Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Expression of MCMs in Endometrial Cancer and its Biological Correlation Analysis

Author(s): Yu Zhen, Hanlin Fu, Lulu Si, Tianjiao Lai, Danxia Chu and Ruixia Guo*

Volume 26, Issue 4, 2023

Published on: 05 September, 2022

Page: [815 - 825] Pages: 11

DOI: 10.2174/1386207325666220705111240

Price: $65

Abstract

Purpose: Minichromosome maintenance (MCM) has been demonstrated to be involved in tumorigenesis and pathogenesis of many cancer types. However, the role of MCMs in endometrial cancer (EC) has not been elucidated.

Materials and Methods: We first employed GEPIA, cBioPortal, and R software to perform the differential expression analysis, survival analysis, and gene alteration analysis of the MCMs family. Then, GSE17025 and GSE63678 datasets and CTPAC were used to verify the mRNA and protein expression levels of MCM4. In addition, the internal mechanism of the MCM4 was investigated by comparing MCM4 expression-correlated differentially expressed genes (DEGs) from GEPIA and MCM4-interacted genes from STRING. Last, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify MCM4-related biological processes.

Results: Compared with normal tissues, only MCM2 and MCM4 expression were significantly upregulated in EC tissues. High expression of MCM4 was related to worse clinicopathological features and poor prognosis in EC cohorts. Additionally, a certain degree of gene alterations in the MCM2-7 gene was observed. By comparing MCM4 expression-correlated DEGs and MCM4- interacted genes, six genes were obtained: SSRP1, ORC1, GINS1, CDK2, DBF4 and GINS3. Functional enrichment analysis suggested that MCM4 may be involved in regulating the biological processes of DNA replication and the p53 signaling pathway.

Conclusion: This was the first comprehensive study to disclose the biological effects of MCMs in EC, indicating that MCM4 could be used as a new prognostic biomarker and potential therapeutic target for EC.

Keywords: Minichromosome maintenance family, endometrial cancer (EC), survival prognosis, genetic alterations, enrichment analysis, DNA replication.

