ErbB2/HER2 receptor tyrosine kinase regulates human papillomavirus promoter activity

Area of Science:

• Virology and Cancer Biology
• Molecular mechanisms of viral oncogenesis
• Signal transduction pathways in HPV infection

Background:

• Human papillomaviruses (HPVs) are a significant cause of cancer, necessitating new therapeutic strategies beyond surgery.
• The viral oncoproteins E6 and E7, controlled by the long control region (LCR), are critical for HPV oncogenesis and immune evasion.
• The role of ErbB2 (HER2/neu) in HPV infection stages was previously uncharacterized, despite its association with cervical cancer.

Purpose of the Study:

• To investigate the role of ErbB2 in the lifecycle of human papillomavirus (HPV), specifically HPV16.
• To determine if ErbB2 influences HPV entry, LCR activity, or viral gene expression.
• To explore the potential of ErbB2 as a therapeutic target for HPV infections and associated cancers.

Main Methods:

• Proteomic analysis to identify co-internalization of HPV16 and ErbB2.
• siRNA-mediated knockdown and pharmacological inhibition of ErbB2.
• Signal transduction assays, promoter activity assays, and quantitative analysis of E6/E7 transcript levels.

Main Results:

• HPV16 entry is independent of ErbB2; however, ErbB2 regulates HPV LCR activity in a concentration- and activation-dependent manner.
• ErbB2 depletion and tyrosine kinase inhibitors (tucatinib, CP-724714) affected downstream Akt and ERK signaling pathways and LCR activity.
• ErbB2 also regulates LCR activity in HPV11 and HPV18, and its depletion significantly decreased E6/E7 oncogene expression in HPV16/18 cell lines.

Conclusions:

• ErbB2 plays a crucial regulatory role in supporting HPV early promoter activity and viral oncogene expression, rather than mediating viral entry.
• Targeting ErbB2, through depletion or kinase inhibition, effectively silences viral gene expression by modulating Akt and ERK signaling.
• ErbB2 represents a promising therapeutic target for treating HPV infections and HPV-associated malignancies by inhibiting viral oncogenesis.