eprintid: 35916
rev_number: 19
eprint_status: archive
userid: 8708
dir: disk0/00/03/59/16
datestamp: 2025-02-03 09:28:14
lastmod: 2025-02-12 13:24:48
status_changed: 2025-02-03 09:28:14
type: doctoralThesis
metadata_visibility: show
creators_name: Strobel, Tobias Dag
title: Evaluating the Role of STAT3 for the Phenotype of HPV-Positive Cervical Cancer Cells
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
abstract: Oncogenic HPV types cause up to 5% of all human cancers worldwide, including cervical cancer. In order to improve cervical cancer treatment options, novel therapeutic strategies are urgently required. As a prevailing concept in the field, the signal transducer and activator of transcription 3 (STAT3) protein is considered to be a highly promising therapeutic target in HPV-positive cancer cells, since it was reported that STAT3 is essential for the proliferation of cervical cancer cells and, furthermore, undergoes mutually stimulatory interactions with the HPV E6/E7 oncogenes. One strategy to block STAT3 could be the application of the iron chelator Ciclopirox (CPX) which induces the destabilization of STAT3 and inhibits the proliferation of HPV-positive cancer cells.

This thesis aimed to explore the role of STAT3 for the malignant phenotype of cervical cancer cells in detail, focusing on its role for cell proliferation, its reported crosstalk with the HPV oncogenes and its significance for the anti-proliferative effects of CPX. By applying a broad spectrum of experimental methods to modulate STAT3 activity or expression, several unexpected findings were obtained. A number of widely used small molecule STAT3 inhibitors inhibited the proliferation not only of parental cervical cancer cells, but also of corresponding STAT3 knockout derivatives, indicating that they act through off-target effects. In contrast, thoroughly controlled depletion of STAT3 by RNA interference or by CRISPR/Cas9 genome editing did not considerably affect cell proliferation, strongly arguing against an essential role of STAT3 for the growth of cervical cancer cells. In line, transcriptome analyses revealed that STAT3 silencing did not affect expression of its putative pro-proliferative target genes in these cells. Further, despite increased STAT3 activation levels in response to therapeutic drugs, such as PI3K or MEK inhibitors, this did not provide therapeutic resistance to cervical cancer cells. In addition, whereas first insights into the mechanism of CPX-induced STAT3 degradation were obtained, STAT3 was found to be dispensable for the anti-proliferative effects of CPX in cervical cancer cells. Finally, and of particular importance for the field of HPV-induced carcinogenesis, no evidence for an appreciable crosstalk between STAT3 and the viral E6/E7 oncogenes was obtained in either direction, by employing multiple experimental strategies.

Collectively, these findings strongly question the prevailing concept that STAT3 is essential for cervical cancer cell proliferation as well as for efficient HPV E6/E7 oncogene expression. Besides providing unexpected novel insights into the significance of STAT3 for the malignant phenotype of cervical cancer cells, these results are also informative to reshape the discussion on STAT3 serving as a highly promising therapeutic target in HPV-positive cancers.
date: 2025
id_scheme: DOI
id_number: 10.11588/heidok.00035916
ppn_swb: 1917124139
own_urn: urn:nbn:de:bsz:16-heidok-359169
date_accepted: 2024-12-16
advisor: HASH(0x55e83b302ac0)
language: eng
bibsort: STROBELTOBEVALUATING20241216
full_text_status: public
place_of_pub: Heidelberg
citation:   Strobel, Tobias Dag  (2025) Evaluating the Role of STAT3 for the Phenotype of HPV-Positive Cervical Cancer Cells.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/35916/7/Tobias_Strobel_Thesis_D365_incl_hyperlinks_v2_PDF_A.pdf