Nuclear factor IB is downregulated in vulvar squamous cell carcinoma (VSCC): Unravelling differentially expressed genes in VSCC through gene expression dataset analysis

Dasgupta,Shatavisha; Ewing‑Graham,Patricia C.; Van Den Bosch,Thierry P.P.; Swagemakers,Sigrid M.A.; Santegoets,Lindy A.M.; Van Doorn,Helena C.; Van Der Spek,Peter J.; Koljenović,Senada; Van Kemenade,Folkert J.

doi:10.3892/ol.2021.12642

Nuclear factor IB is downregulated in vulvar squamous cell carcinoma (VSCC): Unravelling differentially expressed genes in VSCC through gene expression dataset analysis

Authors:
- Shatavisha Dasgupta
- Patricia C. Ewing‑Graham
- Thierry P.P. Van Den Bosch
- Sigrid M.A. Swagemakers
- Lindy A.M. Santegoets
- Helena C. Van Doorn
- Peter J. Van Der Spek
- Senada Koljenović
- Folkert J. Van Kemenade
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Affiliations: Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3000CA Rotterdam, The Netherlands, Department of Obstetrics and Gynecology, Reinier de Graaf Gasthuis, 2625 AD Delft, The Netherlands, Department of Gynecologic Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, 3000CA Rotterdam, The Netherlands
Published online on: March 16, 2021 https://doi.org/10.3892/ol.2021.12642
Article Number: 381
Copyright: © Dasgupta et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Vulvar squamous cell carcinoma (VSCC) comprises two distinct etiopathological subtypes: i) Human papilloma virus (HPV)‑related VSCC, which arises via the precursor high grade squamous intraepithelial lesion (HSIL); and ii) HPV‑independent VSCC, which arises via precursor, differentiated vulvar intraepithelial neoplasia (dVIN), driven by TP53 mutations. However, the mechanism of carcinogenesis of VSCC is poorly understood. The current study aimed to gain insight into VSCC carcinogenesis by identifying differentially expressed genes (DEGs) for each VSCC subtype. The expression of certain DEGs was then further assessed by performing immunohistochemistry (IHC) on whole tissue sections of VSCC and its precursors. Statistical analysis of microarrays was performed on two independent gene expression datasets (GSE38228 and a study from Erasmus MC) on VSCC and normal vulva. DEGs were identified that were similarly (up/down) regulated with statistical significance in both datasets. For HPV‑related VSCCs, this constituted 88 DEGs, and for HPV‑independent VSCCs, this comprised 46 DEGs. IHC was performed on VSCC (n=11), dVIN (n=6), HSIL (n=6) and normal vulvar tissue (n=7) with i) signal transducer and activator of transcription 1 (STAT1; an upregulated DEGs); ii) nuclear factor IB (NFIB; a downregulated DEG); iii) p16 (to determine the HPV status of tissues); and iv) p53 (to confirm the histological diagnoses). Strong and diffuse NFIB expression was observed in the basal and para‑basal layers of normal vulvar tissue, whereas NFIB expression was minimal or completely negative in dVIN and in both subtypes of VSCC. In contrast, no discernable difference was observed in STAT1 expression among normal vulvar tissue, dVIN, HSIL or VSCC. By leveraging bioinformatics, the current study identified DEGs that can facilitate research into VSCC carcinogenesis. The results suggested that NFIB is downregulated in VSCC and its relevance as a diagnostic/prognostic biomarker deserves further exploration.

