HPV-18 E7 Interacts with Elk-1 Leading to Elevation of the Transcriptional Activity of Elk-1 in Cervical Cancer

Abstract

The human papillomavirus (HPV)-18 E7 (E7) oncoprotein is a major transforming protein that is thought to be involved in the development of cervical cancer. It is well-known that E7 stimulates tumour development by inactivating pRb. However, this alone cannot explain the various characteristics acquired by HPV infection. Therefore, we examined other molecules that could help explain the acquired cancer properties during E7-induced cancer development. Using the yeast two-hybrid (Y2H) method, we found that the Elk-1 factor, which is crucial for cell proliferation, invasion, cell survival, anti-apoptotic activity, and cancer development, binds to the E7. By determining which part of E7 binds to which domain of Elk-1 using the Y2H method, it was found that CR2 and CR3 of the E7 and parts 1–206, including the ETS-DNA domain of Elk-1, interact with each other. As a result of their interaction, the transcriptional activity of Elk-1 was increased, thereby increasing the expression of target genes EGR-1, c-fos, and E2F. Additionally, the colony forming assay revealed that overexpression of Elk-1 and E7 promotes C33A cell proliferation. We expect that the discovery of a novel E7 function as an Elk-1 activator could help explain whether the E7 has novel oncogenic activities in addition to p53 inactivation. We also expect that it will offer new methods for developing improved strategies for cervical cancer treatment.

ELK4 Promotes Cell Cycle Progression and Stem Cell-like Characteristics in HPV-associated Cervical Cancer by Regulating the FBXO22/PTEN Axis

“…ELK1 belongs to the ELK family, and it exhibits an increase in the HPV-18-induced transcriptional activity during CC development. 17 In this study, the ELK4 was elevated in the HPV + CC tissue samples and HPV + cell lines, indicating that ELK4 may operate as a molecular target that governs the development of CC. This is the first investigation into the potential functional involvement of ELK4 in CC development.…”

LKB1/STK11 Tumor Suppressor Reduces Angiogenesis by Directly Interacting with VEGFR2 in Tumorigenesis

“…Cervical tumors are a leading cause of tumor-associated mortality, and represent a common gynecological malignancy worldwide, including in the United States. High-risk human papillomavirus (HPV) infection is a significant risk factor for cervical tumor development Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis (Forouzanfar et al, 2011;Hou et al, 2014) with the viral oncoproteins E6 and E7 contributing to tumorigenesis through inactivation of the tumor suppressors p53 and pRb (Howie et al, 2009;Spangle and Münger, 2010;Go et al, 2022). Various oncogenic signaling factors, including the PI3K/Akt pathway, play a critical role in cervical tumor angiogenesis, progression, and metastasis (Hou et al, 2014;Prasad et al, 2015;Rho et al, 2020).…”

“…Cervical tumors are frequently associated with human papillomavirus (HPV) infection, particularly subtypes 16 and 18, and are characterized by pathological angiogenesis ( Tomao et al ., 2014 ; Go et al ., 2022 ). Angiogenesis, the formation of new blood vessels, is a crucial process in tumor progression, and tumor angiogenesis is tightly regulated by vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) signaling pathways ( Rodriguez-Freixinos and Mackay, 2015 ).…”

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

“…HPV16 E7 increases the expression of pyruvate kinaseM2 (PKM2) and trriggers its nonglycolytic function, fostering cervical cancer cell proliferation 147 . HPV18 E7 enhances the transcription of ELK‐1, an activator that stimulates cell proliferation 148 . HPV16 E6 upregulates silent information regulator1, promoting cervical cell proliferation 149 .…”

“… 147 HPV18 E7 enhances the transcription of ELK‐1, an activator that stimulates cell proliferation. 148 HPV16 E6 upregulates silent information regulator1, promoting cervical cell proliferation. 149 Knockdown of AIB7 expression in E1E6 immortalized human cervical cells significantly inhibits cell proliferation, underscoring AIB1 as a promising target for HPV E6 and a biomarker for cervical cancer progression.…”