« Previous Next »
Graphical Abstract

[1]
Amant, F.; Moerman, P.; Neven, P.; Timmerman, D.; Van Limbergen, E.; Vergote, I. Endometrial cancer. Lancet, 2005, 366(9484), 491-505.
[http://dx.doi.org/10.1016/S0140-6736(05)67063-8] [PMID: 16084259]
[2]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin., 2013, 63(1), 11-30.
[http://dx.doi.org/10.3322/caac.21166] [PMID: 23335087]
[3]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin., 2021, 71(1), 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[4]
Brooks, R.A.; Fleming, G.F.; Lastra, R.R.; Lee, N.K.; Moroney, J.W.; Son, C.H.; Tatebe, K.; Veneris, J.L. Current recommendations and recent progress in endometrial cancer. CA Cancer J. Clin., 2019, 69(4), 258-279.
[http://dx.doi.org/10.3322/caac.21561] [PMID: 31074865]
[5]
Basu, A.K. DNA damage, mutagenesis and cancer. Int. J. Mol. Sci., 2018, 19(4), 970.
[http://dx.doi.org/10.3390/ijms19040970]
[6]
Lord, C.J.; Ashworth, A. The DNA damage response and cancer therapy. Nature, 2012, 481(7381), 287-294.
[http://dx.doi.org/10.1038/nature10760]
[7]
Kearsey, S.E.; Labib, K. MCM proteins: Evolution, properties, and role in DNA replication. Biochim. Biophys. Acta, 1998, 1398(2), 113-136.
[http://dx.doi.org/10.1016/S0167-4781(98)00033-5] [PMID: 9689912]
[8]
Tye, B.K. MCM proteins in DNA replication. Annu. Rev. Biochem., 1999, 68(1), 649-686.
[http://dx.doi.org/10.1146/annurev.biochem.68.1.649] [PMID: 10872463]
[9]
Issac, M.S.M.; Yousef, E.; Tahir, M.R.; Gaboury, L.A. MCM2, MCM4, and MCM6 in breast cancer: Clinical utility in diagnosis and prognosis. Neoplasia, 2019, 21(10), 1015-1035.
[http://dx.doi.org/10.1016/j.neo.2019.07.011] [PMID: 31476594]
[10]
Byun, W.S.; Kim, S.; Shin, Y.H.; Kim, W.K.; Oh, D.C.; Lee, S.K. Antitumor activity of Ohmyungsamycin A through the regulation of the Skp2-p27 axis and MCM4 in human colorectal cancer cells. J. Nat. Prod., 2020, 83(1), 118-126.
[http://dx.doi.org/10.1021/acs.jnatprod.9b00918] [PMID: 31894983]
[11]
Guo, F.; Kong, W.N.; Feng, Y.C.; Lv, J.; Zhao, G.; Wu, H.L.; Ai, L.; Zhou, X.; Cai, X.L.; Sun, W.; Ma, X.M. Comprehensive analysis of the expression and prognosis for MCMs in human gastric cancer. Technol. Cancer Res. Treat., 2020, 19, 1533033820970688.
[http://dx.doi.org/10.1177/1533033820970688] [PMID: 33167799]
[12]
Kikuchi, J.; Kinoshita, I.; Shimizu, Y.; Kikuchi, E.; Takeda, K.; Aburatani, H.; Oizumi, S.; Konishi, J.; Kaga, K.; Matsuno, Y.; Birrer, M.J.; Nishimura, M.; Dosaka-Akita, H. Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer. Lung Cancer, 2011, 72(2), 229-237.
[http://dx.doi.org/10.1016/j.lungcan.2010.08.020] [PMID: 20884074]
[13]
Choy, B.; LaLonde, A.; Que, J.; Wu, T.; Zhou, Z. MCM4 and MCM7, potential novel proliferation markers, significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma, and precancerous lesions. Hum. Pathol., 2016, 57, 126-135.
[http://dx.doi.org/10.1016/j.humpath.2016.07.013] [PMID: 27476776]
[14]
Xie, L.; Li, T.; Yang, L.H. E2F2 induces MCM4, CCNE2 and WHSC1 upregulation in ovarian cancer and predicts poor overall survival. Eur. Rev. Med. Pharmacol. Sci., 2017, 21(9), 2150-2156.
[PMID: 28537669]
[15]
Ishimi, Y.; Okayasu, I.; Kato, C.; Kwon, H.J.; Kimura, H.; Yamada, K.; Song, S.Y. Enhanced expression of Mcm proteins in cancer cells derived from uterine cervix. Eur. J. Biochem., 2003, 270(6), 1089-1101.
[http://dx.doi.org/10.1046/j.1432-1033.2003.03440.x] [PMID: 12631269]
[16]
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.
[http://dx.doi.org/10.1093/nar/gkx247] [PMID: 28407145]
[17]
Gao, J.; Aksoy, B.A.; Dogrusoz, U. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal., 2013, 6(269)
[http://dx.doi.org/10.1126/scisignal.2004088]
[18]
