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LETM1 Promotes Gastric Cancer Cell Proliferation, Migration, and Invasion via the PI3K/Akt Signaling Pathway

  • Zhang, Yunfeng (Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University) ;
  • Chen, Lele (Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University) ;
  • Cao, Yifan (Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University) ;
  • Chen, Si (Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University) ;
  • Xu, Chao (Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University) ;
  • Xing, Jun (Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University) ;
  • Zhang, Kaiguang (Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University)
  • Received : 2019.11.27
  • Accepted : 2020.03.06
  • Published : 2020.06.30

Abstract

Purpose: Globally, there is a high incidence of gastric cancer (GC). Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is reported to play a vital role in several human malignancies. However, there is limited understanding of the role of LETM1 in GC. This study aims to investigate the effects of LETM1 on proliferation, migration, and invasion of GC cells. Materials and Methods: The expression levels of LETM1 in the normal gastric mucosal epithelial cells (GES-1) and GC cells were analyzed by quantitative real-time polymerase chain reaction and western blotting. CCK-8, wound healing, and Transwell invasion assays were performed to evaluate the effect of LETM1 knockdown or overexpression on the proliferation, migration, and invasion of the GC cells, respectively. Additionally, the effect of LETM1 knockdown or overexpression on GC cell apoptosis was determined by flow cytometry. Furthermore, the effect of LETM1 knockdown or overexpression on the expression levels of PI3K/Akt signaling pathway-related proteins was evaluated by western blotting. Results: The GC cells exhibited markedly higher mRNA and protein expression levels of LETM1 than the GES-1 cells. Additionally, the knockdown of LETM1 remarkably suppressed the GC cell proliferation, migration, and invasion, and promoted the apoptosis of GC cells, which were reversed upon LETM1 overexpression. Furthermore, the western blotting analysis indicated that LETM1 facilitates GC progression via the PI3K/Akt signaling pathway. Conclusions: LETM1 acts as an oncogenic gene to promote GC cell proliferation, migration, and invasion via the PI3K/Akt signaling pathway. Therefore, LETM1 may be a potential target for GC diagnosis and treatment.

