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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Research

A positive feedback loop between TAZ and miR-942-3p modulates proliferation, angiogenesis, epithelial-mesenchymal transition process, glycometabolism and ROS homeostasis in human bladder cancer

Authors: Feifan Wang, Mengjing Fan, Xuejian Zhou, Yanlan Yu, Yueshu Cai, Hongshen Wu, Yan Zhang, Jiaxin Liu, Shihan Huang, Ning He, Zhenghui Hu, Guoqing Ding, Xiaodong Jin

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Transcriptional coactivator with PDZ-binding motif (TAZ) has been reported to be involved in tumor progression, angiogenesis, epithelial-mesenchymal transition (EMT), glycometabolic modulation and reactive oxygen species (ROS) buildup. Herein, the underlying molecular mechanisms of the TAZ-induced biological effects in bladder cancer were discovered.

Methods

qRT-PCR, western blotting and immunohistochemistry were performed to determine the levels of TAZ in bladder cancer cells and tissues. CCK-8, colony formation, tube formation, wound healing and Transwell assays and flow cytometry were used to evaluate the biological functions of TAZ, miR-942-3p and growth arrest-specific 1 (GAS1). QRT-PCR and western blotting were used to determine the expression levels of related genes. Chromatin immunoprecipitation and a dual-luciferase reporter assay were performed to confirm the interaction between TAZ and miR-942. In vivo tumorigenesis and colorimetric glycolytic assays were also conducted.

Results

We confirmed the upregulation and vital roles of TAZ in bladder cancer. TAZ-induced upregulation of miR-942-3p expression amplified upstream signaling by inhibiting the expression of large tumor suppressor 2 (LATS2, a TAZ inhibitor). MiR-942-3p attenuated the impacts on cell proliferation, angiogenesis, EMT, glycolysis and ROS levels induced by TAZ knockdown. Furthermore, miR-942-3p restrained the expression of GAS1 to modulate biological behaviors.

Conclusion

Our study identified a novel positive feedback loop between TAZ and miR-942-3p that regulates biological functions in bladder cancer cells via GAS1 expression and illustrated that TAZ, miR-942-3p and GAS1 might be potential therapeutic targets for bladder cancer treatment.

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Burge F, Kockelbergh R. Closing the gender gap: can we improve bladder Cancer survival in women? - a systematic review of diagnosis treatment and outcomes. Urol Int. 2016;97:373–9. https://doi.org/10.1159/000449256.CrossRefPubMed

Dobruch J, et al. Gender and bladder Cancer: a collaborative review of etiology, biology, and outcomes. Eur Urol. 2016;69:300–10. https://doi.org/10.1016/j.eururo.2015.08.037.CrossRefPubMed

Thorstenson A, et al. Gender-related differences in urothelial carcinoma of the bladder: a population-based study from the Swedish National Registry of urinary bladder Cancer. Scand J Urol. 2016;50:292–7. https://doi.org/10.3109/21681805.2016.1158207.CrossRefPubMed

Antoni S, et al. Bladder Cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71:96–108. https://doi.org/10.1016/j.eururo.2016.06.010.CrossRefPubMed

Kamat AM, et al. Bladder cancer. Lancet. 2016;388:2796–810. https://doi.org/10.1016/S0140-6736(16)30512-8.CrossRefPubMed

Sanli O, et al. Bladder cancer. Nat Rev Dis Primers. 2017;3:17022. https://doi.org/10.1038/nrdp.2017.22.CrossRefPubMed

Soloway MS. Bladder cancer: lack of progress in bladder cancer--what are the obstacles? Nat Rev Urol. 2013;10:5–6. https://doi.org/10.1038/nrurol.2012.219.CrossRefPubMed

Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and Cancer. Cell. 2015;163:811–28. https://doi.org/10.1016/j.cell.2015.10.044.CrossRefPubMedPubMedCentral

Maugeri-Sacca M, De Maria R. The hippo pathway in normal development and cancer. Pharmacol Ther. 2018;186:60–72. https://doi.org/10.1016/j.pharmthera.2017.12.011.CrossRefPubMed

10.

Zheng X, et al. LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism. Embo J. 2017;36:3325–35. https://doi.org/10.15252/embj.201797609.CrossRefPubMedPubMedCentral

11.

Cox AG, et al. Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth. Embo J. 2018;37. https://doi.org/10.15252/embj.2018100294.

12.

Koo JH, Guan KL. Interplay between YAP/TAZ and metabolism. Cell Metab. 2018;28:196–206. https://doi.org/10.1016/j.cmet.2018.07.010.CrossRefPubMed

13.

Zhang X, et al. The role of YAP/TAZ activity in cancer metabolic reprogramming. Mol Cancer. 2018;17:134. https://doi.org/10.1186/s12943-018-0882-1.CrossRefPubMedPubMedCentral

14.

White SM, et al. YAP/TAZ inhibition induces metabolic and signaling rewiring resulting in targetable vulnerabilities in NF2-deficient tumor cells. Dev Cell. 2019;49:425–443.e429. https://doi.org/10.1016/j.devcel.2019.04.014.CrossRefPubMedPubMedCentral

15.

