Integrative meta‑analysis of gene expression profiles identifies FEN1 and ENDOU as potential diagnostic biomarkers for cervical squamous cell carcinoma

Abstract

Cervical carcinoma is a global public health burden. Given that it is usually asymptomatic at potentially curative stages, the development of clinically accurate tests is critical for early detection and individual risk stratification. The present study performed an integrative meta-analysis of the transcriptomes from 10 cervical carcinoma cohorts, with the aim of identifying biomarkers that are associated with malignant transformation of cervical epithelium, and establish their clinical applicability. From among the top ranked differentially expressed genes, flap structure-specific endonuclease 1 (FEN1) and poly (U)-specific endoribonuclease (ENDOU) were selected for further validation, and their clinical applicability was assessed using immunohistochemically stained microarrays comprising 110 tissue cores, using p16 and Ki67 staining as the comparator tests. The results demonstrated that FEN1 expression was significantly upregulated in 65% of tumor specimens (P=0.0001), with no detectable expression in the non-tumor tissues. Furthermore, its expression was significantly associated with Ki67 staining in tumor samples (P<0.0001), but no association was observed with p16 expression or the presence of human papilloma virus types 16/18, patient age, tumor grade or stage. FEN1 staining demonstrated lower sensitivity than p16 (69.3 vs. 96.8%) and Ki67 (69.3 vs. 76.3%); however, the specificity was identical to p16 and higher than that of Ki67 (100 vs. 71.4%). ENDOU staining was consistent with the microarray results, demonstrating 1% positivity in tumors and 40% positivity in non-tumor tissues. Gene set enrichment analysis of cervical tumors overexpressing FEN1 revealed its association with enhanced growth factor signaling, immune response inhibition and extracellular matrix remodeling, whereas tumors with low ENDOU expression exhibited inhibition of epithelial development and differentiation processes. Taken together, the results of the present study demonstrate the feasibility of the integrative meta-analysis approach to identify relevant biomarkers associated with cervical carcinogenesis. Thus, FEN1 and ENDOU may be useful diagnostic biomarkers for squamous cervical carcinoma. However, further studies are required to determine their diagnostic performance in larger patient cohorts and validate the results presented here.

Combination of downregulating FEN1 and PD‐1 blockade enhances antitumor activity of CD8+ T cells against HNSCC cells in vitro

“…Flap endonuclease‐1 (FEN1), a prototypical member of the RAD2‐superfamily required for proficient DNA replication and the repair of DNA damage, is one of the key tumor suppressor targets for HNSCC predicted by our research group 13 . Interestingly, multiple recent studies have implicated its association with immune response inhibition 14,15 . More surprisingly, in our recent study, we found that overexpressed FEN1 in the tissues and cells of HNSCC was detected, which was associated with an inhibitory immune microenvironment; down‐regulation of FEN1 could not only inhibit PD‐L1 expression, but also exhibit a potential effect on upregulating HLA expression through the interference gamma (IFN‐γ)/Janus kinase (JAK)/signal transmitter and activator transcription 1 (STAT1) pathway 16 .…”

“…13 Interestingly, multiple recent studies have implicated its association with immune response inhibition. 14,15 More surprisingly, in our recent study, we found that overexpressed FEN1 in the tissues and cells of HNSCC was detected, which was associated with an inhibitory immune microenvironment; down-regulation of FEN1 could not only inhibit PD-L1 expression, but also exhibit a potential effect on upregulating HLA expression through the interference gamma (IFN-γ)/Janus kinase (JAK)/signal transmitter and activator transcription 1 (STAT1) pathway. 16 These studies indicate potential links between FEN1 inhibition and enhanced antitumor immunity.…”

The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging

“…EndoU family of endonucleases have been implicated in many processes, including as a tumor biomarker in human beings 77 – 79 , immune response in mice 51 , ER morphology in Xenopus 80 , neurodegeneration in Drosophila 50 , cold tolerance, nucleotide metabolism, lifespan and germline immortality in C. elegans 61 , 81 , 82 , and viral replication and pathogenicity 83 – 85 . Our findings reveal another role of EndoU family proteins in lipolysis and provide mechanistic insights for such a specific function.…”

Microbiota changes: the unseen players in cervical cancer progression

“…However, its reliability is debatable due to its dependence on human interpretation ( Long et al, 2017 ). Despite several alternate cervical cancer screening methods proposed over the years such as cytological testing alone, standalone hrHPV testing, and cytological + hrHPV combination testing (co-testing) ( Curry et al, 2018 ; Kim et al, 2018 ; Terasawa et al, 2022 ), the 5 years survival rate remains a dismal 66% ( Long et al, 2017 ; Basic et al, 2021 ; Qu et al, 2021 ; Hou et al, 2022 ).…”