Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

MicroRNA-372-3p Predicts Response of TACE Patients Treated with Doxorubicin and Enhances Chemosensitivity in Hepatocellular Carcinoma

Author(s): Marwa H. Soliman, Mohamed A. Ragheb, Emad M. Elzayat, Mervat S. Mohamed, Nada El-Ekiaby, Ahmed I. Abdelaziz and Abdel-Hady A. Abdel-Wahab*

Volume 21 , Issue 2 , 2021

Published on: 16 May, 2020

Page: [246 - 253] Pages: 8

DOI: 10.2174/1871520620666200516145830

Price: $65

Abstract

Background: Identification of factors to detect and improve chemotherapy-response in cancer is the main concern. microRNA-372-3p (miR-372-3p) has been demonstrated to play a crucial role in cellular proliferation, apoptosis and metastasis of various cancers including Hepatocellular Carcinoma (HCC). However, its contribution towards Doxorubicin (Dox) chemosensitivity in HCC has never been studied.

Objective: This study aims to investigate the potential role of miR-372-3p in enhancing Dox effects on HCC cell line (HepG2). Additionally, the correlation between miR-372-3p and HCC patients who received Transarterial Chemoembolization (TACE) with Dox treatment has been analyzed.

Methods: Different cell processes were elucidated by cell viability, colony formation, apoptosis and wound healing assays after miR-372-3p transfection in HepG2 cells Furthermore, the miR-372-3p level has been estimated in the blood of primary HCC patients treated with TACE/Dox by quantitative real-time PCR assay. Receiver Operating Curve (ROC) analysis for serum miR-372-3p was constructed for its prognostic significance. Finally, the protein level of Mcl-1, the anti-apoptotic player, has been evaluated using western blot.

Results: We found a significantly higher level of miR-372-3p in the blood of the responder group of HCC patients who received TACE with Dox than of non-responders. Ectopic expression of miR-372-3p reduced cell proliferation, migration and significantly induced apoptosis in HepG2 cells which was coupled with a decrease of anti-apoptotic protein Mcl-1.

Conclusion: Our study demonstrated that miR-372-3p acts as a tumor suppressor in HCC and can act as a predictor biomarker for drug response. Furthermore, the data referred for the first time its potential role in drug sensitivity that might be a therapeutic target for HCC.

Keywords: MicroRNA-372-3p, doxorubicin, chemosensitivity, TACE, Mcl-1, hepatocellular carcinoma.