Keywords

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386. https://doi.org/10.1002/ijc.29210
  2. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet 2016;388:2654-2664. https://doi.org/10.1016/S0140-6736(16)30354-3
  3. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 2002;347:1175-1186. https://doi.org/10.1056/NEJMra020542
  4. Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett 2014;345:196-202. https://doi.org/10.1016/j.canlet.2013.08.016
  5. Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol 2015;16:e60-e70. https://doi.org/10.1016/S1470-2045(14)71016-2
  6. Wu CW, Hsiung CA, Lo SS, Hsieh MC, Chen JH, Li AF, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol 2006;7:309-315. https://doi.org/10.1016/S1470-2045(06)70623-4
  7. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12:354-362. https://doi.org/10.3748/wjg.v12.i3.354
  8. Dassen AE, Lemmens VE, van de Poll-Franse LV, Creemers GJ, Brenninkmeijer SJ, Lips DJ, et al. Trends in incidence, treatment and survival of gastric adenocarcinoma between 1990 and 2007: a population-based study in the Netherlands. Eur J Cancer 2010;46:1101-1110. https://doi.org/10.1016/j.ejca.2010.02.013
  9. Hsieh HL, Tsai MM. Tumor progression-dependent angiogenesis in gastric cancer and its potential application. World J Gastrointest Oncol 2019;11:686-704. https://doi.org/10.4251/wjgo.v11.i9.686
  10. Hart L, Rauch A, Carr AM, Vermeesch JR, O'Driscoll M. LETM1 haploinsufficiency causes mitochondrial defects in cells from humans with Wolf-Hirschhorn syndrome: implications for dissecting the underlying pathomechanisms in this condition. Dis Model Mech 2014;7:535-545. https://doi.org/10.1242/dmm.014464
  11. Li Y, Tran Q, Shrestha R, Piao L, Park S, Park J, et al. LETM1 is required for mitochondrial homeostasis and cellular viability (Review). Mol Med Rep 2019;19:3367-3375.
  12. Piao L, Li Y, Kim SJ, Byun HS, Huang SM, Hwang SK, et al. Association of LETM1 and MRPL36 contributes to the regulation of mitochondrial ATP production and necrotic cell death. Cancer Res 2009;69:3397-3404. https://doi.org/10.1158/0008-5472.CAN-08-3235
  13. Piao L, Li Y, Kim SJ, Sohn KC, Yang KJ, Park KA, et al. Regulation of OPA1-mediated mitochondrial fusion by leucine zipper/EF-hand-containing transmembrane protein-1 plays a role in apoptosis. Cell Signal 2009;21:767-777. https://doi.org/10.1016/j.cellsig.2009.01.020
  14. Chen L, Yang Y, Liu S, Piao L, Zhang Y, Lin Z, et al. High expression of leucine zipper-EF-hand containing transmembrane protein 1 predicts poor prognosis in head and neck squamous cell carcinoma. BioMed Res Int 2014;2014:850316. https://doi.org/10.1155/2014/850316
  15. Yang Z, Ni W, Cui C, Qi W, Piao L, Xuan Y. Identification of LETM1 as a marker of cancer stem-like cells and predictor of poor prognosis in esophageal squamous cell carcinoma. Hum Pathol 2018;81:148-156. https://doi.org/10.1016/j.humpath.2018.07.001
  16. Elmenier FM, Lasheen DS, Abouzid KA. Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer. Eur J Med Chem 2019;183:111718. https://doi.org/10.1016/j.ejmech.2019.111718
  17. Ye B, Jiang LL, Xu HT, Zhou DW, Li ZS. Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol 2012;25:627-636. https://doi.org/10.1177/039463201202500309
  18. Yu HG, Ai YW, Yu LL, Zhou XD, Liu J, Li JH, et al. Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer 2008;122:433-443. https://doi.org/10.1002/ijc.23049
  19. Kobayashi I, Semba S, Matsuda Y, Kuroda Y, Yokozaki H. Significance of Akt phosphorylation on tumor growth and vascular endothelial growth factor expression in human gastric carcinoma. Pathobiology 2006;73:8-17. https://doi.org/10.1159/000093087
  20. Newton AC, Trotman LC. Turning off AKT: PHLPP as a drug target. Annu Rev Pharmacol Toxicol 2014;54:537-558. https://doi.org/10.1146/annurev-pharmtox-011112-140338
  21. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489-501. https://doi.org/10.1038/nrc839
  22. Hwang SK, Piao L, Lim HT, Minai-Tehrani A, Yu KN, Ha YC, et al. Suppression of lung tumorigenesis by leucine zipper/EF hand-containing transmembrane-1. PLoS One 2010;5:e12535. https://doi.org/10.1371/journal.pone.0012535
  23. Piao L, Feng Y, Yang Z, Qi W, Li H, Han H, et al. LETM1 is a potential cancer stem-like cell marker and predicts poor prognosis in colorectal adenocarcinoma. Pathol Res Pract 2019;215:152437. https://doi.org/10.1016/j.prp.2019.152437
  24. Chen L, Zhang K, Ye C, Chen S, Cao Y, Zhang Y. The expression of LETM1 in gastric cancer and its correlation with prognosis. J Anhui Med Univ 2019;54:1430-1434.
  25. Uhlen M, Zhang C, Lee S, Sjostedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science 2017;357:eaan2507. https://doi.org/10.1126/science.aan2507
  26. Szasz AM, Lanczky A, Nagy A, Forster S, Hark K, Green JE, et al. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget 2016;7:49322-49333. https://doi.org/10.18632/oncotarget.10337
  27. Zhang Y, Zhang R, Luo G, Ai K. Long noncoding RNA SNHG1 promotes cell proliferation through PI3K/AKT signaling pathway in pancreatic ductal adenocarcinoma. J Cancer 2018;9:2713-2722. https://doi.org/10.7150/jca.26207
  28. Kim C, Mulder K, Spratlin J. How prognostic and predictive biomarkers are transforming our understanding and management of advanced gastric cancer. Oncologist 2014;19:1046-1055. https://doi.org/10.1634/theoncologist.2014-0006
  29. Puneet, Kazmi HR, Kumari S, Tiwari S, Khanna A, Narayan G. Epigenetic mechanisms and events in gastric cancer-emerging novel biomarkers. Pathol Oncol Res 2018;24:757-770. https://doi.org/10.1007/s12253-018-0410-z
  30. Xu J, Huang B, Li S, Zhang X, Xie T, Xu Y. Knockdown of LETM1 inhibits proliferation and metastasis of human renal cell carcinoma cells. Oncol Lett 2018;16:6377-6382.
  31. Li N, Zheng Y, Xuan C, Lin Z, Piao L, Liu S. LETM1 overexpression is correlated with the clinical features and survival outcome of breast cancer. Int J Clin Exp Pathol 2015;8:12893-12900.
  32. Huang B, Zhang J, Zhang X, Huang C, Hu G, Li S, et al. Suppression of LETM1 by siRNA inhibits cell proliferation and invasion of bladder cancer cells. Oncol Rep 2017;38:2935-2940. https://doi.org/10.3892/or.2017.5959
  33. Piao L, Yang Z, Feng Y, Zhang C, Cui C, Xuan Y. LETM1 is a potential biomarker of prognosis in lung non-small cell carcinoma. BMC Cancer 2019;19:898. https://doi.org/10.1186/s12885-019-6128-9
  34. Burris HA 3rd. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol 2013;71:829-842. https://doi.org/10.1007/s00280-012-2043-3
  35. Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 2014;142:164-175. https://doi.org/10.1016/j.pharmthera.2013.12.004
  36. Soussi T, Wiman KG. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 2007;12:303-312. https://doi.org/10.1016/j.ccr.2007.10.001
  37. Bykov VJ, Eriksson SE, Bianchi J, Wiman KG. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer 2018;18:89-102. https://doi.org/10.1038/nrc.2017.109
  38. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 2002;277:21843-21850. https://doi.org/10.1074/jbc.M109745200

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