Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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

Combined RNAi of CTTN and FGF2 Modulates Cell Migration, Invasion and G1/S Transition of Hepatocellular Carcinoma through Ras/ERK Signaling Pathway

Author(s): Jiaming Zhou*, Jiaxuan Liu, Tiejun Li, Qiang Zhong and Hongyu Yu

Volume 24, Issue 8, 2024

Published on: 29 November, 2023

Page: [791 - 803] Pages: 13

DOI: 10.2174/0115680096254722231025110912

Price: $65

conference banner
Abstract

Background: Most patients with hepatocellular carcinoma (HCC) die of rapid progression and distant metastasis. Gene therapy represents a promising choice for HCC treatment, but the effective targeted methods are still limited.

Objectives: CTTN/cortactin plays a key role in actin polymerization and regulates cytoskeleton remodeling. However, the interaction network of CTTN in HCC is not well understood.

Methods: siRNA was designed for CTTN silencing and Affymetrix GeneChip sequencing was used to obtain the gene profile after CTTN knockdown in the HCC cell line SMMC-7721. Potential interacting genes of CTTN were identified using qRT-PCR. The inhibition on HCC by combined RNA interference (RNAi) of CTTN and fibroblast growth factor 2 (FGF2) was detected.

Results: A total of 1,717 significantly altered genes were screened out and 12 potential interacting genes of CTTN were identified. The interaction of CTTN and FGF2 was validated and combined RNAi of CTTN and FGF2 achieved a synergistic effect, leading to better inhibition of HCC cell migration, invasion and G1/S transition than single knockdown of CTTN or FGF2. Mechanistically, combined RNAi of CTTN and FGF2 modulated the Ras/ERK signaling pathway. In addition, the EMT epithelial marker E-cadherin was upregulated while the mesenchymal marker Vimentin and cell cycle protein Cyclin D1 were downregulated after combined RNAi of CTTN and FGF2. Additionally, qRT-PCR and immunohistochemical staining showed that both CTTN and FGF2 were highly expressed in metastatic HCC tissues.

Conclusion: Combined RNAi of CTTN and FGF2 may be a novel and promising intervention strategy for HCC invasion and metastasis.

Keywords: CTTN, FGF2, migration, invasion, G1/S transition, Ras/ERK.

