nach oben

Esophagus

Erschienen in:

02.04.2020 | Original Article

ATP6V0D2, a subunit associated with proton transport, serves an oncogenic role in esophagus cancer and is correlated with epithelial–mesenchymal transition

verfasst von: Ming Qi, Dong-Mei Liu, Wei Ji, Hai-Ling Wang

Erschienen in: Esophagus | Ausgabe 4/2020

Einloggen, um Zugang zu erhalten

Abstract

Background

The poor prognosis of esophagus cancer (EC) is mainly due to its high invasiveness and metastasis, so it is urgent to search effectively prognostic markers and explore their roles in the mechanism of metastasis.

Materials and methods

Based on the TCGA database, we downloaded the RNA-Seq for analyzing the expression of ATP6V0D2. QRT-PCR was used to test the mRNA levels of ATP6V0D2 in cell lines. Chi-square tests were used to evaluate the correlation between ATP6V0D2 and clinical characteristics. Prognostic values were determined by Kaplan–Meier methods and cox’s regression models. CCK-8 and clone formation assays were employed to evaluate the cell viability, and Transwell assay was implemented to determine the invasive and migratory abilities. Correlations between ATP6V0D2 and motion-related markers were analyzed by the GEPIA database and confirmed by western blot. Moreover, the relationship between ATP6V0D2 and molecules related to cell cycle and apoptosis was also determined by western blot.

Results

A significant increase was observed in 3 EC-related cell lines compared to the normal cell line. ATP6V0D2 has a connection with the poor prognosis and can be considered as an independent prognosticator for patients with EC. Besides, ATP6V0D2 can improve cells viability as well as invasive and migratory abilities. What’s more, downregulation of ATP6V0D2 notably enhanced E-cadherin expression, while decreased N-cadherin, Vimentin, and MMP9 expression, whereas overexpression of ATP6V0D2 presented the opposite outcomes. Furthermore, we found that silencing ATP6V0D2 led to a significant reduction on the protein expression of Cyclin D1, CDK4, Bcl-2, whereas resulted in a notable enhancement on the Bax level.

Conclusion

ATP6V0D2 might be an independent prognosticator for EC patients, and it possibly promotes tumorigenesis by regulating epithelial–mesenchymal transition, cell cycle and apoptosis-related markers, providing the possibility that ATP6V0D2 may be a novel biomarker for the therapeutic intervention of EC.

Nur mit Berechtigung zugänglich

Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86. https://doi.org/10.1002/ijc.29210.CrossRefPubMed

Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66:271–89. https://doi.org/10.3322/caac.21349.CrossRefPubMed

Gupta B, Kumar N. Worldwide incidence, mortality and time trends for cancer of the oesophagus. Eur J Cancer Prev. 2017;26:107–18. https://doi.org/10.1097/cej.0000000000000249.CrossRefPubMed

Lin Y, Totsuka Y, Shan B, et al. Esophageal cancer in high-risk areas of China: research progress and challenges. Ann Epidemiol. 2017;27:215–21. https://doi.org/10.1016/j.annepidem.2016.11.004.CrossRefPubMed

Li JY, Liu BQ, Li GY, et al. Atlas of cancer mortality in the People's Republic of China. An aid for cancer control and research. Int J Epidemiol. 1981;10:127–33. https://doi.org/10.1093/ije/10.2.127.CrossRefPubMed

Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32. https://doi.org/10.3322/caac.21338.CrossRefPubMed

Incarbone R, Bonavina L, Szachnowicz S, et al. Rising incidence of esophageal adenocarcinoma in Western countries: is it possible to identify a population at risk? Dis Esophagus. 2000;13:275–8. https://doi.org/10.1046/j.1442-2050.2000.00132.x.CrossRefPubMed

Lagergren J, Smyth E, Cunningham D, et al. Oesophageal cancer. Lancet. 2017;390:2383–96. https://doi.org/10.1016/s0140-6736(17)31462-9.CrossRefPubMed

Shang L, Wang M. Molecular alterations and clinical relevance in esophageal squamous cell carcinoma. Front Med. 2013;7:401–10. https://doi.org/10.1007/s11684-013-0286-y.CrossRefPubMed

10.

Lambert R. Endoscopic detection and treatment of early esophageal cancer: a critical analysis. Endoscopy. 1995;27:12–8. https://doi.org/10.1055/s-2007-1005626(discussion 58-9).CrossRefPubMed

11.

Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–52. https://doi.org/10.1056/NEJMra035010.CrossRefPubMed

12.

Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol. 2007;8:917–29. https://doi.org/10.1038/nrm2272.CrossRefPubMed

13.

Marshansky V, Rubinstein JL, Gruber G. Eukaryotic V-ATPase: novel structural findings and functional insights. Biochim Biophys Acta. 2014;1837:857–79. https://doi.org/10.1016/j.bbabio.2014.01.018.CrossRefPubMed

14.

Jefferies KC, Cipriano DJ, Forgac M. Function, structure and regulation of the vacuolar (H+)-ATPases. Arch Biochem Biophys. 2008;476:33–42. https://doi.org/10.1016/j.abb.2008.03.025.CrossRefPubMedPubMedCentral

15.

Qin A, Cheng TS, Pavlos NJ, et al. V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption. Int J Biochem Cell Biol. 2012;44:1422–35. https://doi.org/10.1016/j.biocel.2012.05.014.CrossRefPubMed

16.

Stransky L, Cotter K, Forgac M. The function of V-ATPases in cancer. Physiol Rev. 2016;96:1071–91. https://doi.org/10.1152/physrev.00035.2015.CrossRefPubMedPubMedCentral

17.

Kane PM. Targeting reversible disassembly as a mechanism of controlling V-ATPase activity. Curr Protein Pept Sci. 2012;13:117–23. https://doi.org/10.2174/138920312800493142.CrossRefPubMedPubMedCentral

18.

Cotter K, Stransky L, McGuire C, et al. Recent insights into the structure, regulation, and function of the V-ATPases. Trends Biochem Sci. 2015;40:611–22. https://doi.org/10.1016/j.tibs.2015.08.005.CrossRefPubMedPubMedCentral

19.

Capecci J, Forgac M. The function of vacuolar ATPase (V-ATPase) a subunit isoforms in invasiveness of MCF10a and MCF10CA1a human breast cancer cells. J Biol Chem. 2013;288:32731–41. https://doi.org/10.1074/jbc.M113.503771.CrossRefPubMedPubMedCentral

20.

Hirata T, Iwamoto-Kihara A, Sun-Wada GH, et al. Subunit rotation of vacuolar-type proton pumping ATPase: relative rotation of the G and C subunits. J Biol Chem. 2003;278:23714–9. https://doi.org/10.1074/jbc.M302756200.CrossRefPubMed

21.

Fukamachi T, Ikeda S, Saito H, et al. Expression of acidosis-dependent genes in human cancer nests. Mol Clin Oncol. 2014;2:1160–6. https://doi.org/10.3892/mco.2014.344.CrossRefPubMedPubMedCentral

22.

Yang J, Guo F, Yuan L, et al. Elevated expression of the V-ATPase D2 subunit triggers increased energy metabolite levels in Kras(G12D) -driven cancer cells. J Cell Biochem. 2019. https://doi.org/10.1002/jcb.28448.CrossRefPubMedPubMedCentral

23.

Morimura T, Fujita K, Akita M, et al. The proton pump inhibitor inhibits cell growth and induces apoptosis in human hepatoblastoma. Pediatr Surg Int. 2008;24:1087–94. https://doi.org/10.1007/s00383-008-2229-2.CrossRefPubMed

24.

Pennathur A, Gibson MK, Jobe BA, et al. Oesophageal carcinoma. Lancet. 2013;381:400–12. https://doi.org/10.1016/s0140-6736(12)60643-6.CrossRefPubMed

25.

Zhang JX, Tong ZT, Yang L, et al. PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma. Int J Cancer. 2013;132:2567–77. https://doi.org/10.1002/ijc.27930.CrossRefPubMed

26.

Ge XS, Ma HJ, Zheng XH, et al. HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway. Cancer Sci. 2013;104:1675–82. https://doi.org/10.1111/cas.12296.CrossRefPubMedPubMedCentral

27.

Li J, Zhang BZ, Qin YR, et al. CD68 and interleukin 13, prospective immune markers for esophageal squamous cell carcinoma prognosis prediction. Oncotarget. 2016;7:15525–38. https://doi.org/10.18632/oncotarget.6900.CrossRefPubMedPubMedCentral

28.

Zeidel ML, Silva P, Seifter JL. Intracellular pH regulation and proton transport by rabbit renal medullary collecting duct cells. Role of plasma membrane proton adenosine triphosphatase. J Clin Investig. 1986;77:113–20. https://doi.org/10.1172/jci112264.CrossRefPubMedPubMedCentral

29.

Smith AN, Borthwick KJ, Karet FE. Molecular cloning and characterization of novel tissue-specific isoforms of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in autosomal recessive distal renal tubular acidosis. Gene. 2002;297:169–77. https://doi.org/10.1016/s0378-1119(02)00884-3.CrossRefPubMed

30.

Liu N, Luo J, Kuang D, et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2alpha-mediated tumor progression. J Clin Investig. 2019;129:631–46. https://doi.org/10.1172/jci123027.CrossRefPubMedPubMedCentral

31.

Hernandez A, Serrano G, Herrera-Palau R, et al. Intraorganellar acidification by V-ATPases: a target in cell proliferation and cancer therapy. Recent Pat Anticancer Drug Discov. 2010;5:88–98. https://doi.org/10.2174/157489210790936216.CrossRefPubMed

32.

Martinez-Zaguilan R, Lynch RM, Martinez GM, et al. Vacuolar-type H(+)-ATPases are functionally expressed in plasma membranes of human tumor cells. Am J Physiol. 1993;265:C1015–29. https://doi.org/10.1152/ajpcell.1993.265.4.C1015.CrossRefPubMed

33.

Finbow ME, Harrison MA. The vacuolar H+-ATPase: a universal proton pump of eukaryotes. Biochem J. 1997;324(Pt 3):697–712. https://doi.org/10.1042/bj3240697.CrossRefPubMedPubMedCentral

34.

Hinton A, Bond S, Forgac M. V-ATPase functions in normal and disease processes. Pflugers Arch. 2009;457:589–98. https://doi.org/10.1007/s00424-007-0382-4.CrossRefPubMed

35.

McGuire C, Cotter K, Stransky L, et al. Regulation of V-ATPase assembly and function of V-ATPases in tumor cell invasiveness. Biochim Biophys Acta. 2016;1857:1213–8. https://doi.org/10.1016/j.bbabio.2016.02.010.CrossRefPubMedPubMedCentral

36.

Komatsu S, Shioaki Y, Ichikawa D, et al. Survival and clinical evaluation of salvage operation for cervical lymph node recurrence in esophageal cancer. Hepatogastroenterology. 2005;52:796–9. https://doi.org/10.1364/JOSAA.16.002136.CrossRefPubMed

37.

Li S, Qin X, Chai S, et al. Modulation of E-cadherin expression promotes migration ability of esophageal cancer cells. Sci Rep. 2016;6:21713. https://doi.org/10.1038/srep21713.CrossRefPubMedPubMedCentral

38.

Jung S, Hong HK, Bo YO, et al. Abstract LB-186: Twist-1 overexpression modulates cancer progression according to the microsatellite instability status in colorectal cancer cell lines. Cancer Res. 2014;74:LB-186–LB-186. https://doi.org/10.1158/1538-7445.AM2014-LB-186.CrossRef

39.

Yeung KT, Yang J. Epithelial–mesenchymal transition in tumor metastasis. Mol Oncol. 2017;11:28–39. https://doi.org/10.1002/1878-0261.12017.CrossRefPubMed

40.

Dongre A, Weinberg RA. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20:69–84. https://doi.org/10.1038/s41580-018-0080-4.CrossRefPubMed

41.

Wang G, Tang J, Zhan W, et al. CBX8 suppresses tumor metastasis via repressing snail in esophageal squamous cell carcinoma. Theranostics. 2017;7:3478–88. https://doi.org/10.7150/thno.20717.CrossRefPubMedPubMedCentral

42.

Wang L, Li M, Zhan Y, et al. Down-regulation of POTEG predicts poor prognosis in esophageal squamous cell carcinoma patients. Mol Carcinog. 2018;57:886–95. https://doi.org/10.1002/mc.22809.CrossRefPubMedPubMedCentral

43.

