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Combinatorial Chemistry & High Throughput Screening

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

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Research Article

FEN1 Status and Its Correlation with Clinicopathologic Characteristic in Colorectal Cancer

Author(s): Yundi Guo, Zixuan Du, Yuanshuai Zhou, Haijun Sun, Rui Liang, Min-Xuan Sun, Zaixiang Tang* and Song-Bai Liu*

Volume 25, Issue 6, 2022

Published on: 01 April, 2021

Page: [1040 - 1046] Pages: 7

DOI: 10.2174/1386207324666210401113351

Abstract

Objective: The goal of this study was to investigate the status of FEN1 in colorectal cancer (CRC) and determine the potential correlation between FEN1 expression level and clinicopathological parameters in CRC patients.

Methods: Expression of FEN1 in CRC tissue on tissue microarray was detected using immunohistochemistry (IHC). The relationship between FEN1 expression status and clinicopathologic characteristics of CRC was analyzed by the Chi-square test. The survival data of TCGA Colon Cancer (COAD) were obtained from ucsc xena browser (https://xenabrowser.net/). Patients were separated into higher and lower expression groups by median FEN1 expression. The association with prognosis of CRC patients was determined by Kaplan-Meier survival analysis with Log-rank test.

Results: FEN1expression level and cellular localization had wide variability among different individuals; we classified the staining results into four types: both positive in nucleus and cytoplasm, both negative in nucleus and cytoplasm, only positive in the nucleus, only positive in the cytoplasm. Moreover, FEN1 expression status only correlated with patient’s metastasis status, and the patients in the NLCL group showed more risk of cancer cell metastasis.

Conclusion: Our results indicate that FEN1 expression level and cellular localization had wide variability in CRC and is not a promising biomarker in CRC.

Keywords: Colorectal cancer, FEN1, clinicopathologic characteristic, prognosis, IHC, COAD.