« Previous Next »
Graphical Abstract

[1]
Shen, B.; Shi, J.P.; Zhu, Z.X.; He, Z.D.; Liu, S.Y.; Shi, W.; Zhang, Y.X.; Ying, H.Y.; Wang, J.; Xu, R.F.; Fang, F.; Chang, H.X.; Chen, Z.; Zhang, N.N. EGFR inhibition overcomes resistance to FGFR4 inhibition and potentiates FGFR4 inhibitor therapy in hepatocellular carcinoma. Mol Cancer Ther., 2023, 22(12), 1479-1492.http://dx.doi.org/10.1158/1535-7163.MCT-23-0096 PMID:37710057
[2]
Ringelhan, M.; Pfister, D.; O’Connor, T.; Pikarsky, E.; Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol., 2018, 19(3), 222-232.
[http://dx.doi.org/10.1038/s41590-018-0044-z] [PMID: 29379119]
[3]
Gong, Q.Z.; Xiao, D.; Gong, G.Y.; Xu, J.; Wen, X.D.; Feng, F.; Qu, W. EH-42: A novel small molecule induces apoptosis and inhibits migration and invasion of human hepatoma cells through suppressing STAT3 signaling pathway. Curr. Cancer Drug Targets, 2019, 19(7), 583-593.
[http://dx.doi.org/10.2174/1568009619666181226094814] [PMID: 30585547]
[4]
Wang, K.; Shang, F.; Chen, D.; Cao, T.; Wang, X.; Jiao, J.; He, S.; Liang, X. Protein liposomes-mediated targeted acetylcholinesterase gene delivery for effective liver cancer therapy. J. Nanobiotechnology, 2021, 19(1), 31.
[http://dx.doi.org/10.1186/s12951-021-00777-9] [PMID: 33482834]
[5]
Cao, M.; Gao, Y.; Zhan, M.; Qiu, N.; Piao, Y.; Zhou, Z.; Shen, Y. Glycyrrhizin acid and glycyrrhetinic acid modified polyethyleneimine for targeted DNA delivery to hepatocellular carcinoma. Int. J. Mol. Sci., 2019, 20(20), 5074.
[http://dx.doi.org/10.3390/ijms20205074] [PMID: 31614879]
[6]
Abdel-Mohsen, H.T.; Abdullaziz, M.A.; El Kerdawy, A.M.; Ragab, F.A.F.; Flanagan, K.J.; Mahmoud, A.E.E.; Ali, M.M.; El Diwani, H.I.; Senge, M.O. Targeting receptor tyrosine kinase VEGFR-2 in Hepatocellular Cancer: Rational design, synthesis and biological evaluation of 1,2-disubstituted benzimidazoles. Molecules, 2020, 25(4), 770.
[http://dx.doi.org/10.3390/molecules25040770] [PMID: 32053964]
[7]
Wang, Y.; Zhao, Y.; Li, M.; Hou, H.; Jian, Z.; Li, W.; Li, P.; Ma, F.; Liu, M.; Liu, H.; Xue, H. Conversion of primary liver cancer after targeted therapy for liver cancer combined with AFP-targeted CAR T-cell therapy: A case report. Front. Immunol., 2023, 14, 1180001.
[http://dx.doi.org/10.3389/fimmu.2023.1180001] [PMID: 37256142]
[8]
Bouitbir, J.; Panajatovic, M.V.; Krähenbühl, S. Mitochondrial toxicity associated with imatinib and sorafenib in isolated rat heart fibers and the cardiomyoblast H9c2 cell line. Int. J. Mol. Sci., 2022, 23(4), 2282.
[http://dx.doi.org/10.3390/ijms23042282] [PMID: 35216404]
[9]
Lin, Z.; Niu, Y.; Wan, A.; Chen, D.; Liang, H.; Chen, X.; Sun, L.; Zhan, S.; Chen, L.; Cheng, C.; Zhang, X.; Bu, X.; He, W.; Wan, G. RNAm6 A methylation regulates sorafenib resistance in liver cancer through FOXO 3-mediated autophagy. EMBO J., 2020, 39(12), e103181.
[http://dx.doi.org/10.15252/embj.2019103181] [PMID: 32368828]
[10]
Yamaguchi, H.; Condeelis, J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta, 2007, 1773(5), 642-652.
[http://dx.doi.org/10.1016/j.bbamcr.2006.07.001] [PMID: 16926057]
[11]
Thiery, J.P.; Acloque, H.; Huang, R.Y.J.; Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell, 2009, 139(5), 871-890.
