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.
Highlights
Progression to cervical cancer is a multi-step process etiologically-linked with persistent infection of high-risk human papillomaviruses (HPVs)
The E2: E6 ratio in clinical samples with reference to the plasmid control was calculated by the following formula: Normalized E2: E6 ratio of clinical samples = (IDV E2: IDV E6) samples /(IDV E2: IDV E6) plasmid pSTAT3 correlates with HPV16 viral load and physical state in cervical carcinogenesis where IDV indicates integrated densitometric values of DNA band of HPV16 E2 amplicon (IDV) or HPV16 E6 (IDV) amplicon of the plasmid and sample DNA
Level of pSTAT3 (Y705) was analyzed by immunoblotting in a total of 130 HPV16 positive cases comprising 60 pre-cancer (LSIL– 30; high grade squamous intraepithelial lesions (HSIL)– 30) and 70 cancer tissues and a correlation was examined with respective viral load and physical state of HPV16 genome from corresponding cervical lesions (Fig 1)
Summary
Progression to cervical cancer is a multi-step process etiologically-linked with persistent infection of high-risk human papillomaviruses (HPVs). Clinical implication and the reasons behind such discrepant observations, the confounding factors responsible for the phenomenon, are not clear as yet Despite these variations, high-risk HPV viral load and physical state are proposed as potentially useful markers that could predict progressive high-grade cervical lesions [15,16,17]. A set of transcription factors like STAT3, AP-1, NF-κB, SP1, NF-1, c/EBP, Oct-1, KRF-1, YY1, and GRE have been proposed to play a regulatory role in HPV infection due to the presence of their cognate cis-elements in the URR [20,21,22] These factors are responsible for the cell-type-specific viral gene expression and contribute to the tissue tropism of HPVs [20,23]. To maintain homogeneity of the analysis, and to avoid confounding variables, cervical precancer and cancer tissues having non-HPV16 or multiple infections were excluded from the study
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