دورية أكاديمية
E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2.
| العنوان: | E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2. |
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| المؤلفون: | Liu Q; Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China.; Department of General Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225000, Jiangsu Province, People's Republic of China., Song C; Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China.; Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China., Li J; Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China., Liu M; Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China., Fu L; Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China., Jiang J; Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China., Zeng Z; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guiyang, 550001, Guizhou, People's Republic of China., Zhu H; Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People's Republic of China. zhuhaitao@gmc.edu.cn. |
| المصدر: | Medical oncology (Northwood, London, England) [Med Oncol] 2022 Jun 18; Vol. 39 (9), pp. 124. Date of Electronic Publication: 2022 Jun 18. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Springer Country of Publication: United States NLM ID: 9435512 Publication Model: Electronic Cited Medium: Internet ISSN: 1559-131X (Electronic) Linking ISSN: 13570560 NLM ISO Abbreviation: Med Oncol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2011- : New York : Springer Original Publication: Northwood, Middlesex, England : Science and Technology Letters, c1994- |
| مواضيع طبية MeSH: | Deoxycytidine*/analogs & derivatives , Deoxycytidine*/pharmacology , Drug Resistance, Neoplasm* , E2F2 Transcription Factor*/genetics , E2F2 Transcription Factor*/metabolism , Pancreatic Neoplasms*/drug therapy , Pancreatic Neoplasms*/genetics , Pancreatic Neoplasms*/metabolism, Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Humans ; Ribonucleoside Diphosphate Reductase/biosynthesis ; Ribonucleoside Diphosphate Reductase/genetics ; Ribonucleoside Diphosphate Reductase/metabolism ; Up-Regulation/drug effects ; Gemcitabine |
| مستخلص: | Both pro-oncogenic and anti-oncogenic effects of E2F2 have been revealed in different malignancies. However, the precise role of E2F2 in pancreatic cancer, in particular in relation to therapeutic intervention with gemcitabine, remains unclear. In this study, the effect of E2F2 on the proliferation and cell cycle modulation of pancreatic cancer cells, and whether E2F2 plays a role in the treatment of pancreatic cancer cells by gemcitabine, were investigated. The expression of E2F2 in pancreatic cancer was assessed by various methods including bioinformatics prediction, Western blotting, and real-time PCR. The effect of E2F2 on the proliferation and cell cycling of pancreatic cancer cells was analyzed by tissue culture and flow cytometry. In addition, the effect of E2F2 on the intervention of pancreatic cancer by gemcitabine was investigated using both in vitro and in vivo approaches. The expression of E2F2 was found to be significantly increased in pancreatic cancer tissues and cell lines. The pathogenic capacity of E2F2 lied in the fact that this transcription factor promoted the transformation of pancreatic cancer cell cycle from G1-phase to S-phase, thus enhancing the proliferation of pancreatic cancer cells. Furthermore, the expression of E2F2 was increased in pancreatic cancer cells in the presence of gemcitabine, and the augmented expression of E2F2 upregulated the gemcitabine resistance-related gene RRM2 and its downstream signaling molecule deoxycytidine kinase (DCK). The resistance of pancreatic cancer cells to gemcitabine was confirmed using both in vitro and in vivo models. In this study, E2F2 has been demonstrated for the first time to play a pro-oncogenic role in pancreatic cancer by promoting the transition of the cell cycle from G1-phase to S-phase and, therefore, enhancing the proliferation of pancreatic cancer cells. E2F2 has also been demonstrated to enhance the chemotherapy resistance of pancreatic cancer cells to gemcitabine by upregulating the expression of RRM2 and DCK that is downstream of RRM2. (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) |