[http://dx.doi.org/10.1016/j.cell.2009.11.007] [PMID: 19945376]
[12]
Weed, S.A.; Karginov, A.V.; Schafer, D.A.; Weaver, A.M.; Kinley, A.W.; Cooper, J.A.; Parsons, J.T. Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex. J. Cell Biol., 2000, 151(1), 29-40.
[http://dx.doi.org/10.1083/jcb.151.1.29] [PMID: 11018051]
[13]
Uruno, T.; Liu, J.; Zhang, P.; Fan, Y.; Egile, C.; Li, R.; Mueller, S.C.; Zhan, X. Activation of Arp2/3 complex-mediated actin polymerization by cortactin. Nat. Cell Biol., 2001, 3(3), 259-266.
[http://dx.doi.org/10.1038/35060051] [PMID: 11231575]
[14]
Yuan, B.Z.; Zhou, X.; Zimonjic, D.B.; Durkin, M.E.; Popescu, N.C. Amplification and overexpression of the EMS 1 oncogene, a possible prognostic marker, in human hepatocellular carcinoma. J. Mol. Diagn., 2003, 5(1), 48-53.
[http://dx.doi.org/10.1016/S1525-1578(10)60451-5] [PMID: 12552080]
[15]
Li, Y.; Fu, Y.; Hu, X.; Sun, L.; Tang, D.; Li, N.; Peng, F.; Fan, X. The HBx–CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1. Cell Death Dis., 2019, 10(6), 405.
[http://dx.doi.org/10.1038/s41419-019-1650-x] [PMID: 31138777]
[16]
Zhou, J.; Chen, L.; Zhang, Y.; Wu, Y.; Wang, G.; He, S.; Guo, Z.; Wei, Y. Synergistic effect of EMS1-shRNA and sorafenib on proliferation, migration, invasion and endocytosis of SMMC-7721. J. Mol. Histol., 2014, 45(2), 205-216.
[http://dx.doi.org/10.1007/s10735-013-9543-2] [PMID: 24127012]
[17]
Hou, Y.; Zou, Q.; Ge, R.; Shen, F.; Wang, Y. The critical role of CD133+CD44+/high tumor cells in hematogenous metastasis of liver cancers. Cell Res., 2012, 22(1), 259-272.
[http://dx.doi.org/10.1038/cr.2011.139] [PMID: 21862973]
[18]
Mashiko, T.; Masuoka, Y.; Nakano, A.; Tsuruya, K.; Hirose, S.; Hirabayashi, K.; Kagawa, T.; Nakagohri, T. Intussusception due to hematogenous metastasis of hepatocellular carcinoma to the small intestine: A case report. World J. Gastroenterol., 2020, 26(42), 6698-6705.
[http://dx.doi.org/10.3748/wjg.v26.i42.6698] [PMID: 33268957]
[19]
Nakanishi, K.; Sakamoto, M.; Yamasaki, S.; Todo, S.; Hirohashi, S. Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma. Cancer, 2005, 103(2), 307-312.
[http://dx.doi.org/10.1002/cncr.20774] [PMID: 15593087]
[20]
Llovet, J.M.; Bruix, J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology, 2008, 48(4), 1312-1327.
[http://dx.doi.org/10.1002/hep.22506] [PMID: 18821591]
[21]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
[http://dx.doi.org/10.1016/S0092-8674(00)81683-9] [PMID: 10647931]
[22]
Tunduguru, R.; Zhang, J.; Aslamy, A.; Salunkhe, V.A.; Brozinick, J.T.; Elmendorf, J.S.; Thurmond, D.C. The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)–mediated glucose uptake into skeletal muscle cells. J. Biol. Chem., 2017, 292(46), 19034-19043.
[http://dx.doi.org/10.1074/jbc.M117.801340] [PMID: 28972183]
[23]
Siton, O.; Ideses, Y.; Albeck, S.; Unger, T.; Bershadsky, A.D.; Gov, N.S.; Bernheim-Groswasser, A. Cortactin releases the brakes in actin- based motility by enhancing WASP-VCA detachment from Arp2/3 branches. Curr. Biol., 2011, 21(24), 2092-2097.
[http://dx.doi.org/10.1016/j.cub.2011.11.010] [PMID: 22169534]
[24]
