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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

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

Research Article

Ras-related Protein in Brain 4A (Rab4A) is Downregulated by miR-496 to inhibit the Progression of Gastric Cancer

Author(s): Rui Su, Meng Su and Yan Lu*

Volume 27, Issue 18, 2024

Published on: 16 October, 2023

Page: [2734 - 2740] Pages: 7

DOI: 10.2174/0113862073260841231010055245

Price: $65

Abstract

Introduction: Ras-related protein in brain 4A (Rab4A), as a member of the Rab family, is involved in the intracellular circulation of membrane receptors or endocytic substances and regulates the progression of multiple tumors.

Methods: From our results, the knockdown of Rab4A inhibited the proliferation, migration and invasion in AGS cells. Importantly, the surface expression of epidermal growth factor receptor (EGFR) declined significantly in Rab4A knockdown cells. The downstream pathway of EGFR was also inhibited after the transfection of Rab4A-specific siRNA, including AKT and β-catenin pathways.

Result: In addition, miR-496 down-regulated the expression of Rab4A in AGS cells. The result of the luciferase reporter assay showed that miR-496 could bind to the 3’UTR of Rab4A.

Conclusion: In conclusion, the expression of Rab4A is inhibited by miR-496, and the knockdown of Rab4A inhibits the proliferation, migration and invasion through down-regulating the surface expression of EGFR. Rab4A is a potential target in the treatment of gastric cancer.