Kim J, et al. YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest. 2017;127:3441–61. https://doi.org/10.1172/jci93825.CrossRefPubMedPubMedCentral

16.

Han LL, Yin XR, Zhang SQ. miR-103 promotes the metastasis and EMT of hepatocellular carcinoma by directly inhibiting LATS2. Int J Oncol. 2018;53:2433–44. https://doi.org/10.3892/ijo.2018.4580.CrossRefPubMedPubMedCentral

17.

Hu Y, et al. miR-665 promotes hepatocellular carcinoma cell migration, invasion, and proliferation by decreasing Hippo signaling through targeting PTPRB. Cell Death Dis. 2018;9:954. https://doi.org/10.1038/s41419-018-0978-y.CrossRefPubMedPubMedCentral

18.

Yao P, et al. ANKHD1 silencing suppresses the proliferation, migration and invasion of CRC cells by inhibiting YAP1-induced activation of EMT. Am J Cancer Res. 2018;8:2311–24.PubMedPubMedCentral

19.

Braitsch CM, et al. LATS1/2 suppress NFkappaB and aberrant EMT initiation to permit pancreatic progenitor differentiation. PLoS Biol. 2019;17:e3000382. https://doi.org/10.1371/journal.pbio.3000382.CrossRefPubMedPubMedCentral

20.

Karvonen H, Barker H, Kaleva L, Niininen W, Ungureanu D. Molecular mechanisms associated with ROR1-mediated drug resistance: crosstalk with hippo-YAP/TAZ and BMI-1 pathways. Cells. 2019;8. https://doi.org/10.3390/cells8080812.

21.

De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110. https://doi.org/10.1038/nrc3447.CrossRefPubMed

22.

Diepenbruck M, Christofori G. Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol. 2016;43:7–13. https://doi.org/10.1016/j.ceb.2016.06.002.CrossRefPubMed

23.

Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019;29:212–26. https://doi.org/10.1016/j.tcb.2018.12.001.CrossRefPubMed

24.

Lemasters JJ. The mitochondrial permeability transition: from biochemical curiosity to pathophysiological mechanism. Gastroenterology. 1998;115:783–6.CrossRefPubMed

25.

Singh M, Yelle N, Venugopal C, Singh SK. EMT: mechanisms and therapeutic implications. Pharmacol Ther. 2018;182:80–94. https://doi.org/10.1016/j.pharmthera.2017.08.009.CrossRefPubMed

26.

Xu Z, et al. Sodium butyrate inhibits colorectal Cancer cell migration by Downregulating Bmi-1 through enhanced miR-200c expression. Mol Nutr Food Res. 2018;62:e1700844. https://doi.org/10.1002/mnfr.201700844.CrossRefPubMed

27.

Wang F, et al. Sodium butyrate inhibits migration and induces AMPK-mTOR pathway-dependent autophagy and ROS-mediated apoptosis via the miR-139-5p/Bmi-1 axis in human bladder cancer cells. FASEB J. 2020. https://doi.org/10.1096/fj.201902626R.

28.

Meng Z, Moroishi T, Guan KL. Mechanisms of hippo pathway regulation. Genes Dev. 2016;30:1–17. https://doi.org/10.1101/gad.274027.115.CrossRefPubMedPubMedCentral

29.

Zhao B, Li L, Lei Q, Guan KL. The hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24:862–74. https://doi.org/10.1101/gad.1909210.CrossRefPubMedPubMedCentral

30.

Lin KC, et al. Regulation of hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nat Cell Biol. 2017;19:996–1002. https://doi.org/10.1038/ncb3581.CrossRefPubMedPubMedCentral

31.

Lin KC, Park HW, Guan KL. Regulation of the hippo pathway transcription factor TEAD. Trends Biochem Sci. 2017;42:862–72. https://doi.org/10.1016/j.tibs.2017.09.003.CrossRefPubMedPubMedCentral

32.

Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136:642–55. https://doi.org/10.1016/j.cell.2009.01.035.CrossRefPubMedPubMedCentral

33.

Kloosterman WP, Plasterk RH. The diverse functions of microRNAs in animal development and disease. Dev Cell. 2006;11:441–50. https://doi.org/10.1016/j.devcel.2006.09.009.CrossRefPubMed

34.

Trang P, Weidhaas JB, Slack FJ. MicroRNAs as potential cancer therapeutics. Oncogene. 2008;27(Suppl 2):S52–7. https://doi.org/10.1038/onc.2009.353.CrossRefPubMed

35.

Chen Z, et al. miR-190b promotes tumor growth and metastasis via suppressing NLRC3 in bladder carcinoma. FASEB J. 2020. https://doi.org/10.1096/fj.201901764R.

36.

Jin H, et al. Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy. Autophagy. 2020:1–15. https://doi.org/10.1080/15548627.2020.1733262.

37.

Del Sal G, Ruaro ME, Philipson L, Schneider C. The growth arrest-specific gene, gas1, is involved in growth suppression. Cell. 1992;70:595–607. https://doi.org/10.1016/0092-8674(92)90429-g.CrossRefPubMed

38.

