Label‐free cervicovaginal fluid proteome profiling reflects the cervix neoplastic transformation

Abstract

Cervicovaginal fluid (CVF) is a valuable source of clinical information about the female reproductive tract in both nonpregnant and pregnant women. The aim of this study is to specify the CVF proteome at different stages of cervix neoplastic transformation by label-free quantitation approach based on liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The proteome composition of CVF from 40 women of reproductive age with human papillomavirus (HPV)-associated cervix neoplastic transformation (low-grade squamous intraepithelial lesion [LSIL], high-grade squamous intraepithelial lesion [HSIL], and CANCER) was investigated. Hierarchical clustering and principal component analysis (PCA) of the proteomic data obtained by a label-free quantitation approach show the distribution of the sample set between four major clusters (no intraepithelial lesion or malignancy [NILM], LSIL, HSIL and CANCER) depending on the form of cervical lesion. Multisample ANOVA with subsequentWelch's t test resulted in 117 that changed significantly across the four clinical stages, including 27 proteins significantly changed in cervical cancer. Some of them were indicated as promising biomarkers previously (ACTN4, VTN, ANXA1, CAP1, ANXA2, and MUC5B). CVF proteomic data from the discovery stage were analyzed by the partial least squares-discriminant analysis (PLS-DA) method to build a statistical model, allowing to differentiate severe dysplasia (HSIL and CANCER) from the mild/normal stage (NILM and LSIL), and receiver operating characteristic (ROC) area under the curve (AUC) were obtained on an independent set of 33 samples. The sensitivity of the model was 77%, and the specificity was 94%; AUC was equal to 0.87. CVF proteome proved to be reflect the stage of cervical epithelium neoplastic process.

<p>Combined Detection of ACTN4 and SCC-Ag is a Promising Serological Biomarker for Cervical Intraepithelial Neoplasia 3 or Worse: A Case–Control Study</p>

“…To our knowledge, ACTN4 has a potential screening capacity for early cancer, including CC, in fluids and bloods collected from the human body. Comparable results for ACTN4 were obtained by Starodubtseva, N. L, 16 Geert A. A.…”

“…In addition, HPV16 E6, a famous HR-HPVrelated oncoprotein, is involved in CC cell migration and invasion via ACTN4. 15 Furthermore, it has been reported that ACTN4 from cervicovaginal fluid can discriminate patients with CC and patients infected by HR-HPV, [16][17][18] and ACTN4 mRNA in serum is elevated in patients with breast cancer. 19 Therefore, ACTN4 in blood may have potential screening abilities for early cervical lesions.…”

Progressive and Prognostic Performance of an Extracellular Matrix-Receptor Interaction Signature in Gastric Cancer

“…In a variety of tumors, such as cervix neoplasia [ 27 ], ovarian cancer [ 28 ], and prostate cancer [ 29 ], VTN was considered a promising biomarker, which encoded vitronectin, an adhesive glycoprotein that connected cells with ECM. Recently, a report also revealed that VTN was a poor prognostic factor in gastric cancer [ 30 ].…”

Molecular markers for cervical cancer screening

“…Neoplastic transformation of the cervix may be reflected in the CVF as revealed by label-free proteome profiling. Research by Starodubtseva et al [123] compared the CVF proteome at different stages of neoplastic transformation of the cervix (LSIL, HSIL, and cancer) and identified six potential biomarkers, ACTN4, VTN, ANXA1, CAP1, ANXA2, and MUC5B [124.] Again, considerably more work is needed to substantiate these findings in view of turning them into useful starting points for developing an improved triage test in cervical cancer population screening [125][126][127].…”