Graphical Abstract
[1]
Ji, J.; Wang, X.W. Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin. Oncol., 2012, 39(4), 461-472.
[http://dx.doi.org/10.1053/j.seminoncol.2012.05.011] [PMID: 22846863]
[2]
Zhang, Y.; Guan, D.X.; Shi, J.; Gao, H.; Li, J.J.; Zhao, J.S.; Qiu, L.; Liu, J.; Li, N.; Guo, W.X.; Xue, J.; Zhou, F.G.; Wu, M.C.; Wang, H.Y.; Xie, D.; Cheng, S.Q. All-trans retinoic acid potentiates the chemotherapeutic effect of cisplatin by inducing differentiation of tumor initiating cells in liver cancer. J. Hepatol., 2013, 59(6), 1255-1263.
[http://dx.doi.org/10.1016/j.jhep.2013.07.009] [PMID: 23867314]
[3]
Varela, M.; Real, M.I.; Burrel, M.; Forner, A.; Sala, M.; Brunet, M.; Ayuso, C.; Castells, L.; Montañá, X.; Llovet, J.M.; Bruix, J. Chemoembolization of hepatocellular carcinoma with drug eluting beads: Efficacy and doxorubicin pharmacokinetics. J. Hepatol., 2007, 46(3), 474-481.
[http://dx.doi.org/10.1016/j.jhep.2006.10.020] [PMID: 17239480]
[4]
Lencioni, R. Chemoembolization for hepatocellular carcinoma. Semin. Oncol., 2012, 39(4), 503-509.
[http://dx.doi.org/10.1053/j.seminoncol.2012.05.004] [PMID: 22846867]
[5]
Raoul, J-L.; Gilabert, M.; Piana, G. How to define transarterial chemoembolization failure or refractoriness: A European perspective. Liver Cancer, 2014, 3(2), 119-124.
[http://dx.doi.org/10.1159/000343867] [PMID: 24945002]
[6]
Thorn, C.F.; Oshiro, C.; Marsh, S.; Hernandez-Boussard, T.; McLeod, H.; Klein, T.E.; Altman, R.B. Doxorubicin pathways: Pharmacodynamics and adverse effects. Pharmacogenet. Genomics, 2011, 21(7), 440-446.
[http://dx.doi.org/10.1097/FPC.0b013e32833ffb56] [PMID: 21048526]
[7]
Cox, J.; Weinman, S. Mechanisms of doxorubicin resistance in hepatocellular carcinoma. Hepat. Oncol., 2016, 3(1), 57-59.
[http://dx.doi.org/10.2217/hep.15.41] [PMID: 26998221]
[8]
Barraud, L.; Merle, P.; Soma, E.; Lefrançois, L.; Guerret, S.; Chevallier, M.; Dubernet, C.; Couvreur, P.; Trépo, C.; Vitvitski, L. Increase of doxorubicin sensitivity by doxorubicin-loading into nanoparticles for hepatocellular carcinoma cells in vitro and in vivo. J. Hepatol., 2005, 42(5), 736-743.
[http://dx.doi.org/10.1016/j.jhep.2004.12.035] [PMID: 15826724]
[9]
AlQahtani, A.D.; Al-Mansoori, L.; Bashraheel, S.S.; Rashidi, F.B.; Al-Yafei, A.; Elsinga, P.; Domling, A.; Goda, S.K. Production of “biobetter” glucarpidase variants to improve drug detoxification and antibody directed enzyme prodrug therapy for cancer treatment. Eur. J. Pharm. Sci., 2019, 127, 79-91.
[http://dx.doi.org/10.1016/j.ejps.2018.10.014] [PMID: 30343151]
[10]
Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 2004, 116(2), 281-297.
[http://dx.doi.org/10.1016/S0092-8674(04)00045-5] [PMID: 14744438]
[11]
Calin, G.A.; Croce, C.M. MicroRNA-cancer connection: The beginning of a new tale. Cancer Res., 2006, 66(15), 7390-7394.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0800] [PMID: 16885332]
[12]
Michlewski, G.; Cáceres, J.F. Post-transcriptional control of miRNA biogenesis. RNA, 2019, 25(1), 1-16.
[http://dx.doi.org/10.1261/rna.068692.118] [PMID: 30333195]
[13]
Chi, Y.; Zhou, D. MicroRNAs in colorectal carcinoma--from pathogenesis to therapy. J. Exp. Clin. Cancer Res., 2016, 35(1), 43.
[http://dx.doi.org/10.1186/s13046-016-0320-4] [PMID: 26964533]