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[1]
Kuipers, E.J.; Grady, W.M.; Lieberman, D.; Seufferlein, T.; Sung, J.J.; Boelens, P.G.; van de Velde, C.J.; Watanabe, T. Colorectal cancer. Nat. Rev. Dis. Primers, 2015, 1, 15065.
[http://dx.doi.org/10.1038/nrdp.2015.65] [PMID: 27189416]
[2]
Lech, G.; Słotwiński, R.; Słodkowski, M.; Krasnodębski, I.W. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances. World J. Gastroenterol., 2016, 22(5), 1745-1755.
[http://dx.doi.org/10.3748/wjg.v22.i5.1745] [PMID: 26855534]
[3]
Ogunwobi, O.O.; Mahmood, F.; Akingboye, A. Biomarkers in Colorectal Cancer: Current Research and Future Prospects. Int. J. Mol. Sci., 2020, 21(15)E5311
[http://dx.doi.org/10.3390/ijms21155311] [PMID: 32726923]
[4]
Hases, L.; Ibrahim, A.; Chen, X.; Liu, Y.; Hartman, J.; Williams, C. The Importance of Sex in the Discovery of Colorectal Cancer Prognostic Biomarkers. Int. J. Mol. Sci., 2021, 22(3), 1354.
[http://dx.doi.org/10.3390/ijms22031354] [PMID: 33572952]
[5]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[6]
Pirim, D. Integrative analyses of molecular pathways and key candidate biomarkers associated with colorectal cancer. Cancer Biomark., 2020, 27(4), 555-568.
[http://dx.doi.org/10.3233/CBM-191263] [PMID: 32176635]
[7]
Gherman, A.; Balacescu, L.; Gheorghe-Cetean, S.; Vlad, C.; Balacescu, O.; Irimie, A.; Lisencu, C. Current and New Predictors for Treatment Response in Metastatic Colorectal Cancer. The Role of Circulating miRNAs as Biomarkers. Int. J. Mol. Sci., 2020, 21(6)E2089
[http://dx.doi.org/10.3390/ijms21062089] [PMID: 32197436]
[8]
Bresalier, R.S.; Grady, W.M.; Markowitz, S.D.; Nielsen, H.J.; Batra, S.K.; Lampe, P.D. Biomarkers for Early Detection of Colorectal Cancer: The Early Detection Research Network, a Framework for Clinical Translation. Cancer Epidemiol. Biomarkers Prev., 2020, 29(12), 2431-2440.
[http://dx.doi.org/10.1158/1055-9965.EPI-20-0234] [PMID: 32299850]
[9]
Malla, S.B.; Fisher, D.J.; Domingo, E.; Blake, A.; Hassanieh, S.; Redmond, K.L.; Richman, S.D.; Youdell, M.; Walker, S.M.; Logan, G.E.; Chatzipli, A.; Amirkhah, R.; Humphries, M.P.; Craig, S.G.; McDermott, U.; Seymour, M.T.; Morton, D.G.; Quirke, P.; West, N.P.; Salto-Tellez, M.; Kennedy, R.D.; Johnston, P.G.; Tomlinson, I.; Koelzer, V.H.; Campo, L.; Kaplan, R.S.; Longley, D.B.; Lawler, M.; Maughan, T.S.; Brown, L.C.; Dunne, P.D.S. CORT consortium. In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer. Clin. Cancer Res., 2021, 27(1), 288-300.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-3237] [PMID: 33028592]
[10]
Shigeyasu, K.; Toden, S.; Ozawa, T.; Matsuyama, T.; Nagasaka, T.; Ishikawa, T.; Sahoo, D.; Ghosh, P.; Uetake, H.; Fujiwara, T.; Goel, A. The PVT1 lncRNA is a novel epigenetic enhancer of MYC, and a promising risk-stratification biomarker in colorectal cancer. Mol. Cancer, 2020, 19(1), 155.
[http://dx.doi.org/10.1186/s12943-020-01277-4] [PMID: 33148262]
[11]
Sveen, A.; Kopetz, S.; Lothe, R.A. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat. Rev. Clin. Oncol., 2020, 17(1), 11-32.
[http://dx.doi.org/10.1038/s41571-019-0241-1] [PMID: 31289352]
[12]
Kleeman, S.O.; Koelzer, V.H.; Jones, H.J.; Vazquez, E.G.; Davis, H.; East, J.E.; Arnold, R.; Koppens, M.A.; Blake, A.; Domingo, E.; Cunningham, C.; Beggs, A.D.; Pestinger, V.; Loughrey, M.B.; Wang, L.M.; Lannagan, T.R.; Woods, S.L.; Worthley, D.; Consortium, S.C.; Tomlinson, I.; Dunne, P.D.; Maughan, T.; Leedham, S.J. Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification. Gut, 2020, 69(6), 1092-1103.
[http://dx.doi.org/10.1136/gutjnl-2019-319126] [PMID: 31563876]
[13]
Dekker, E.; Tanis, P.J.; Vleugels, J.L.A.; Kasi, P.M.; Wallace, M.B. Colorectal cancer. Lancet, 2019, 394(10207), 1467-1480.
[http://dx.doi.org/10.1016/S0140-6736(19)32319-0] [PMID: 31631858]
[14]
