Feedback between E2F1 and CIP2A regulated by human papillomavirus E7 in cervical cancer: implications for prognosis

Previously, we found that cancerous inhibitor of protein phosphatase 2A (CIP2A) plays a key role in the malignant transformation of cervical cancer. Here, we further explore whether and how CIP2A is regulated by human papillomavirus E7 (HPV E7) and the prognostic value of CIP2A in cervical cancer. We demonstrated a positive feedback loop between the E2F transcription factor 1 (E2F1) and CIP2A at the transcription level in HeLa and SiHa cells by real-time PCR and western blot analysis. The feedback, regulated by HPV E7, was further confirmed by their sub-cellular co-expression seen on immunofluorescence and immunohistochemistry staining in vitro and in vivo. Moreover, CIP2A and E2F1 expression was greatly elevated in human cervical cancer tissue. CIP2A expression was tightly associated with tumor size, depth of invasion and lymph node metastasis in 184 cases of cervical cancer. Kaplan-Meier and Cox proportional-hazards regression analyses revealed poor overall and disease-free survival of patients with CIP2A-E2F1 co-expression, and high CIP2A-E2F1 co-expression was an independent risk factor for overall survival of patients. Therefore, CIP2A-E2F1 expression might be a valuable indicator to predict outcome and guide personal treatment in cervical cancer.