[14]
Jansson, M.D.; Lund, A.H. MicroRNA and cancer. Mol. Oncol., 2012, 6(6), 590-610.
[http://dx.doi.org/10.1016/j.molonc.2012.09.006] [PMID: 23102669]
[15]
Song, J.H.; Meltzer, S.J. MicroRNAs in pathogenesis, diagnosis, and treatment of gastroesophageal cancers. Gastroenterology, 2012, 143(1), 35-47.
[http://dx.doi.org/10.1053/j.gastro.2012.05.003]
[16]
Eldeeb, M.A.; Fahlman, R.P.; Esmaili, M.; Ragheb, M.A. Regulating apoptosis by degradation: The N-end rule-mediated regulation of apoptotic proteolytic fragments in mammalian cells. Int. J. Mol. Sci., 2018, 19(11), 3414.
[http://dx.doi.org/10.3390/ijms19113414] [PMID: 30384441]
[17]
Nagy, Á.; Lánczky, A.; Menyhárt, O.; Győrffy, B. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci. Rep., 2018, 8(1), 9227.
[http://dx.doi.org/10.1038/s41598-018-27521-y] [PMID: 29907753]
[18]
Kim, S.S.; Cho, H.J.; Nam, J.S.; Kim, H.J.; Kang, D.R.; Won, J.H.; Kim, J.; Kim, J.K.; Lee, J.H.; Kim, B.H.; Lee, M.Y.; Cho, S.W.; Cheong, J.Y. Plasma microRNA-21, 26a, and 29a-3p as predictive markers for treatment response following transarterial chemoembolization in patients with hepatocellular carcinoma. J. Korean Med. Sci., 2018, 33(1)e6
[http://dx.doi.org/10.3346/jkms.2018.33.e6] [PMID: 29215815]
[19]
Wu, G.; Liu, H.; He, H.; Wang, Y.; Lu, X.; Yu, Y.; Xia, S.; Meng, X.; Liu, Y. miR-372 down-regulates the oncogene ATAD2 to influence hepatocellular carcinoma proliferation and metastasis. BMC Cancer, 2014, 14(1), 107.
[http://dx.doi.org/10.1186/1471-2407-14-107] [PMID: 24552534]
[20]
Chen, X.; Hao, B.; Han, G.; Liu, Y.; Dai, D.; Li, Y.; Wu, X.; Zhou, X.; Yue, Z.; Wang, L.; Cao, Y.; Liu, J. miR-372 regulates glioma cell proliferation and invasion by directly targeting PHLPP2. J. Cell. Biochem., 2015, 116(2), 225-232.
[http://dx.doi.org/10.1002/jcb.24949] [PMID: 25160587]
[21]
Huang, X.; Huang, M.; Kong, L.; Li, Y. miR-372 suppresses tumour proliferation and invasion by targeting IGF2BP1 in renal cell carcinoma. Cell Prolif., 2015, 48(5), 593-599.
[http://dx.doi.org/10.1111/cpr.12207] [PMID: 26332146]
[22]
Gu, H.; Guo, X.; Zou, L.; Zhu, H.; Zhang, J. Upregulation of microRNA-372 associates with tumor progression and prognosis in hepatocellular carcinoma. Mol. Cell. Biochem., 2013, 375(1-2), 23-30.
[http://dx.doi.org/10.1007/s11010-012-1521-6] [PMID: 23291979]
[23]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)). Method. Methods, 2001, 25(4), 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[24]
Van Meerloo, J.; Kaspers, G.J.; Cloos, J. Cell sensitivity assays: The MTT assay. InCancer cell culture; Springer, 2011, pp. 237-245.
[http://dx.doi.org/10.1007/978-1-61779-080-5_20]
[25]
Rodriguez, L.G.; Wu, X.; Guan, J-L. Wound-healing assay. InCell Migration; Springer, 2005, pp. 23-29.
[26]
Singh, A.K.; Roy, N.K.; Anip, A.; Banik, K.; Monisha, J.; Bordoloi, D.; Kunnumakkara, A.B. Different methods to inhibit chemoresistance in Hepatocellular carcinoma. InCancer Cell Chemoresistance and Chemosensitization; World Scientific: Singapore, 2018, p. 373.
[http://dx.doi.org/10.1142/9789813208575_0013]
[27]
Huang, S.; He, X. The role of microRNAs in liver cancer progression. Br. J. Cancer, 2011, 104(2), 235-240.
[http://dx.doi.org/10.1038/sj.bjc.6606010] [PMID: 21102580]
