Abnormal Spindle-like Microcephaly-associated Protein Promotes Proliferation by Regulating Cell Cycle in Epithelial Ovarian Cancer

Overview

Journal Gland Surg

Publisher AME Publishing Company

Specialty Endocrinology

Date 2022 May 9

PMID 35531115

Authors

Yiguo Wu

Yujuan You

Ling Chen

Yue Liu

Yujuan Liu

Weiming Lou

Fen Fu

Affiliations

Soon will be listed here.

Abstract

Background: Epithelial ovarian cancer (EOC) ranks first for female gynecological tumor-related deaths. Due to the limited efficacy of traditional chemotherapy strategies, potential therapeutic targets are urgently needed. Previous studies have reported a relationship between abnormal spindle-like microcephaly-associated protein (ASPM) and ovarian cancer based on immunohistochemistry (IHC) and bioinformatics analysis. However, the potential role of ASPM in the proliferation of ovarian cancer cells and its molecular mechanism remain to be elucidated. Therefore, we aimed to further investigate the potential role of ASPM and its underlying mechanism in EOC using integrated online databases, clinical samples, and cell models.

Methods: We used online databases (Gene Expression Profiling Interactive Analysis, Cbioportal and Kaplan-Meier Plotter) to analyze differential ASPM expression in ovarian carcinoma and explore its prognostic value in ovarian cancer (OvCa) patients. Immunohistochemistry staining based on a clinical tissue microarray (TMA) comprised 75 cases of EOC tissue and 5 cases of adjacent normal ovary tissue was used to detect the ASPM expression and analyze the relationship between ASPM expression and EOC characteristics. Various cell function experiments related to tumorigenesis were performed including the CCK8 assay, 5-ethynyl-2'-deoxyuridine (EdU), colony formation assay and Transwell assay in EOC cell models (A2780 and OVCAR3) with knocked down ASPM by small interfering RNA (siRNA) to observe its role. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was conducted to determine the signaling pathways in which ASPM was involved in the pathogenesis of ovarian cancer. Analysis of cell cycle distribution using flow cytometry was further performed to verify the pathways.

Results: The expression profile based on data from The Cancer Genome Atlas (TCGA) database confirmed ASPM expression in EOC was higher compared with normal tissue, and further analysis suggested that higher expression was correlated with worse patient prognosis. Immunohistochemical analysis further indicated that ASPM was highly expressed in OvCa tissues and associated with a higher pathological stage, grade, and positive lymphatic metastasis. Cell models with knocked down ASPM by small interfering RNA (siRNA) significantly inhibited proliferation and migration. KEGG pathway enrichment and cell cycle analysis showed that ASPM silencing could inhibit ovarian cancer cell proliferation via synthesis (S) phase arrest.

Conclusions: Our study confirmed that ASPM promoted proliferation and caused S phase arrest in EOC cells. ASPM may become a potential molecular marker for early screening and a valuable therapeutic target in EOC.

Keywords: Abnormal spindle-like microcephaly-associated protein (ASPM); epithelial ovarian cancer (EOC); prognosis; proliferation.

Citing Articles

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References

Hu G, Yan Z, Zhang C, Cheng M, Yan Y, Wang Y . FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression. J Exp Clin Cancer Res. 2019; 38(1):188. PMC: 6507024. DOI: 10.1186/s13046-019-1202-3. View

Letard P, Drunat S, Vial Y, Duerinckx S, Ernault A, Amram D . Autosomal recessive primary microcephaly due to ASPM mutations: An update. Hum Mutat. 2017; 39(3):319-332. DOI: 10.1002/humu.23381. View

Hsu C, Liao W, Chan T, Chen W, Lee C, Shan Y . The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis. J Pathol. 2019; 249(4):498-508. PMC: 6899738. DOI: 10.1002/path.5341. View

Pai V, Hsu C, Chan T, Liao W, Chuu C, Chen W . ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling. Oncogene. 2018; 38(8):1340-1353. DOI: 10.1038/s41388-018-0497-4. View