[1]
Thrift, A.P.; El-Serag, H.B. Burden of gastric cancer. Clin. Gastroenterol. Hepatol., 2020, 18(3), 534-542.
[http://dx.doi.org/10.1016/j.cgh.2019.07.045] [PMID: 31362118]
[2]
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.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Homma, Y.; Hiragi, S.; Fukuda, M. Rab family of small GTPases: An updated view on their regulation and functions. FEBS J., 2021, 288(1), 36-55.
[http://dx.doi.org/10.1111/febs.15453] [PMID: 32542850]
[4]
Tang, D.; Cao, F.; Yan, C.; Fang, K.; Ma, J.; Gao, L.; Sun, B.; Wang, G. Extracellular vesicle/macrophage axis: Potential targets for inflammatory disease intervention. Front. Immunol., 2022, 13, 705472.
[http://dx.doi.org/10.3389/fimmu.2022.705472] [PMID: 35769456]
[5]
Tzeng, H.T.; Wang, Y.C. Rab-mediated vesicle trafficking in cancer. J. Biomed. Sci., 2016, 23(1), 70.
[http://dx.doi.org/10.1186/s12929-016-0287-7] [PMID: 27716280]
[6]
Gopal Krishnan, P.D.; Golden, E.; Woodward, E.A.; Pavlos, N.J.; Blancafort, P. Rab GTPases: Emerging oncogenes and tumor suppressive regulators for the editing of survival pathways in cancer. Cancers, 2020, 12(2), 259.
[http://dx.doi.org/10.3390/cancers12020259] [PMID: 31973201]
[7]
Jin, H.; Tang, Y.; Yang, L.; Peng, X.; Li, B.; Fan, Q.; Wei, S.; Yang, S.; Li, X.; Wu, B.; Huang, M.; Tang, S.; Liu, J.; Li, H. Rab GTPases: Central coordinators of membrane trafficking in cancer. Front. Cell Dev. Biol., 2021, 9, 648384.
[http://dx.doi.org/10.3389/fcell.2021.648384] [PMID: 34141705]
[8]
Kaur, S.; Chen, Y.; Shenoy, S.K. Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling. J. Biol. Chem., 2020, 295(49), 16630-16642.
[http://dx.doi.org/10.1074/jbc.RA120.014532] [PMID: 32967969]
[9]
Tubbesing, K.; Ward, J.; Abini-Agbomson, R.; Malhotra, A.; Rudkouskaya, A.; Warren, J.; Lamar, J.; Martino, N.; Adam, A.P.; Barroso, M. Complex Rab4-mediated regulation of endosomal size and EGFR activation. Mol. Cancer Res., 2020, 18(5), 757-773.
[http://dx.doi.org/10.1158/1541-7786.MCR-19-0052] [PMID: 32019812]
[10]
Do, M.T.; Chai, T.F.; Casey, P.J.; Wang, M. Isoprenylcysteine carboxylmethyltransferase function is essential for RAB4A-mediated integrin β3 recycling, cell migration and cancer metastasis. Oncogene, 2017, 36(41), 5757-5767.
[http://dx.doi.org/10.1038/onc.2017.183] [PMID: 28604748]
[11]
Barbarin, A.; Frade, R. Procathepsin L secretion, which triggers tumour progression, is regulated by Rab4a in human melanoma cells. Biochem. J., 2011, 437(1), 97-107.
[http://dx.doi.org/10.1042/BJ20110361] [PMID: 21501115]
[12]
Cao, G.J.; Wang, D.; Zeng, Z.P.; Wang, G.X.; Hu, C.J.; Xing, Z.F. Direct interaction between Rab5a and Rab4a enhanced epidermal growth factor-stimulated proliferation of gastric cancer cells. World J. Gastrointest. Oncol., 2021, 13(10), 1492-1505.
[http://dx.doi.org/10.4251/wjgo.v13.i10.1492] [PMID: 34721780]
[13]
Morey, P.; Pfannkuch, L.; Pang, E.; Boccellato, F.; Sigal, M.; Imai-Matsushima, A.; Dyer, V.; Koch, M.; Mollenkopf, H.J.; Schlaermann, P.; Meyer, T.F. Helicobacter pylori depletes cholesterol in gastric glands to prevent interferon gamma signaling and escape the inflammatory response. Gastroenterology, 2018, 154(5), 1391-1404.e9.
[http://dx.doi.org/10.1053/j.gastro.2017.12.008] [PMID: 29273450]
[14]
Su, R.; Zhao, E.; Zhang, J. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer. Open Med., 2021, 16(1), 1206-1214.
[http://dx.doi.org/10.1515/med-2021-0313] [PMID: 34514167]
[15]
Li, S.; Lu, C.; Li, X.; Li, F.; Zhao, Y.; Xu, M.; Jia, H.; Yuan, S. LncRNA HOXA10-AS functions as an oncogene by binding miR-6509-5p to upregulate Y-box binding protein 1 in gastric cancer. Bioengineered, 2022, 13(5), 11373-11387.
[http://dx.doi.org/10.1080/21655979.2022.2059615] [PMID: 35521747]
[16]