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1	Prieske K, Alawi M, Oliveira-Ferrer L, Jaeger A, Eylmann K, Burandt E, Schmalfeldt B, Joosse SA and Woelber L: Genomic characterization of vulvar squamous cell carcinoma. Gynecol Oncol. 158:547–554. 2020. View Article : Google Scholar : PubMed/NCBI
2	Dasgupta S, Ewing-Graham PC, Swagemakers SMA, van der Spek PJ, van Doorn HC, Noordhoek Hegt V, Koljenović S and van Kemenade FJ: Precursor lesions of vulvar squamous cell carcinoma-histology and biomarkers: A systematic review. Crit Rev Oncol Hematol. 147:1028662020. View Article : Google Scholar : PubMed/NCBI
3	de Martel C, Georges D, Bray F, Ferlay J and Clifford GM: Global burden of cancer attributable to infections in 2018: A worldwide incidence analysis. Lancet Glob Health. 8:e180–e190. 2020. View Article : Google Scholar : PubMed/NCBI
4	Zeimet AG: Molecular characterization of vulvar squamous cell cancer: High time to gain ground. Gynecol Oncol. 158:519–520. 2020. View Article : Google Scholar : PubMed/NCBI
5	Han MR, Shin S, Park HC, Kim MS, Lee SH, Jung SH, Song SY, Lee SH and Chung YJ: Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva. Exp Mol Med. 50:e4422018. View Article : Google Scholar : PubMed/NCBI
6	Weberpals JI, Lo B, Duciaume MM, Spaans JN, Clancy AA, Dimitroulakos J, Goss GD and Sekhon HS: Vulvar squamous cell carcinoma (VSCC) as two diseases: HPV status identifies distinct mutational profiles including oncogenic fibroblast growth factor receptor 3. Clin Cancer Res. 23:4501–4510. 2017. View Article : Google Scholar : PubMed/NCBI
7	Nooij LS, Ter Haar NT, Ruano D, Rakislova N, van Wezel T, Smit VTHBM, Trimbos BJBMZ, Ordi J, van Poelgeest MIE and Bosse T: Genomic characterization of vulvar (Pre)cancers identifies distinct molecular subtypes with prognostic significance. Clin Cancer Res. 23:6781–6789. 2017. View Article : Google Scholar : PubMed/NCBI
8	Zieba S, Pouwer AW, Kowalik A, Zalewski K, Rusetska N, Bakuła-Zalewska E, Kopczyński J, Pijnenborg JMA, de Hullu JA and Kowalewska M: Somatic mutation profiling in premalignant lesions of vulvar squamous cell carcinoma. Int J Mol Sci. 21:48802020. View Article : Google Scholar
9	Williams EA, Werth AJ, Sharaf R, Montesion M, Sokol ES, Pavlick DC, McLaughlin-Drubin M, Erlich R, Toma H, Williams KJ, et al: Vulvar squamous cell carcinoma: Comprehensive genomic profling of HPV⁺ versus HPV-forms reveals distinct sets of potentially actionable molecular targets. JCO Precis Oncol. 4:647–661. 2020. View Article : Google Scholar
10	Tessier-Cloutier B, Kortekaas KE, Thompson E, Pors J, Chen J, Ho J, Prentice LM, McConechy MK, Chow C, Proctor L, et al: Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status. Mod Pathol. 33:1595–1605. 2020. View Article : Google Scholar : PubMed/NCBI
11	Tessier-Cloutier B, Pors J, Thompson E, Ho J, Prentice L, McConechy M, Aguirre-Hernandez R, Miller R, Leung S, Proctor L, et al: Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome. Mod Pathol. 34:508–518. 2021. View Article : Google Scholar : PubMed/NCBI
12	Ge Y, Zhang C, Xiao S, Liang L, Liao S, Xiang Y, Cao K, Chen H and Zhou Y: Identification of differentially expressed genes in cervical cancer by bioinformatics analysis. Oncol Lett. 16:2549–2558. 2018.PubMed/NCBI
13	Micci F, Panagopoulos I, Haugom L, Dahlback HS, Pretorius ME, Davidson B, Abeler VM, Tropé CG, Danielsen HE and Heim S: Genomic aberration patterns and expression profiles of squamous cell carcinomas of the vulva. Genes Chromosomes Cancer. 52:551–563. 2013. View Article : Google Scholar : PubMed/NCBI
14	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
15	Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, Guo Y, Stephens R, Baseler MW, Lane HC and Lempicki RA: DAVID bioinformatics resources: Expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 35((Web Server Issue)): W169–W175. 2007. View Article : Google Scholar : PubMed/NCBI
16	Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI
17	Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI
18	Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, et al: STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47D:D607–D613. 2019. View Article : Google Scholar
19	Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z: GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45W:W98–W102. 2017. View Article : Google Scholar
20	Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, et al: The lower anogenital squamous terminology standardization project for HPV-associated lesions: Background and consensus recommendations from the college of American pathologists and the American society for colposcopy and cervical pathology. Arch Pathol Lab Med. 136:1266–1297. 2012. View Article : Google Scholar : PubMed/NCBI
21	Kortekaas KE, Solleveld-Westerink N, Tessier-Cloutier B, Rutten TA, Poelgeest MIE, Gilks CB, Hoang LN and Bosse T: Performance of the pattern-based interpretation of p53 immunohistochemistry as a surrogate for TP53 mutations in vulvar squamous cell carcinoma. Histopathology. 77:92–99. 2020. View Article : Google Scholar : PubMed/NCBI
22	Heller DS, Day T, Allbritton JI, Scurry J, Radici G, Welch K and Preti M; ISSVD Difficult Pathologic Diagnoses Committee, : Diagnostic criteria for differentiated vulvar intraepithelial neoplasia and vulvar aberrant maturation. J Low Genit Tract Dis. 25:57–70. 2021. View Article : Google Scholar : PubMed/NCBI
23	Li Y, Sun C, Tan Y, Li L, Zhang H, Liang Y, Zeng J and Zou H: Transcription levels and prognostic significance of the NFI family members in human cancers. PeerJ. 8:e88162020. View Article : Google Scholar : PubMed/NCBI
24	Kim BR, Coyaud E, Laurent EMN, St-Germain J, Van de Laar E, Tsao MS, Raught B and Moghal N: Identification of the SOX2 interactome by BioID reveals EP300 as a mediator of SOX2-dependent squamous differentiation and lung squamous cell carcinoma growth. Mol Cell Proteomics. 16:1864–1888. 2017. View Article : Google Scholar : PubMed/NCBI
25	Brustmann H and Brunner A: Immunohistochemical expression of SOX2 in vulvar intraepithelial neoplasia and squamous cell carcinoma. Int J Gynecol Pathol. 32:323–328. 2013. View Article : Google Scholar : PubMed/NCBI
26	Wu S, Wu Y, Lu Y, Yue Y, Cui C, Yu M, Wang S, Liu M, Zhao Y and Sun Z: STAT1 expression and HPV16 viral load predict cervical lesion progression. Oncol Lett. 20:282020.PubMed/NCBI