An X, Huang Y, Zhao P . Expression of ASPM in colonic adenocarcinoma and its clinicopathologic significance. Int J Clin Exp Pathol. 2020; 10(8):8968-8973. PMC: 6965391. View

Zhou J, Wang H, Sun W, Han N, Chen L . ASPM is a predictor of overall survival and has therapeutic potential in endometrial cancer. Am J Transl Res. 2020; 12(5):1942-1953. PMC: 7270042. View

Siegel R, Miller K, Fuchs H, Jemal A . Cancer Statistics, 2021. CA Cancer J Clin. 2021; 71(1):7-33. DOI: 10.3322/caac.21654. View

Wu P, Heins Z, Muller J, Katsnelson L, de Bruijn I, Abeshouse A . Integration and Analysis of CPTAC Proteomics Data in the Context of Cancer Genomics in the cBioPortal. Mol Cell Proteomics. 2019; 18(9):1893-1898. PMC: 6731080. DOI: 10.1074/mcp.TIR119.001673. View

Ye Q, Lei L, Aili A . Identification of potential targets for ovarian cancer treatment by systematic bioinformatics analysis. Eur J Gynaecol Oncol. 2015; 36(3):283-9. View

10.

Xu Z, Zhang Q, Luh F, Jin B, Liu X . Overexpression of the ASPM gene is associated with aggressiveness and poor outcome in bladder cancer. Oncol Lett. 2019; 17(2):1865-1876. PMC: 6341836. DOI: 10.3892/ol.2018.9762. View

11.

Johnson M, Sun X, Kodani A, Borges-Monroy R, Girskis K, Ryu S . Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size. Nature. 2018; 556(7701):370-375. PMC: 6095461. DOI: 10.1038/s41586-018-0035-0. View

12.

Kouprina N, Pavlicek A, Collins N, Nakano M, Noskov V, Ohzeki J . The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein. Hum Mol Genet. 2005; 14(15):2155-65. DOI: 10.1093/hmg/ddi220. View

13.

Jiao X, Qin B, You P, Cai J, Zang Y . The prognostic value of TP53 and its correlation with EGFR mutation in advanced non-small cell lung cancer, an analysis based on cBioPortal data base. Lung Cancer. 2018; 123:70-75. DOI: 10.1016/j.lungcan.2018.07.003. View

14.

Gao J, Aksoy B, Dogrusoz U, Dresdner G, Gross B, Sumer S . Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6(269):pl1. PMC: 4160307. DOI: 10.1126/scisignal.2004088. View

15.

Ning G, Huang Y, Zhen L, Xu W, Jiao Q, Yang F . Transcriptional expressions of Chromobox 1/2/3/6/8 as independent indicators for survivals in hepatocellular carcinoma patients. Aging (Albany NY). 2018; 10(11):3450-3473. PMC: 6286817. DOI: 10.18632/aging.101658. View

16.

Saeaib N, Peeyananjarassri K, Liabsuetrakul T, Buhachat R, Myriokefalitaki E . Hormone replacement therapy after surgery for epithelial ovarian cancer. Cochrane Database Syst Rev. 2020; 1:CD012559. PMC: 7027384. DOI: 10.1002/14651858.CD012559.pub2. View

17.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

18.

Komatsu M, Yoshimaru T, Matsuo T, Kiyotani K, Miyoshi Y, Tanahashi T . Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis. Int J Oncol. 2012; 42(2):478-506. DOI: 10.3892/ijo.2012.1744. View

19.

Zhou W, Sun W, Yung M, Dai S, Cai Y, Chen C . Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance. Oncogene. 2018; 37(29):3981-3997. PMC: 6054535. DOI: 10.1038/s41388-018-0238-8. View

20.

Alsiary R, Bruning-Richardson A, Bond J, Morrison E, Wilkinson N, Bell S . Deregulation of microcephalin and ASPM expression are correlated with epithelial ovarian cancer progression. PLoS One. 2014; 9(5):e97059. PMC: 4022499. DOI: 10.1371/journal.pone.0097059. View