| References: | Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34. (PMID: 3062040210.3322/caac.21551) Macgregor-Das AM, Iacobuzio-Donahue CA. Molecular pathways in pancreatic carcinogenesis. J Surg Oncol. 2013;107:8–14. (PMID: 2280668910.1002/jso.23213) Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. The Lancet. 2011;378:607–20. (PMID: 10.1016/S0140-6736(10)62307-0) Manuel H. Pancreatic cancer. N Engl J Med. 2010;362(17):1605–17. (PMID: 10.1056/NEJMra0901557) Paez D, Labonte MJ, Lenz HJ. Pancreatic cancer: medical management (novel chemotherapeutics). Gastroenterol Clin North Am. 2012;41:189–209. (PMID: 2234125810.1016/j.gtc.2011.12.004) Brand RE, Tempero MA. Pancreatic cancer. Curr Opin Oncol. 1998;10(4):362–6. (PMID: 970240510.1097/00001622-199807000-00014) Cavalcante LDS, Monteiro G. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol. 2014;741:8–16. (PMID: 10.1016/j.ejphar.2014.07.041) Heinemann V, Xu YZ, Chubb S, et al. Cellular elimination of 2’,2’-difluorodeoxycytidine 5’-triphosphate: a mechanism of self-potentiation. Cancer Res. 1992;52(3):533–9. (PMID: 1732039) Hertel LW, Boder GB, Kroin JS, et al. Evaluation of the antitumor activity of gemcitabine (2’,2’-difluoro-2’-deoxycytidine). Cancer Res. 1990;50(14):4417–22. (PMID: 2364394) Veltkamp SA, Beijnen JH, Schellens JH. Prolonged versus standard gemcitabine infusion: translation of molecular pharmacology to new treatment strategy. Oncologist. 2008;13:261–76. (PMID: 1837853610.1634/theoncologist.2007-0215) Bergman AM, Pinedo HM, Peters GJ. Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine). Drug Resist Updates. 2002;5(1):19–33. (PMID: 10.1016/S1368-7646(02)00002-X) Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–13. https://doi.org/10.1200/JCO.1997.15.6.2403 . (PMID: 10.1200/JCO.1997.15.6.24039196156) Kleespies A, Jauch KW, Bruns CJ. Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer? Drug Resist Updates. 2006;9(1–2):1–18. (PMID: 10.1016/j.drup.2006.02.002) Muller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassilli E, et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 2001;15:267–85. (PMID: 1115990831261910.1101/gad.864201) Wu N, Xiao L, Zhao X, et al. miR-125b regulates the proliferation of glioblastoma stem cells by targeting E2F2. FEBS Lett. 2012;586(21):3831–9. (PMID: 2299981910.1016/j.febslet.2012.08.023) Li Y, Huang J, Yang D, Xiang S, Sun J, Li H, et al. Expression patterns of E2F transcription factors and their potential prognostic roles in breast cancer. Oncol Lett. 2018;15:9216–30. (PMID: 298448245958806) Sun CC, Zhou Q, Hu W, Li SJ, Zhang F, Chen ZL, et al. Transcriptional E2F1/2/5/8 as potential targets and transcriptional E2F3/6/7 as new biomarkers for the prognosis of human lung carcinoma. Aging. 2018;10:973–87. (PMID: 29754146599039910.18632/aging.101441) Wen L, Cheng F, Zhou Y, Yin C. MiR-26a enhances the sensitivity of gastric cancer cells to cisplatin by targeting NRAS and E2F2. Saudi J Gastroenterol. 2015;21:313–9. (PMID: 26458859463225710.4103/1319-3767.166206) Dong Q, Meng P, Wang T, Qin W, Qin W, Wang F, et al. MicroRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2. PLoS ONE. 2010;5:e10147. (PMID: 20418948285468510.1371/journal.pone.0010147) Li T, Luo W, Liu K, Lv X, Xi T. miR-31 promotes proliferation of colon cancer cells by targeting E2F2. Biotechnol Lett. 2015;37:523–32. (PMID: 2536225810.1007/s10529-014-1715-y) Furuse J. Treatments for pancreatic cancer with oligometastasis. Gan to kagaku ryoho Cancer Chemother. 2017;44(10):827–30. Benevolenskaya EV, Frolov MV. Emerging links between E2F control and mitochondrial function. Cancer Res. 2015;75:619–23. (PMID: 25634216433289010.1158/0008-5472.CAN-14-2173) Dick FA, Goodrich DW, Sage J, Dyson NJ. Non-canonical functions of the RB protein in cancer. Nat Rev Cancer. 2018;18(7):442–51. (PMID: 29692417669367710.1038/s41568-018-0008-5) Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine. Oncogene. 2004;23:1539–48. (PMID: 1466105610.1038/sj.onc.1207272) Bhutia YD, Hung SW, Krentz M, Patel D, Lovin D, Manoharan R, et al. Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein. PLoS ONE. 2013;8:e53436. (PMID: 23335963354607610.1371/journal.pone.0053436) Grolmusz VK, Karászi K, Micsik T, et al. Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. Am J Cancer Res. 2016;6(9):2041–53. (PMID: 277259095043113) Wang N, Zhan T, Ke T, Huang X, Ke D, Wang Q, et al. Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer. Br J Cancer. 2014;110:1034–44. (PMID: 24423925392989410.1038/bjc.2013.817) Hu Q, Qin Y, Xiang J, Liu W, Xu W, Sun Q, et al. dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer. Cell Prolif. 2018;51:e12456. (PMID: 29701272652885110.1111/cpr.12456) Goan YG, Zhou B, Hu E, Mi S, Yen Y. Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res. 1999;59(17):4204–7. (PMID: 10485455) Obama K, Kanai M, Kawai Y, Fukushima M, Takabayashi A. Role of retinoblastoma protein and E2F–1 transcription factor in the acquisition of 5-fluorouracil resistance by colon cancer cells. Int J Oncol. 2002;21(2):309–14. (PMID: 12118326) Yan LH, Wang XT, Yang J, et al. Reversal of multidrug resistance in gastric cancer cells by E2F–1 downregulation in vitro and in vivo. J Cell Biochem. 2014;115(1):34–41. (PMID: 2403812210.1002/jcb.24652) Chu J, Zhu Y, Liu Y, et al. E2F7 overexpression leads to tamoxifen resistance in breast cancer cells by competing with E2F1 at miR-15a/16 promoter. Oncotarget. 2015;6(31):31944–57. (PMID: 26397135474165210.18632/oncotarget.5128) Ivey-Hoyle M, Conroy R, Huber HE, Goodhart PJ, Oliff A, Heimbrook DC. Cloning and characterization of E2F–2, a novel protein with the biochemical properties of transcription factor E2F. Mol Cell Biol. 1993;13(12):7802–12. (PMID: 8246995364852) Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Sarkar FH. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2010;8:27–33. (PMID: 2110253210.1038/nrgastro.2010.188) Hubner RA, Worsnop F, Cunningham D, et al. Gemcitabine plus capecitabine in unselected patients with advanced pancreatic cancer. Pancreas. 2013;42(3):511–5. (PMID: 2346232410.1097/MPA.0b013e31826c6aee) Inal A, Kos FT, Algin E, et al. Prognostic factors in patients with advanced pancreatic cancer treated with gemcitabine alone or gemcitabine plus cisplatin: retrospective analysis of a multicenter study. J BUON. 2012;17(1):102–5. (PMID: 22517701) Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol. 2013;31(13):1640–8. (PMID: 2354708110.1200/JCO.2012.43.3680) Hung SW, Mody HR, Govindarajan R. Overcoming nucleoside analog chemoresistance of pancreatic cancer: a therapeutic challenge. Cancer Lett. 2012;320(2):138–49. (PMID: 22425961356909410.1016/j.canlet.2012.03.007) Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960–6. (PMID: 1745267710.1200/JCO.2006.07.9525) Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010;28(22):3617–22. (PMID: 20606091291731710.1200/JCO.2010.28.1386) Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011;12(3):256–62. (PMID: 2130695310.1016/S1470-2045(11)70004-3) Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol. 2010;28(22):3605–10. (PMID: 20606093291731510.1200/JCO.2009.25.7550) Goncalves A, Gilabert M, Francois E, et al. BAYPAN study: a double-blind phase III andomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23(11):2799–805. (PMID: 2277182710.1093/annonc/mds135) Oshi M, Takahashi H, Tokumaru Y, et al. The E2F pathway score as a predictive biomarker of response to neoadjuvant therapy in ER+/HER2 breast cancer. Cells. 2020;9(7):1643. (PMID: 740796810.3390/cells9071643) Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–7. (PMID: 20981102314894010.1038/nature09515) |
| معلومات مُعتمدة: | 81960429 National Natural Science Foundation of China; [2018]5779-31 Guizhou Science and Technology Department |
| فهرسة مساهمة: | Keywords: Chemoresistance; E2F2; Gemcitabine; Pancreatic cancer |
| المشرفين على المادة: | 0 (Antimetabolites, Antineoplastic) 0 (E2F2 Transcription Factor) 0 (E2F2 protein, human) 0W860991D6 (Deoxycytidine) EC 1.17.4.- (ribonucleotide reductase M2) EC 1.17.4.1 (Ribonucleoside Diphosphate Reductase) 0 (Gemcitabine) |
| تواريخ الأحداث: | Date Created: 20220618 Date Completed: 20220621 Latest Revision: 20221207 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1007/s12032-022-01715-x |
| PMID: | 35716217 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1559-131X |
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| DOI: | 10.1007/s12032-022-01715-x |