Decreased Expression of PTENP1 by Smoking Induces Drug Resistance Through c-MYC Activation in HPV+ Oropharyngeal Squamous Cell Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Smokers have increased risk of cancer recurrence, drug resistance, metastasis and mortality while the mechanism of smoking in cancer recurrence remains unclear. PTENP1 is a long non-coding RNA that protect PTEN expression as miRNA sponge, resulting in a reduction in tumor invasiveness and growth. Decreased PTENP1 expression has been associated with worse prognosis in multiple cancer types. In this study, we examine smoking induced PTENP1 suppression in HPV+ oropharyngeal squamous cell carcinoma (OPSCC) as a mechanism of treatment resistance. <h3>Materials/Methods</h3> We examined expression of PTENP1 in primary and paired recurrent HNSCC tumor tissue from 7 patients (6 of 7 patients are active smokers). We investigate the role of PTENP1 in cancer drug resistance by over-expressing or knocking down PTENP1 in HNSCC cell lines. <h3>Results</h3> We demonstrate that reduced PTENP1 expression and increased expression of HPV16 E2, E6, E7 in all recurrent tumors compared to paired primaries from HPV+ OPSCC patients. We then examined the relationship between HPV oncogene expression and PTENP1 in a treatment resistant, CSC-induced cell line. Similar to clinical samples, we demonstrate increased HPV16 E6 and E7 expression, and decreased PTENP1 expression in CSC induced cancer cells compared to parental cells. We identify smoking-induced Protein kinase C down-regulation as the mechanism of PTENP1 suppression. Decreased expression of PTENP1 results in c-MYC and HPV16 E6, and E7 activation. When cancer cells were treated with phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, PTENP1 was reactivated and CSC induced cancer cells were re-sensitized to treatment with cisplatin by suppressing c-MYC expression. <h3>Conclusion</h3> This is the first study to demonstrate the association between PTENP1 suppression, treatment resistance, and smoking exposure in HPV+ OPSCC. This novel mechanism of cisplatin resistance via the PTENP1-MYC axis may have important implications for the development of future targeted therapies