Barrett, T.; Wilhite, S.E.; Ledoux, P.; Evangelista, C.; Kim, I.F.; Tomashevsky, M.; Marshall, K.A.; Phillippy, K.H.; Sherman, P.M.; Holko, M.; Yefanov, A.; Lee, H.; Zhang, N.; Robertson, C.L.; Serova, N.; Davis, S.; Soboleva, A. NCBI GEO: Archive for functional genomics data sets-update. Nucleic Acids Res., 2013, 41(Database issue), D991-D995.
[http://dx.doi.org/10.1093/nar/gks1193] [PMID: 23193258]
[19]
Chandrashekar, D.S.; Bashel, B.; Balasubramanya, S.A.H.; Creighton, C.J.; Ponce-Rodriguez, I.; Chakravarthi, B.V.S.K.; Varambally, S. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8), 649-658.
[http://dx.doi.org/10.1016/j.neo.2017.05.002] [PMID: 28732212]
[20]
Navani, S. Manual evaluation of tissue microarrays in a high-throughput research project: The contribution of Indian surgical pathology to the Human Protein Atlas (HPA) project. Proteomics, 2016, 16(8), 1266-1270.
[http://dx.doi.org/10.1002/pmic.201500409] [PMID: 26748468]
[21]
Szklarczyk, D.; Morris, J.H.; Cook, H.; Kuhn, M.; Wyder, S.; Simonovic, M.; Santos, A.; Doncheva, N.T.; Roth, A.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res., 2017, 45(D1), D362-D368.
[http://dx.doi.org/10.1093/nar/gkw937] [PMID: 27924014]
[22]
Bardou, P.; Mariette, J.; Escudié, F.; Djemiel, C.; Klopp, C. jvenn: An interactive Venn diagram viewer. BMC Bioinformatics, 2014, 15(1), 293.
[http://dx.doi.org/10.1186/1471-2105-15-293] [PMID: 25176396]
[23]
Jeruzalmi, D.; O’Donnell, M.; Kuriyan, J. Crystal structure of the processivity clamp loader gamma (gamma) complex of E. coli DNA polymerase III. Cell, 2001, 106(4), 429-441.
[http://dx.doi.org/10.1016/S0092-8674(01)00463-9] [PMID: 11525729]
[24]
Ishimi, Y. A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J. Biol. Chem., 1997, 272(39), 24508-24513.
[http://dx.doi.org/10.1074/jbc.272.39.24508] [PMID: 9305914]
[25]
Tatsumi, R.; Ishimi, Y. An MCM4 mutation detected in cancer cells affects MCM4/6/7 complex formation. J. Biochem., 2017, 161(3), 259-268.
[http://dx.doi.org/10.1093/jb/mvw065å] [PMID: 27794528]
[26]
Wang, X.; Ishimi, Y. Function of the amino-terminal region of human MCM4 in helicase activity. J. Biochem., 2018, 164(6), 449-460.
[http://dx.doi.org/10.1093/jb/mvy072] [PMID: 30184107]
[27]
Stoeber, K.; Tlsty, T.D.; Happerfield, L.; Thomas, G.A.; Romanov, S.; Bobrow, L.; Williams, E.D.; Williams, G.H. DNA replication licensing and human cell proliferation. J. Cell Sci., 2001, 114(Pt 11), 2027-2041.
[http://dx.doi.org/10.1242/jcs.114.11.2027] [PMID: 11493639]
[28]
Xu, Y.; Yang, X.; Si, T.; Yu, H.; Li, Y.; Xing, W.; Guo, Z. MCM4 in human hepatocellular carcinoma: A potent prognostic factor associated with cell proliferation. Biosci. Trends, 2021, 15(2), 100-106.
[http://dx.doi.org/10.5582/bst.2021.01016] [PMID: 33716256]
[29]
Saini, S.; Hirata, H.; Majid, S.; Dahiya, R. Functional significance of cytochrome P450 1B1 in endometrial carcinogenesis. Cancer Res., 2009, 69(17), 7038-7045.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1691] [PMID: 19690133]
[30]
Enomoto, T.; Fujita, M.; Inoue, M.; Rice, J.M.; Nakajima, R.; Tanizawa, O.; Nomura, T. Alterations of the p53 tumor suppressor gene and its association with activation of the c-K-ras-2 protooncogene in premalignant and malignant lesions of the human uterine endometrium. Cancer Res., 1993, 53(8), 1883-1888.
[PMID: 8385572]
[31]
Yun, H.J.; Hyun, S.K.; Park, J.H.; Kim, B.W.; Kwon, H.J. Widdrol activates DNA damage checkpoint through the signaling Chk2-p53-Cdc25A-p21-MCM4 pathway in HT29 cells. Mol. Cell. Biochem., 2012, 363(1-2), 281-289.
[http://dx.doi.org/10.1007/s11010-011-1180-z] [PMID: 22160829]

Rights & Permissions Print Cite
Article Metrics
30
3
© 2024 Bentham Science Publishers | Privacy Policy