Tegtmeyer, N.; Harrer, A.; Rottner, K.; Backert, S. Helicobacter pylori CagA induces cortactin y-470 phosphorylation-dependent gastric epithelial cell scattering via Abl, Vav2 and Rac1 activation. Cancers., 2021, 13(16), 4241.
[http://dx.doi.org/10.3390/cancers13164241] [PMID: 34439396]
[25]
Tehrani, S.; Tomasevic, N.; Weed, S.; Sakowicz, R.; Cooper, J.A. Src phosphorylation of cortactin enhances actin assembly. Proc. Natl. Acad. Sci., 2007, 104(29), 11933-11938.
[http://dx.doi.org/10.1073/pnas.0701077104] [PMID: 17606906]
[26]
Martini, V.; Gattazzo, C.; Frezzato, F.; Trimarco, V.; Pizzi, M.; Chiodin, G.; Severin, F.; Scomazzon, E.; Guzzardo, V.; Saraggi, D.; Raggi, F.; Martinello, L.; Facco, M.; Visentin, A.; Piazza, F.; Brunati, A.M.; Semenzato, G.; Trentin, L. Cortactin, a Lyn substrate, is a checkpoint molecule at the intersection of BCR and CXCR4 signalling pathway in chronic lymphocytic leukaemia cells. Br. J. Haematol., 2017, 178(1), 81-93.
[http://dx.doi.org/10.1111/bjh.14642] [PMID: 28419476]
[27]
Hu, P.H.; Pan, L.H.; Wong, P.T.Y.; Chen, W.H.; Yang, Y.Q.; Wang, H.; Xiang, J.J.; Xu, M. 125 I-labeled anti-bFGF monoclonal antibody inhibits growth of hepatocellular carcinoma. World J. Gastroenterol., 2016, 22(21), 5033-5041.
[http://dx.doi.org/10.3748/wjg.v22.i21.5033] [PMID: 27275095]
[28]
Allahmoradi, H.; Asghari, S.M.; Ahmadi, A.; Assareh, E.; Nazari, M. Anti-tumor and anti-metastatic activity of the FGF2 118–126 fragment dependent on the loop structure. Biochem. J., 2022, 479(12), 1285-1302.
[http://dx.doi.org/10.1042/BCJ20210830] [PMID: 35638868]
[29]
Jin, X.; Chen, H.; Li, D.; Li, A.; Wang, W.; Gu, W. Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors. J Enzyme Inhib. Med. Chem., 2019, 34(1), 955-972.
[http://dx.doi.org/10.1080/14756366.2019.1605364]
[30]
Wang, Z.; Li, X.; Li, Q.; Zhou, J. Targeting CXCL5 in pancreatic cancer cells inhibits cancer xenograft growth by reducing proliferation and inhibiting EMT progression. Dig. Dis. Sci., 2023, 68(3), 841-851.
[http://dx.doi.org/10.1007/s10620-022-07529-1] [PMID: 35650416]
[31]
Wang, Y.; Li, Y.; Wang, L.; Chen, B.; Zhu, M.; Ma, C.; Mu, C.; Tao, A.; Li, S.; Luo, L.; Ma, P.; Ji, S.; Lan, T. Cinnamaldehyde suppressed EGF-induced EMT process and inhibits ovarian cancer progression through PI3K/AKT pathway. Front. Pharmacol., 2022, 13, 779608.
[http://dx.doi.org/10.3389/fphar.2022.779608] [PMID: 35645793]
[32]
Kowalczyk, M.M.; Barańska, M.; Fendler, W.; Borkowska, E.M.; Kobos, J.; Borowiec, M.; Pietruszewska, W. G870A polymorphic variants of CCND1 gene and cyclin D1 protein expression as prognostic markers in laryngeal lesions. Diagnostics., 2022, 12(5), 1059.
[http://dx.doi.org/10.3390/diagnostics12051059] [PMID: 35626215]
[33]
Milman, T.; Eiger-Moscovich, M.; Henry, R.K.; Ida, C.M.; Ruben, M.; Shields, C.L.; Lally, S.E.; Penne, R.B.; Stefanyszyn, M.A.; Bilyk, J.R.; Rapuano, C.J.; Rabinowitz, M.; Eagle, R.C., Jr Cyclin D1 expression and molecular genetic findings in periocular histiocytoses and neoplasms of macrophage-dendritic cell lineage. Am. J. Ophthalmol., 2022, 242, 36-51.
[http://dx.doi.org/10.1016/j.ajo.2022.05.009] [PMID: 35594918]

Rights & Permissions Print Cite
Article Metrics
17
3
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy