Level of phospho-STAT3 (Tyr705) correlates with copy number and physical state of human papillomavirus 16 genome in cervical precancer and cancer lesions

Abstract

Our earlier studies indicated an important role of inducible transcription factor STAT3 in the establishment of persistent infection of human papillomavirus (HPV) type 16 and promotion of cervical carcinogenesis. Since HPV load and its physical state are two potential determinants of this virally-induced carcinogensis, though with some exceptions, we extended our study to examine the role of active STAT3 level in cervical precancer and cancer lesions and it’s association with HPV viral load and physical state. An elevated level of active STAT3 was measured by assessing phospho-STAT3-Y705 (pSTAT3), in tumor tissues harboring higher viral load irrespective of the disease grade. Physical state analysis of HPV16 by assessing the degree of amplification of full length E2 and comparing it with E6 (E2:E6 ratio), which predominantly represent episomal form of HPV16, revealed low or undetectable pSTAT3. A strong pSTAT3 immunoreactivity was found in tissues those harbored either mixed or predominantly integrated form of viral genome. Cumulative analysis of pSTAT3 expression, viral load and physical state demonstrated a direct correlation between pSTAT3 expression, viral load and physical state of HPV. The study suggests that there exists a strong clinical correlation between level of active STAT3 expression and HPV genome copy number, and integrated state of the virus that may play a pivotal role in promotion/maintanence of tumorigenic phenotype.

From Microbiome to Inflammation: The Key Drivers of Cervical Cancer

“…The upstream regulatory regions of some transcription factors, such as NF-κB and signal transducers and activators of transcription 3 (STAT3), contain homeopathic elements associated with carcinogenesis ( Gupta et al, 2018 ). These transcription factors may influence the regulation of the HPV genome ( Shukla et al, 2019 ). Activation of the janus kinase (JAK)/STAT pathway plays an important role in immune escape.…”

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

“…We now know that the expression of the HPV genome depends mainly on host transcription factors, and some transcription factors such as AP-1, NF-κB, and also STAT3 may play a regulatory role in HPV infection owing to the presence of its cis-related elements in the upstream regulatory regions (URRs) and its association with the degree of carcinogenesis [ 102 ]. Arany et al suggested that STAT3 could bind to HPV16 upstream of the URR, driving the expression of E7 [ 103 ].…”

“…Arany et al suggested that STAT3 could bind to HPV16 upstream of the URR, driving the expression of E7 [ 103 ]. However, STAT3 also affects the expression of E6; different studies show the inhibition of STAT3 with the STAT3 inhibitor cryptotanshinone or STAT3-specific siRNA or its blocking of tyrosine phosphorylation by AG490 or curcumin as a consequence the reduction of E6 and E7, which are two viral oncoproteins that are very relevant in transformation and carcinogenesis processes [ 99 , 102 , 103 , 104 ]. The decrease of STAT3 in cervical tumor cells has a drastic effect, inducing an increase in the expression of cell cycle control proteins such as p21, pRB, and p53, showing a decrease in cyclin D1 expression with an increase in the induction of apoptosis, which is produced by a decrease in pro-apoptotic proteins and an increase in the activation of effector caspases [ 99 , 104 ].…”

Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

“…Additional studies demonstrated a significant correlation between high levels of STAT3 phosphorylation and a high HPV16 viral load and integration of the viral genome, suggesting that the induction of STAT3 phosphorylation by HPV during the viral life cycle may contribute to genome integration and cancer development by an as yet unknown mechanism [152]. In keratinocytes, STAT3 has been demonstrated to have an important role in epithelial differentiation, proliferation, cell migration and survival [139,[149][150][151].…”