Yi, W.R.; Tu, M.J.; Yu, A.X.; Lin, J.; Yu, A.M. Bioengineered miR-34a modulates mitochondrial inner membrane protein 17 like 2 (MPV17L2) expression toward the control of cancer cell mitochondrial functions. Bioengineered, 2022, 13(5), 12489-12503.
[http://dx.doi.org/10.1080/21655979.2022.2076399] [PMID: 35579419]
[17]
Li, J.H.; Liu, S.; Zhou, H.; Qu, L.H.; Yang, J.H. starBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res., 2014, 42(D1), D92-D97.
[http://dx.doi.org/10.1093/nar/gkt1248] [PMID: 24297251]
[18]
Yang, J.H.; Li, J.H.; Shao, P.; Zhou, H.; Chen, Y.Q.; Qu, L.H. starBase: A database for exploring microRNA-mRNA interaction maps from argonaute CLIP-Seq and degradome-seq data. Nucleic Acids Res., 2011, 39(Database issue), D202-D209.
[http://dx.doi.org/10.1093/nar/gkq1056] [PMID: 21037263]
[19]
Yousaf, M.; Ali, M. Modulation of ABCG2 surface expression by Rab5 and Rab21 to overcome multidrug resistance in cancer cells. Xenobiotica, 2020, 50(8), 988-996.
[http://dx.doi.org/10.1080/00498254.2020.1716107] [PMID: 31928387]
[20]
Bannister, J.P.; Bulley, S.; Leo, M.D.; Kidd, M.W.; Jaggar, J.H. Rab25 influences functional Ca v 1.2 channel surface expression in arterial smooth muscle cells. Am. J. Physiol. Cell Physiol., 2016, 310(11), C885-C893.
[http://dx.doi.org/10.1152/ajpcell.00345.2015] [PMID: 27076616]
[21]
Seixas, E.; Escrevente, C.; Seabra, M.C.; Barral, D.C. Rab GTPase regulation of bacteria and protozoa phagocytosis occurs through the modulation of phagocytic receptor surface expression. Sci. Rep., 2018, 8(1), 12998.
[http://dx.doi.org/10.1038/s41598-018-31171-5] [PMID: 30158654]
[22]
Wong, P.P.; Muñoz-Félix, J.M.; Hijazi, M.; Kim, H.; Robinson, S.D.; De Luxán-Delgado, B.; Rodríguez-Hernández, I.; Maiques, O.; Meng, Y.M.; Meng, Q.; Bodrug, N.; Dukinfield, M.S.; Reynolds, L.E.; Elia, G.; Clear, A.; Harwood, C.; Wang, Y.; Campbell, J.J.; Singh, R.; Zhang, P.; Schall, T.J.; Matchett, K.P.; Henderson, N.C.; Szlosarek, P.W.; Dreger, S.A.; Smith, S.; Jones, J.L.; Gribben, J.G.; Cutillas, P.R.; Meier, P.; Sanz-Moreno, V.; Hodivala-Dilke, K.M. Cancer burden is controlled by mural cell-β3-integrin regulated crosstalk with tumor cells. Cell, 2020, 181(6), 1346-1363.e21.
[http://dx.doi.org/10.1016/j.cell.2020.02.003] [PMID: 32473126]
[23]
Guo, G.; Gong, K.; Wohlfeld, B.; Hatanpaa, K.J.; Zhao, D.; Habib, A.A. Ligand-independent EGFR signaling. Cancer Res., 2015, 75(17), 3436-3441.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-0989] [PMID: 26282175]
[24]
Song, M.; Bode, A.M.; Dong, Z.; Lee, M.H. AKT as a therapeutic target for cancer. Cancer Res., 2019, 79(6), 1019-1031.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-2738] [PMID: 30808672]
[25]
Zhang, Y.; Wang, X. Targeting the Wnt/β-catenin signaling pathway in cancer. J. Hematol. Oncol., 2020, 13(1), 165.
[http://dx.doi.org/10.1186/s13045-020-00990-3] [PMID: 33276800]
[26]
Huang, C.; Liu, J.; He, L.; Wang, F.; Xiong, B.; Li, Y.; Yang, X. The long noncoding RNA noncoding RNA activated by DNA damage (NORAD)-microRNA-496-Interleukin-33 axis affects carcinoma-associated fibroblasts-mediated gastric cancer development. Bioengineered, 2021, 12(2), 11738-11755.
[http://dx.doi.org/10.1080/21655979.2021.2009412] [PMID: 34895039]
[27]
Lu, W.; Kang, Y. Epithelial-mesenchymal plasticity in cancer progression and metastasis. Dev. Cell, 2019, 49(3), 361-374.
[http://dx.doi.org/10.1016/j.devcel.2019.04.010] [PMID: 31063755]
[28]
Kachhap, S.K.; Faith, D.; Qian, D.Z.; Shabbeer, S.; Galloway, N.L.; Pili, R.; Denmeade, S.R.; DeMarzo, A.M.; Carducci, M.A. The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin. PLoS One, 2007, 2(9), e844.
[http://dx.doi.org/10.1371/journal.pone.0000844] [PMID: 17786215]

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