He X, Xu X, Zhu G, et al. Circulating uPA as a potential prognostic biomarker for resectable esophageal squamous cell carcinoma. Medicine. 2019;98:e14717. https://doi.org/10.1097/md.0000000000014717.CrossRefPubMedPubMedCentral

44.

Xia T, Tong S, Fan K, et al. XBP1 induces MMP-9 expression to promote proliferation and invasion in human esophageal squamous cell carcinoma. Am J Cancer Res. 2016;6:2031–40.PubMedPubMedCentral

45.

Yamamoto H, Vinitketkumnuen A, Adachi Y, et al. Association of matrilysin-2 (MMP-26) expression with tumor progression and activation of MMP-9 in esophageal squamous cell carcinoma. Carcinogenesis. 2004;25:2353–60. https://doi.org/10.1093/carcin/bgh270.CrossRefPubMed

46.

Pachmayr E, Treese C, Stein U. Underlying mechanisms for distant metastasis—molecular biology. Visc Med. 2017;33:11–20. https://doi.org/10.1159/000454696.CrossRefPubMedPubMedCentral

47.

John RR, Malathi N, Ravindran C, et al. Mini review: multifaceted role played by cyclin D1 in tumor behavior. Indian J Dent Res. 2017;28:187–92. https://doi.org/10.4103/ijdr.IJDR_697_16.CrossRefPubMed

48.

Gao YB, Chen ZL, Li JG, et al. Genetic landscape of esophageal squamous cell carcinoma. Nat Genet. 2014;46:1097–102. https://doi.org/10.1038/ng.3076.CrossRefPubMed

49.

Zhang H, Xia J, Wang K, et al. Serum autoantibodies in the early detection of esophageal cancer: a systematic review. Tumour Biol. 2015;36:95–109. https://doi.org/10.1007/s13277-014-2878-9.CrossRefPubMed

50.

Wei W, Wang Y, Yu X, et al. Expression of TP53, BCL-2, and VEGFA genes in esophagus carcinoma and its biological significance. Med Sci Monit. 2015;21:3016–22. https://doi.org/10.12659/msm.894640.CrossRefPubMedPubMedCentral

51.

Appelman HD, Matejcic M, Parker MI, et al. Progression of esophageal dysplasia to cancer. Ann N Y Acad Sci. 2014;1325:96–107. https://doi.org/10.1111/nyas.12523.CrossRefPubMed

52.

Xu XL, Zheng WH, Tao KY, et al. p53 is an independent prognostic factor in operable esophageal squamous cell carcinoma: a large-scale study with a long follow-up. Med Oncol. 2014;31:257. https://doi.org/10.1007/s12032-014-0257-4.CrossRefPubMed

Titel: ATP6V0D2, a subunit associated with proton transport, serves an oncogenic role in esophagus cancer and is correlated with epithelial–mesenchymal transition
verfasst von: Ming Qi
Dong-Mei Liu
Wei Ji
Hai-Ling Wang
Publikationsdatum: 02.04.2020
Verlag: Springer Singapore
Erschienen in: Esophagus / Ausgabe 4/2020
Print ISSN: 1612-9059
Elektronische ISSN: 1612-9067
DOI: https://doi.org/10.1007/s10388-020-00735-8

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

25.04.2024 | Hypotonie | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

ATP6V0D2, a subunit associated with proton transport, serves an oncogenic role in esophagus cancer and is correlated with epithelial–mesenchymal transition

Abstract

Background

Materials and methods

Results

Conclusion

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Update Innere Medizin

Springer Medizin

Abstract

Background

Materials and methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2020

Submucosal gland neoplasms of the esophagus: an update and review

Peroral endoscopic shorter versus longer myotomy for the treatment of achalasia: a comparative retrospective study

Review of early endoscopic findings in patients with local recurrence after definitive chemoradiotherapy for esophageal squamous cell carcinoma

Holographic image-guided thoracoscopic surgery: possibility of usefulness for esophageal cancer patients with abnormal artery

Efficacy of prewarming prophylaxis method for intraoperative hypothermia during thoracoscopic esophagectomy

Prophylactic steroid administration against strictures is not enough for mucosal defects involving the entire circumference of the esophageal lumen after esophageal endoscopic submucosal dissection (ESD)

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Update Innere Medizin