[28]
Cho, W.J.; Shin, J.M.; Kim, J.S.; Lee, M.R.; Hong, K.S.; Lee, J-H.; Koo, K.H.; Park, J.W.; Kim, K-S. miR-372 regulates cell cycle and apoptosis of ags human gastric cancer cell line through direct regulation of LATS2. Mol. Cells, 2009, 28(6), 521-527.
[http://dx.doi.org/10.1007/s10059-009-0158-0] [PMID: 19937137]
[29]
Yu, J.; Jin, L.; Jiang, L.; Gao, L.; Zhou, J.; Hu, Y.; Li, W.; Zhi, Q.; Zhu, X. Serum miR-372 is a diagnostic and prognostic biomarker in patients with early colorectal cancer. Anticancer. Agents Med. Chem., 2016, 16(4), 424-431.
[http://dx.doi.org/10.2174/1871520615666150716110406] [PMID: 26179262]
[30]
Tian, R-Q.; Wang, X-H.; Hou, L-J.; Jia, W-H.; Yang, Q.; Li, Y-X.; Liu, M.; Li, X.; Tang, H. MicroRNA-372 is down-regulated and targets cyclin-dependent kinase 2 (CDK2) and cyclin A1 in human cervical cancer, which may contribute to tumorigenesis. J. Biol. Chem., 2011, 286(29), 25556-25563.
[http://dx.doi.org/10.1074/jbc.M111.221564] [PMID: 21646351]
[31]
Wu, G.; Wang, Y.; Lu, X.; He, H.; Liu, H.; Meng, X.; Xia, S.; Zheng, K.; Liu, B. Low mir-372 expression correlates with poor prognosis and tumor metastasis in hepatocellular carcinoma. BMC Cancer, 2015, 15(1), 182.
[http://dx.doi.org/10.1186/s12885-015-1214-0] [PMID: 25880458]
[32]
Wang, J.; Liu, X.; Wu, H.; Ni, P.; Gu, Z.; Qiao, Y.; Chen, N.; Sun, F.; Fan, Q. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res., 2010, 38(16), 5366-5383.
[http://dx.doi.org/10.1093/nar/gkq285] [PMID: 20423907]
[33]
Vousden, K.H.; Lu, X. Live or let die: The cell’s response to p53. Nat. Rev. Cancer, 2002, 2(8), 594-604.
[http://dx.doi.org/10.1038/nrc864] [PMID: 12154352]
[34]
Xue, J.; Chi, Y.; Chen, Y.; Huang, S.; Ye, X.; Niu, J.; Wang, W.; Pfeffer, L.M.; Shao, Z.M.; Wu, Z.H.; Wu, J. MiRNA-621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity. Oncogene, 2016, 35(4), 448-458.
[http://dx.doi.org/10.1038/onc.2015.96] [PMID: 25867061]
[35]
El-Deiry, W.S. The role of p53 in chemosensitivity and radiosensitivity. Oncogene, 2003, 22(47), 7486-7495.
[http://dx.doi.org/10.1038/sj.onc.1206949] [PMID: 14576853]
[36]
Morgan, R.G.; Ridsdale, J.; Payne, M.; Heesom, K.J.; Wilson, M.C.; Davidson, A.; Greenhough, A.; Davies, S.; Williams, A.C.; Blair, A.; Waterman, M.L.; Tonks, A.; Darley, R.L. LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells. Haematologica, 2019, 104(7), 1365-1377.
[http://dx.doi.org/10.3324/haematol.2018.202846] [PMID: 30630973]
[37]
Opyrchal, M.; Salisbury, J.L.; Iankov, I.; Goetz, M.P.; McCubrey, J.; Gambino, M.W.; Malatino, L.; Puccia, G.; Ingle, J.N.; Galanis, E.; D’Assoro, A.B. Inhibition of Cdk2 kinase activity selectively targets the CD44+/CD24/Low stem-like subpopulation and restores chemosensitivity of SUM149PT triple-negative breast cancer cells. Int. J. Oncol., 2014, 45(3), 1193-1199.
[http://dx.doi.org/10.3892/ijo.2014.2523] [PMID: 24970653]
[38]
Onder, T.T.; Gupta, P.B.; Mani, S.A.; Yang, J.; Lander, E.S.; Weinberg, R.A. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res., 2008, 68(10), 3645-3654.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-2938] [PMID: 18483246]
[39]