Cho, Y.H.; Ro, E.J.; Yoon, J.S.; Mizutani, T.; Kang, D.W.; Park, J.C.; Il Kim, T.; Clevers, H.; Choi, K.Y. 5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation. Nat. Commun., 2020, 11(1), 5321.
[http://dx.doi.org/10.1038/s41467-020-19173-2] [PMID: 33087710]
[15]
Daitoku, N.; Miyamoto, Y.; Sakamoto, Y.; Tokunaga, R.; Hiyoshi, Y.; Nagai, Y.; Iwatsuki, M.; Iwagami, S.; Yoshida, N.; Baba, H. Prognostic significance of serum p53 antibody according to KRAS status in metastatic colorectal cancer patients. Int. J. Clin. Oncol., 2020, 25(4), 651-659.
[http://dx.doi.org/10.1007/s10147-019-01599-4] [PMID: 31834556]
[16]
Deng, X.; Li, S.; Kong, F.; Ruan, H.; Xu, X.; Zhang, X.; Wu, Z.; Zhang, L.; Xu, Y.; Yuan, H.; Peng, H.; Yang, D.; Guan, M. Long noncoding RNA PiHL regulates p53 protein stability through GRWD1/RPL11/MDM2 axis in colorectal cancer. Theranostics, 2020, 10(1), 265-280.
[http://dx.doi.org/10.7150/thno.36045] [PMID: 31903119]
[17]
Najumudeen, A.K.; Ceteci, F.; Fey, S.K.; Hamm, G.; Steven, R.T.; Hall, H.; Nikula, C.J.; Dexter, A.; Murta, T.; Race, A.M.; Sumpton, D.; Vlahov, N.; Gay, D.M.; Knight, J.R.P.; Jackstadt, R.; Leach, J.D.G.; Ridgway, R.A.; Johnson, E.R.; Nixon, C.; Hedley, A.; Gilroy, K.; Clark, W.; Malla, S.B.; Dunne, P.D.; Rodriguez-Blanco, G.; Critchlow, S.E.; Mrowinska, A.; Malviya, G.; Solovyev, D.; Brown, G.; Lewis, D.Y.; Mackay, G.M.; Strathdee, D.; Tardito, S.; Gottlieb, E.; Takats, Z.; Barry, S.T.; Goodwin, R.J.A.; Bunch, J.; Bushell, M.; Campbell, A.D.; Sansom, O.J. CRUK Rosetta Grand Challenge Consortium. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nat. Genet., 2021, 53(1), 16-26.
[http://dx.doi.org/10.1038/s41588-020-00753-3] [PMID: 33414552]
[18]
Jiffry, J.; Thavornwatanayong, T.; Rao, D.; Fogel, E.J.; Saytoo, D.; Nahata, R.; Guzik, H.; Chaudhary, I.; Augustine, T.; Goel, S.; Maitra, R. Oncolytic Reovirus (pelareorep) Induces Autophagy in KRAS-mutated Colorectal Cancer. Clin. Cancer Res., 2021, 27(3), 865-876.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-2385] [PMID: 33168658]
[19]
Liu, J.; Ke, F.; Chen, T.; Zhou, Q.; Weng, L.; Tan, J.; Shen, W.; Li, L.; Zhou, J.; Xu, C.; Cheng, H.; Zhou, J. MicroRNAs that regulate PTEN as potential biomarkers in colorectal cancer: a systematic review. J. Cancer Res. Clin. Oncol., 2020, 146(4), 809-820.
[http://dx.doi.org/10.1007/s00432-020-03172-3] [PMID: 32146564]
[20]
Zhang, Y.; Liu, X.; Zhang, J.; Xu, Y.; Shao, J.; Hu, Y.; Shu, P.; Cheng, H. Inhibition of miR-19a partially reversed the resistance of colorectal cancer to oxaliplatin via PTEN/PI3K/AKT pathway. Aging (Albany NY), 2020, 12(7), 5640-5650.
[http://dx.doi.org/10.18632/aging.102929] [PMID: 32209726]
[21]
Harrington, J.J.; Lieber, M.R. The characterization of a mammalian DNA structure-specific endonuclease. EMBO J., 1994, 13(5), 1235-1246.
[http://dx.doi.org/10.1002/j.1460-2075.1994.tb06373.x] [PMID: 8131753]
[22]
Shen, B.; Nolan, J.P.; Sklar, L.A.; Park, M.S. Essential amino acids for substrate binding and catalysis of human flap endonuclease 1. J. Biol. Chem., 1996, 271(16), 9173-9176.
[http://dx.doi.org/10.1074/jbc.271.16.9173] [PMID: 8621570]
[23]
Kim, K.; Biade, S.; Matsumoto, Y. Involvement of flap endonuclease 1 in base excision DNA repair. J. Biol. Chem., 1998, 273(15), 8842-8848.
[http://dx.doi.org/10.1074/jbc.273.15.8842] [PMID: 9535864]
[24]
Liu, S.; Lu, G.; Ali, S.; Liu, W.; Zheng, L.; Dai, H.; Li, H.; Xu, H.; Hua, Y.; Zhou, Y.; Ortega, J.; Li, G.M.; Kunkel, T.A.; Shen, B. Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex. EMBO J., 2015, 34(13), 1829-1843.
[http://dx.doi.org/10.15252/embj.201489865] [PMID: 25921062]
[25]
Guo, Z.; Kanjanapangka, J.; Liu, N.; Liu, S.; Liu, C.; Wu, Z.; Wang, Y.; Loh, T.; Kowolik, C.; Jamsen, J.; Zhou, M.; Truong, K.; Chen, Y.; Zheng, L.; Shen, B. Sequential posttranslational modifications program FEN1 degradation during cell-cycle progression. Mol. Cell, 2012, 47(3), 444-456.
