues. We then confirmed that HPV-positive HNSCC cell line, UPCI:SCC152 cells, express Ror2 higher than HPV-negative cell lines as previously reported. Suppressed expression of HPV E6/7 resulted in reduced expression levels of Ror2. We also revealed that Ror2 downregulation significantly inhibited the proliferation of UPCI:SCC152 cells without inducing apoptosis. Moreover, Ror2 knockdown decelerated G(1)/S phase progression and abrogated invasive migration of UPCI:SCC152 cells. These results provide strong evidence that E6 and/or E7 oncoproteins regulate the progression of HPV-positive HNSCC by upregulating Ror2 expression, suggesting that Ror2 could potentially be a novel target in HPV-related cancers.