Gandalovičová, A.; Rosel, D.; Fernandes, M.; Veselý, P.; Heneberg, P.; Čermák, V.; Petruželka, L.; Kumar, S.; Sanz-Moreno, V.; Brábek, J. Migrastatics-anti-metastatic and anti-invasion drugs: promises and challenges. Trends Cancer, 2017, 3(6), 391-406.
[http://dx.doi.org/10.1016/j.trecan.2017.04.008] [PMID: 28670628]
[40]
Kosaka, N.; Iguchi, H.; Ochiya, T. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci., 2010, 101(10), 2087-2092.
[http://dx.doi.org/10.1111/j.1349-7006.2010.01650.x] [PMID: 20624164]
[41]
Ferracin, M.; Veronese, A.; Negrini, M. Micromarkers: miRNAs in cancer diagnosis and prognosis. Expert Rev. Mol. Diagn., 2010, 10(3), 297-308.
[http://dx.doi.org/10.1586/erm.10.11] [PMID: 20370587]
[42]
Kramer, D.A.; Eldeeb, M.A.; Wuest, M.; Mercer, J.; Fahlman, R.P. Proteomic characterization of EL4 lymphoma-derived tumors upon chemotherapy treatment reveals potential roles for lysosomes and caspase-6 during tumor cell death in vivo. Proteomics, 2017, 17(12)1700060
[http://dx.doi.org/10.1002/pmic.201700060] [PMID: 28508578]
[43]
Eldeeb, M.A.; Ragheb, M.A. Post-translational N-terminal arginylation of protein fragments: A pivotal portal to proteolysis. Curr. Protein Pept. Sci., 2018, 19(12), 1214-1223.
[http://dx.doi.org/10.2174/1389203719666180809113122] [PMID: 30091410]
[44]
Eldeeb, M.A.; Ragheb, M.A.; Fon, E.A. Cell death: N-degrons fine-tune pyroptotic cell demise. Curr. Biol., 2019, 29(12), R588-R591.
[http://dx.doi.org/10.1016/j.cub.2019.05.004] [PMID: 31211982]
[45]
Eldeeb, M.A.; Siva-Piragasam, R.; Ragheb, M.A.; Esmaili, M.; Salla, M.; Fahlman, R.P. A molecular toolbox for studying protein degradation in mammalian cells. J. Neurochem., 2019, 151(4), 520-533.
[http://dx.doi.org/10.1111/jnc.14838] [PMID: 31357232]
[46]
Eldeeb, M.A.; Fahlman, R.P.; Ragheb, M.A.; Esmaili, M. Does N-terminal protein acetylation lead to protein degradation? BioEssays, 2019, 41(11)e1800167
[http://dx.doi.org/10.1002/bies.201800167] [PMID: 31549739]
[47]
Baer-Dubowska, W.; Majchrzak-Celińska, A.; Cichocki, M. Pharmocoepigenetics: A new approach to predicting individual drug responses and targeting new drugs. Pharmacol. Rep., 2011, 63(2), 293-304.
[http://dx.doi.org/10.1016/S1734-1140(11)70498-4] [PMID: 21602587]
[48]
Khodadoust, M.S.; Verhaegen, M.; Kappes, F.; Riveiro-Falkenbach, E.; Cigudosa, J.C.; Kim, D.S.; Chinnaiyan, A.M.; Markovitz, D.M.; Soengas, M.S. Melanoma proliferation and chemoresistance controlled by the DEK oncogene. Cancer Res., 2009, 69(16), 6405-6413.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1063] [PMID: 19679545]
[49]
Zarogoulidis, P.; Petanidis, S.; Kioseoglou, E.; Domvri, K.; Anestakis, D.; Zarogoulidis, K. MiR-205 and miR-218 expression is associated with carboplatin chemoresistance and regulation of apoptosis via Mcl-1 and Survivin in lung cancer cells. Cell. Signal., 2015, 27(8), 1576-1588.
[http://dx.doi.org/10.1016/j.cellsig.2015.04.009] [PMID: 25917317]
[50]
Singh, R.; Letai, A.; Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol., 2019, 20(3), 175-193.
[http://dx.doi.org/10.1038/s41580-018-0089-8] [PMID: 30655609]
[51]
Meinzinger, J.; Jäck, H-M.; Pracht, K. miRNA meets plasma cells “How tiny RNAs control antibody responses”. Clin. Immunol., 2018, 186, 3-8.
[http://dx.doi.org/10.1016/j.clim.2017.07.015] [PMID: 28736279]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy