Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

E2F1 Reduces Sorafenib’s Sensitivity of Esophageal Carcinoma Cells via Modulating the miR-29c-3p/COL11A1 Signaling Axis

Author(s): Zhifeng Ma, Ting Zhu, Haiyong Wang, Bin Wang, Linhai Fu and Guangmao Yu*

Volume 17, 2024

Published on: 04 May, 2023

Article ID: e060323214360 Pages: 25

DOI: 10.2174/1874467216666230306101653



Objective: Esophageal carcinoma (ESCA) is a common malignancy characterized by high morbidity and mortality. Our work managed to dissect the modulatory mechanism of E2F1/miR-29c-3p/COL11A1 in the malignant progression and sensitivity of ESCA cells to sorafenib.

Methods: Via bioinformatics approaches, we identified the target miRNA. Subsequently, CCK-8, cell cycle analysis, and flow cytometry were used to check the biological influences of miR-29c-3p on ESCA cells. TransmiR, mirDIP, miRPathDB, and miRDB databases were used as tools for the prediction of upstream transcription factors and downstream genes of miR-29c-3p. The targeting relationship of genes was detected via RNA immunoprecipitation and chromatin immunoprecipitation, which was further validated by dual-luciferase assay. Finally, in vitro experiments revealed the way E2F1/miR-29c-3p/COL11A1 affected sorafenib’s sensitivity, and in vivo experiments were used to verify the way E2F1 and sorafenib impacted ESCA tumor growth.

Results: miR-29c-3p, downregulated in ESCA, could suppress ESCA cell viability, arrest the cell cycle in the G0/G1 phase, and impel apoptosis. E2F1 was found to be upregulated in ESCA and it could abate the transcriptional activity of miR-29c-3p. COL11A1 was found to be a downstream target of miR-29c-3p to enhance cell viability, induce cell cycle arrest in S phase, and constrain apoptosis. Cellular and animal experiments together demonstrated that E2F1 abated the sorafenib’s sensitivity of ESCA cells via miR-29c-3p/COL11A1.

Conclusion: E2F1 affected the viability, cell cycle, and apoptosis of ESCA cells by modulating miR-29c-3p/COL11A1, and it attenuated the sensitivity of ESCA cells to sorafenib, shedding new light on the treatment of ESCA.

Keywords: Sorafenib, E2F1, miR-29c-3p, COL11A1, Malignant progression, Drug sensitivity.

Liu, H.; Zhang, Q.; Lou, Q.; Zhang, X.; Cui, Y.; Wang, P.; Yang, F.; Wu, F.; Wang, J.; Fan, T.; Li, S. Differential Analysis of lncRNA, miRNA and mRNA Expression Profiles and the Prognostic Value of lncRNA in Esophageal Cancer. Pathol. Oncol. Res., 2020, 26(2), 1029-1039.
[] [PMID: 30972633]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[] [PMID: 33538338]
Abnet, C.C.; Arnold, M.; Wei, W.Q. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology, 2018, 154(2), 360-373.
[] [PMID: 28823862]
Arnold, M.; Soerjomataram, I.; Ferlay, J.; Forman, D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut, 2015, 64(3), 381-387.
[] [PMID: 25320104]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[] [PMID: 25651787]
Zhang, K.; Zhang, B.; Bai, Y.; Dai, L. E2F1 promotes cancer cell sensitivity to cisplatin by regulating the cellular DNA damage response through miR-26b in esophageal squamous cell carcinoma. J. Cancer, 2020, 11(2), 301-310.
[] [PMID: 31897226]
Ku, G.Y. Systemic therapy for esophageal cancer: chemotherapy. Chin. Clin. Oncol., 2017, 6(5), 49.
[] [PMID: 29129089]
Wang, G.; Guo, S.; Zhang, W.; Li, Z.; Xu, J.; Li, D.; Wang, Y.; Zhan, Q. a comprehensive analysis of alterations in dna damage repair pathways reveals a potential way to enhance the radio-sensitivity of esophageal squamous cell cancer. Front. Oncol., 2020, 10, 575711.
[] [PMID: 33178606]
Zhang, K.; Dai, L.; Zhang, B.; Xu, X.; Shi, J.; Fu, L.; Chen, X.; Li, J.; Bai, Y. miR-203 is a direct transcriptional target of E2F1 and causes G1 arrest in esophageal cancer cells. J. Cell. Physiol., 2015, 230(4), 903-910.
[] [PMID: 25216463]
Cam, H.; Dynlacht, B.D. Emerging roles for E2F: beyond the G1/S transition and DNA replication. Cancer Cell, 2003, 3(4), 311-316.
[] [PMID: 12726857]
Chen, H.Z.; Tsai, S.Y.; Leone, G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat. Rev. Cancer, 2009, 9(11), 785-797.
[] [PMID: 19851314]
Polager, S.; Ginsberg, D. p53 and E2f: partners in life and death. Nat. Rev. Cancer, 2009, 9(10), 738-748.
[] [PMID: 19776743]
Li, B.; Xu, W.W.; Guan, X.Y.; Qin, Y.R.; Law, S.; Lee, N.P.; Chan, K.T.; Tam, P.Y.; Li, Y.Y.; Chan, K.W.; Yuen, H.F.; Tsao, S.W.; He, Q.Y.; Cheung, A.L. Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance. Clin. Cancer Res., 2016, 22(5), 1243-1255.
[] [PMID: 26475334]
He, S.; Feng, M.; Liu, M.; Yang, S.; Yan, S.; Zhang, W.; Wang, Z.; Hu, C.; Xu, Q.; Chen, L.; Zhu, H.; Xu, N. P21-activated kinase 7 mediates cisplatin-resistance of esophageal squamous carcinoma cells with Aurora-A overexpression. PLoS One, 2014, 9(12), e113989.
[] [PMID: 25436453]
Han, D.L.; Wang, L.L.; Zhang, G.F.; Yang, W.F.; Chai, J.; Lin, H.M.; Fu, Z.; Yu, J.M. MiRNA-485-5p, inhibits esophageal cancer cells proliferation and invasion by down-regulating O-linked N-acetylglucosamine transferase. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(7), 2809-2816.
[PMID: 31002132]
Wang, Z.; Li, T.E.; Chen, M.; Pan, J.J.; Shen, K.W. miR-106b-5p contributes to the lung metastasis of breast cancer via targeting CNN1 and regulating Rho/ROCK1 pathway. Aging, 2020, 12(2), 1867-1887.
[] [PMID: 31986487]
Fu, H.; Zhang, J.; Pan, T.; Ai, S.; Tang, L.; Wang, F. miR378a enhances the sensitivity of liver cancer to sorafenib by targeting VEGFR, PDGFRbeta and cRaf. Mol. Med. Rep., 2018, 17(3), 4581-4588.
[] [PMID: 29328399]
Li, L.; Shou, H.; Wang, Q.; Liu, S. Investigation of the potential theranostic role of KDM5B/miR-29c signaling axis in paclitaxel resistant endometrial carcinoma. Gene, 2019, 694, 76-82.
[] [PMID: 30658067]
Hu, Z.; Cai, M.; Zhang, Y.; Tao, L.; Guo, R. miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway. Cell Cycle, 2020, 19(2), 193-206.
[] [PMID: 31885310]
Zhou, B.; Lu, Q.; Liu, J.; Fan, L.; Wang, Y.; Wei, W.; Wang, H.; Sun, G. Melatonin increases the sensitivity of hepatocellular carcinoma to sorafenib through the perk-atf4-beclin1 pathway. Int. J. Biol. Sci., 2019, 15(9), 1905-1920.
[] [PMID: 31523192]
Liu, H.; Wang, X.; Shi, G.; Jiang, L.; Liu, X. Tiam1 siRNA enhanced the sensitivity of sorafenib on esophageal squamous cell carcinoma in vivo. Tumour Biol., 2014, 35(8), 8249-8258.
[] [PMID: 24852430]
Knoll, S.; Emmrich, S.; Putzer, B.M. The E2F1-miRNA cancer progression network. Adv. Exp. Med. Biol., 2013, 774, 135-147.
[] [PMID: 23377972]
Chang, Y.S.; Adnane, J.; Trail, P.A.; Levy, J.; Henderson, A.; Xue, D.; Bortolon, E.; Ichetovkin, M.; Chen, C.; McNabola, A.; Wilkie, D.; Carter, C.A.; Taylor, I.C.; Lynch, M.; Wilhelm, S. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother. Pharmacol., 2007, 59(5), 561-574.
[] [PMID: 17160391]
Liu, L.; Cao, Y.; Chen, C.; Zhang, X.; McNabola, A.; Wilkie, D.; Wilhelm, S.; Lynch, M.; Carter, C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res., 2006, 66(24), 11851-11858.
[] [PMID: 17178882]
Yu, C.; Friday, B.B.; Lai, J.P.; Yang, L.; Sarkaria, J.; Kay, N.E.; Carter, C.A.; Roberts, L.R.; Kaufmann, S.H.; Adjei, A.A. Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol. Cancer Ther., 2006, 5(9), 2378-2387.
[] [PMID: 16985072]
Yang, C.; Dong, Z.; Hong, H.; Dai, B.; Song, F.; Geng, L.; Lu, J.; Yang, J.; Sui, C.; Xu, M. Circfn1 mediates sorafenib resistance of hepatocellular carcinoma cells by sponging mir-1205 and regulating e2f1 expression. Mol. Ther. Nucleic Acids, 2020, 22, 421-433.
[] [PMID: 33230446]
Huang, F.L.; Yu, S.J. Esophageal cancer: Risk factors, genetic association, and treatment. Asian J. Surg., 2018, 41(3), 210-215.
[] [PMID: 27986415]
Xia, X.; Liu, Z.; Qin, Q.; Di, X.; Zhang, Z.; Sun, X.; Ge, X. Long-Term Survival in Nonsurgical Esophageal Cancer Patients Who Received Consolidation Chemotherapy Compared With Patients Who Received Concurrent Chemoradiotherapy Alone: A Systematic Review and Meta-Analysis. Front. Oncol., 2021, 10, 604657.
[] [PMID: 33489910]
Dai, K.Y.; Yu, Y.C.; Leu, Y.S.; Chi, C.W.; Chan, M.L.; Tsai, C.H.; Lin, H.C.; Huang, W.C.; Chen, Y.J. Neoadjuvant chemoradiotherapy and larynx-preserving surgery for cervical esophageal cancer. J. Clin. Med., 2020, 9(2)
[] [PMID: 32024132]
Feng, S.; Luo, S.; Ji, C.; Shi, J. miR-29c-3p regulates proliferation and migration in ovarian cancer by targeting KIF4A. World J. Surg. Oncol., 2020, 18(1), 315.
[] [PMID: 33261630]
Chen, C.; Huang, Z.; Mo, X.; Song, Y.; Li, X.; Li, X.; Zhang, M. RETRACTED ARTICLE: The circular RNA 001971/miR-29c-3p axis modulates colorectal cancer growth, metastasis, and angiogenesis through VEGFA. J. Exp. Clin. Cancer Res., 2020, 39(1), 91.
[] [PMID: 32430042]
Wu, H.; Zhang, W.; Wu, Z.; Liu, Y.; Shi, Y.; Gong, J.; Shen, W.; Liu, C. miR-29c-3p regulates DNMT3B and LATS1 methylation to inhibit tumor progression in hepatocellular carcinoma. Cell Death Dis., 2019, 10(2), 48.
[] [PMID: 30718452]
Wang, L.; Yu, T.; Li, W.; Li, M.; Zuo, Q.; Zou, Q.; Xiao, B. The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3. Oncogene, 2019, 38(17), 3134-3150.
[] [PMID: 30626935]
Fischer, H.; Stenling, R.; Rubio, C.; Lindblom, A. Colorectal carcinogenesis is associated with stromal expression of COL11A1 and COL5A2. Carcinogenesis, 2001, 22(6), 875-878.
[] [PMID: 11375892]
Badea, L.; Herlea, V.; Dima, S.O.; Dumitrascu, T.; Popescu, I. Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepatogastroenterology, 2008, 55(88), 2016-2027.
[PMID: 19260470]
Chong, I.W.; Chang, M.Y.; Chang, H.C.; Yu, Y.P.; Sheu, C.C.; Tsai, J.R.; Hung, J.Y.; Chou, S.H.; Tsai, M.S.; Hwang, J.J.; Lin, S.R. Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non-small cell lung cancer. Oncol. Rep., 2006, 16(5), 981-988.
[] [PMID: 17016581]
Li, A.; Li, J.; Lin, J.; Zhuo, W.; Si, J. COL11A1 is overexpressed in gastric cancer tissues and regulates proliferation, migration and invasion of HGC-27 gastric cancer cells in vitro. Oncol. Rep., 2017, 37(1), 333-340.
[] [PMID: 28004111]
Wu, Y.H.; Huang, Y.F.; Chang, T.H.; Chou, C.Y. Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF-kappaB-mediated IKKbeta expression. Int. J. Cancer, 2017, 141(11), 2305-2317.
[] [PMID: 28815582]
Wei, L.; Lee, D.; Law, C.T.; Zhang, M.S.; Shen, J.; Chin, D.W.; Zhang, A.; Tsang, F.H.; Wong, C.L.; Ng, I.O.; Wong, C.C.; Wong, C.M. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat. Commun., 2019, 10(1), 4681.
[] [PMID: 31615983]
Rini, B.I.; Pal, S.K.; Escudier, B.J.; Atkins, M.B.; Hutson, T.E.; Porta, C.; Verzoni, E.; Needle, M.N.; McDermott, D.F. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol., 2020, 21(1), 95-104.
[] [PMID: 31810797]
Zhang, Y.N.; Wu, X.Y.; Zhong, N.; Deng, J.; Zhang, L.; Chen, W.; Li, X.; Zhong, C.J. Stimulatory effects of sorafenib on human nonsmall cell lung cancer cells in vitro by regulating MAPK/ERK activation. Mol. Med. Rep., 2014, 9(1), 365-369.
[] [PMID: 24213303]

© 2024 Bentham Science Publishers | Privacy Policy