[http://dx.doi.org/10.1016/j.molcel.2012.05.042] [PMID: 22749529]
[26]
Ali, S.; Zheng, L.; Shen, B. FEN1-mediated α-segment error editing during Okazaki fragment maturation. Cell Cycle, 2015, 14(12), 1767.
[http://dx.doi.org/10.1080/15384101.2015.1046306] [PMID: 26039417]
[27]
Isohookana, J.; Haapasaari, K.M.; Soini, Y.; Leppänen, J.; Karihtala, P. Proteins of the retinoblastoma pathway, FEN1 and MGMT are novel potential prognostic biomarkers in pancreatic adenocarcinoma. Pathol. Res. Pract., 2018, 214(6), 840-847.
[http://dx.doi.org/10.1016/j.prp.2018.04.016] [PMID: 29735403]
[28]
Wang, J.; Zhou, L.; Li, Z.; Zhang, T.; Liu, W.; Liu, Z.; Yuan, Y.C.; Su, F.; Xu, L.; Wang, Y.; Zhou, X.; Xu, H.; Hua, Y.; Wang, Y.J.; Zheng, L.; Teng, Y.E.; Shen, B. YY1 suppresses FEN1 over-expression and drug resistance in breast cancer. BMC Cancer, 2015, 15, 50.
[http://dx.doi.org/10.1186/s12885-015-1043-1] [PMID: 25885449]
[29]
Abdel-Fatah, T.M.; Russell, R.; Albarakati, N.; Maloney, D.J.; Dorjsuren, D.; Rueda, O.M.; Moseley, P.; Mohan, V.; Sun, H.; Abbotts, R.; Mukherjee, A.; Agarwal, D.; Illuzzi, J.L.; Jadhav, A.; Simeonov, A.; Ball, G.; Chan, S.; Caldas, C.; Ellis, I.O.; Wilson, D.M., III; Madhusudan, S. Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer. Mol. Oncol., 2014, 8(7), 1326-1338.
[http://dx.doi.org/10.1016/j.molonc.2014.04.009] [PMID: 24880630]
[30]
Balakrishnan, L.; Bambara, R.A. Flap endonuclease 1. Annu. Rev. Biochem., 2013, 82, 119-138.
[http://dx.doi.org/10.1146/annurev-biochem-072511-122603] [PMID: 23451868]
[31]
Li, J.L.; Wang, J.P.; Chang, H.; Deng, S.M.; Du, J.H.; Wang, X.X.; Hu, H.J.; Li, D.Y.; Xu, X.B.; Guo, W.Q.; Song, Y.H.; Guo, Z.; Sun, M.X.; Wu, Y.W.; Liu, S.B. FEN1 inhibitor increases sensitivity of radiotherapy in cervical cancer cells. Cancer Med., 2019, 8(18), 7774-7780.
[http://dx.doi.org/10.1002/cam4.2615] [PMID: 31670906]
[32]
Wang, K.; Xie, C.; Chen, D. Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis. Int. J. Mol. Med., 2014, 33(5), 1268-1274.
[http://dx.doi.org/10.3892/ijmm.2014.1682] [PMID: 24590400]
[33]
Nikolova, T.; Christmann, M.; Kaina, B. FEN1 is overexpressed in testis, lung and brain tumors. Anticancer Res., 2009, 29(7), 2453-2459.
[PMID: 19596913]
[34]
Lu, X.; Liu, R.; Wang, M.; Kumar, A.K.; Pan, F.; He, L.; Hu, Z.; Guo, Z. Inhibition of FEN1 Increases Arsenic Trioxide-Induced ROS Accumulation and Cell Death: Novel Therapeutic Potential for Triple Negative Breast Cancer. Frontiers in oncology, 2020, 10, 425.
[35]
Xin, X.; Wen, T.; Gong, L.B.; Deng, M.M.; Hou, K.Z.; Xu, L.; Shi, S.; Qu, X.J.; Liu, Y.P.; Che, X.F.; Teng, Y.E. Inhibition of FEN1 Increases Arsenic Trioxide-Induced ROS Accumulation and Cell Death: Novel Therapeutic Potential for Triple Negative Breast Cancer. Front. Oncol., 2020, 10, 425.
[http://dx.doi.org/10.3389/fonc.2020.00425] [PMID: 32318339]
[36]
He, L.; Hu, Z.; Sun, Y.; Zhang, M.; Zhu, H.; Jiang, L.; Zhang, Q.; Mu, D.; Zhang, J.; Gu, L.; Yang, Y.; Pan, F.Y.; Jia, S.; Guo, Z. PRMT1 is critical to FEN1 expression and drug resistance in lung cancer cells. DNA Repair (Amst.), 2020, 95102953
[http://dx.doi.org/10.1016/j.dnarep.2020.102953] [PMID: 32861926]
[37]
Yang, M.; Guo, H.; Wu, C.; He, Y.; Yu, D.; Zhou, L.; Wang, F.; Xu, J.; Tan, W.; Wang, G.; Shen, B.; Yuan, J.; Wu, T.; Lin, D. Functional FEN1 polymorphisms are associated with DNA damage levels and lung cancer risk. Hum. Mutat., 2009, 30(9), 1320-1328.
[http://dx.doi.org/10.1002/humu.21060] [PMID: 19618370]
[38]
Azambuja, D.B.; Leguisamo, N.M.; Gloria, H.C.; Kalil, A.N.; Rhoden, E.; Saffi, J. Prognostic impact of changes in base excision repair machinery in sporadic colorectal cancer. Pathol. Res. Pract., 2018, 214(1), 64-71.
[http://dx.doi.org/10.1016/j.prp.2017.11.012] [PMID: 29254784]

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