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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00213


 Anna Chiarini1*,  Daisong Liu2*, Mario Rassu3,  Ubaldo Armato1, Claudio Eccher4 and  Ilaria Dal Pra1*
  • 1Unità di Istologia ed Embrologia Umana, Dipartimento di Medicina, Università di Verona, Italy
  • 2Plastic Surgery Department, Third Xiangya Hospital, Central South University, China
  • 3Microbiology & Virology Unit, San Bortolo Hospital, Italy
  • 4Casa di Cura Villa Bianca, Italy

Oncogenic human papilloma viruses (HPVs) promote human cervical carcinoma (HCC) development, the fourth most common feminine cancer. A lengthy oncodevelopmental phasehistopathologically defined as Cervical Intraepithelial Neoplasia (CIN) stages 1-to-3, or cytologically as Low- or High-grade Squamous Intraepithelial Lesions (LSIL or HSIL) or Atypical Squamous Lesions of Undetermined Significance (ASCUS)precedes the final HCC outcome. HCC screenings through cytology and HPV DNA genotyping are regularly performed in Western countries. Faulty cytology screening or incomplete genotyping or patient’s noncompliance with indicated follow-ups can let slip a diagnosis of oncoprogression. The well-known problematic triage of LSIL/ASCUS patients could be solved if novel biomarker tests would flank cytology and HPV genotyping. Here, anonymized leftovers of fresh cervical epithelium scrapings from twice (LSIL/ASCUS and high-risk (HR)-HPV DNA)-positive and twice (Pap smear- and HPV DNA)-negative (control) patients, served to assess the biomarker worth of three HCC-related proteins, i.e., B-MYB (or MYBL2), Cancerous Inhibitor of PP2A (CIP-2a), and transketolase-like1 (TKTL1). Anonymity of the leftovers was strictly preserved along all the steps of the study and storage at -80°C in an ad hoc freezing solution, protein extraction, standardized Western immunoblotting, and protein band densitometry analysis were all performed under blind conditions. Only after completing the tests on all the scrapings, their anonymous yet code-corresponding HPV-genotyping and cytology data allowed to categorize them as belonging to the twice-positive or twice-negative groups. Descriptive statistics showed that the three proteins levels significantly increased in the twice-positive vs. twice-negative scrapings. Diagnostic ROC curve analysis identified Optimal Decision Thresholds and hence showed that TKTL1 and CIP-2a proteins are useful biomarkers (Sensitivity, 0.91-0.93; Specificity, 0.77-0.83) of an ongoing HR-HPV-driven oncogenesis. Logistic Regression coupled with Likelihood-Ratio Tests confirmed that a highly significant relation exists between increasing TKTL1/CIP-2a protein levels and HR-HPV-driven oncoprogression. Besides this proof of concept drawn from unknown samples, our data show that cytology, HPV DNA genotyping, and TKTL1/CIP-2a assays can be performed on the same cervical epithelium scrapings. This would simplify and speed up the management of LSIL/ASCUS patients by discriminating those immediately needing colposcopy referral from those eligible for a delayed follow-up.

Keywords: LSIL – low-grade squamous intraepithelial lesions, ASCUS (abnormal squamous cells of undetermined significance), Human cervical carcinoma, oncogenic papillomaviruses, TKTL1 protein, CIP-2A protein, B-MYB protein, predictive biomarker

Received: 22 Aug 2018; Accepted: 11 Mar 2019.

Edited by:

Sarah M. Temkin, Virginia Commonwealth University, United States

Reviewed by:

Katrina Mark, School of Medicine, University of Maryland, United States
Leonel Maldonado, University of South Alabama, United States  

Copyright: © 2019 Chiarini, Liu, Rassu, Armato, Eccher and Dal Pra. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Anna Chiarini, Unità di Istologia ed Embrologia Umana, Dipartimento di Medicina, Università di Verona, Verona, Veneto, Italy,
Dr. Daisong Liu, Plastic Surgery Department, Third Xiangya Hospital, Central South University, Changsha, China,
Dr. Ilaria Dal Pra, Unità di Istologia ed Embrologia Umana, Dipartimento di Medicina, Università di Verona, Verona, Veneto, Italy,