Ma Y, Qin H, Cui Y. MiR-34a targets GAS1 to promote cell proliferation and inhibit apoptosis in papillary thyroid carcinoma via PI3K/Akt/bad pathway. Biochem Biophys Res Commun. 2013;441:958–63. https://doi.org/10.1016/j.bbrc.2013.11.010.CrossRefPubMed

39.

Mo H, et al. WT1 is involved in the Akt-JNK pathway dependent autophagy through directly regulating Gas1 expression in human osteosarcoma cells. Biochem Biophys Res Commun. 2016;478:74–80. https://doi.org/10.1016/j.bbrc.2016.07.090.CrossRefPubMed

40.

Gao L, Wang S, Meng J, Sun Y. LncRNA LUADT1 promotes Oral squamous cell carcinoma cell proliferation by regulating miR-34a/GAS1 Axis. Cancer Manag Res. 2020;12:3401–7. https://doi.org/10.2147/cmar.S238830.CrossRefPubMedPubMedCentral

41.

Sarkar S, et al. Microglia induces Gas1 expression in human brain tumor-initiating cells to reduce tumorigenecity. Sci Rep. 2018;8:15286. https://doi.org/10.1038/s41598-018-33306-0.CrossRefPubMedPubMedCentral

42.

Conceicao AL, et al. Downregulation of OCLN and GAS1 in clear cell renal cell carcinoma. Oncol Rep. 2017;37:1487–96. https://doi.org/10.3892/or.2017.5414.CrossRefPubMed

43.

Li Q, et al. Gas1 inhibits metastatic and metabolic phenotypes in colorectal carcinoma. Mol Cancer Res. 2016;14:830–40. https://doi.org/10.1158/1541-7786.MCR-16-0032.CrossRefPubMed

44.

Jiménez A, et al. A soluble form of GAS1 inhibits tumor growth and angiogenesis in a triple negative breast cancer model. Exp Cell Res. 2014;327:307–17. https://doi.org/10.1016/j.yexcr.2014.06.016.CrossRefPubMed

45.

Yang D, et al. MiR-942 mediates hepatitis C virus-induced apoptosis via regulation of ISG12a. PLoS One. 2014;9:e94501. https://doi.org/10.1371/journal.pone.0094501.CrossRefPubMedPubMedCentral

46.

Xu CY, Dong JF, Chen ZQ, Ding GS, Fu ZR. MiR-942-3p promotes the proliferation and invasion of hepatocellular carcinoma cells by targeting MBL2. Cancer Control. 2019;26:1073274819846593. https://doi.org/10.1177/1073274819846593.CrossRefPubMedPubMedCentral

47.

Holden JK, Cunningham CN. Targeting the hippo pathway and cancer through the TEAD family of transcription factors. Cancers (Basel). 2018;10. https://doi.org/10.3390/cancers10030081.

48.

Sanchez-Hernandez L, Hernandez-Soto J, Vergara P, Gonzalez RO, Segovia J. Additive effects of the combined expression of soluble forms of GAS1 and PTEN inhibiting glioblastoma growth. Gene Ther. 2018;25:439–49. https://doi.org/10.1038/s41434-018-0020-0.CrossRefPubMed

49.

Hansen CG, Moroishi T, Guan KL. YAP and TAZ: a nexus for hippo signaling and beyond. Trends Cell Biol. 2015;25:499–513. https://doi.org/10.1016/j.tcb.2015.05.002.CrossRefPubMedPubMedCentral

50.

Moya IM, Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol. 2019;20:211–26. https://doi.org/10.1038/s41580-018-0086-y.CrossRefPubMed

51.

Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15:73–9. https://doi.org/10.1038/nrc3876.CrossRefPubMedPubMedCentral

52.

Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of Cancer. Cancer Cell. 2016;29:783–803. https://doi.org/10.1016/j.ccell.2016.05.005.CrossRefPubMedPubMedCentral

53.

Boopathy GTK, Hong W. Role of hippo pathway-YAP/TAZ signaling in angiogenesis. Front Cell Dev Biol. 2019;7:49. https://doi.org/10.3389/fcell.2019.00049.CrossRefPubMedPubMedCentral

54.

Pulkkinen HH, et al. BMP6/TAZ-hippo signaling modulates angiogenesis and endothelial cell response to VEGF. Angiogenesis. 2020. https://doi.org/10.1007/s10456-020-09748-4.

55.

Yuan W, et al. TAZ sensitizes EGFR wild-type non-small-cell lung cancer to gefitinib by promoting amphiregulin transcription. Cell Death Dis. 2019;10:283. https://doi.org/10.1038/s41419-019-1519-z.CrossRefPubMedPubMedCentral

56.

Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29:4741–51. https://doi.org/10.1038/onc.2010.215.CrossRefPubMedPubMedCentral

57.

Lei QY, et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008;28:2426–36. https://doi.org/10.1128/mcb.01874-07.CrossRefPubMedPubMedCentral

58.

Cordenonsi M, et al. The hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759–72. https://doi.org/10.1016/j.cell.2011.09.048.CrossRefPubMed

59.

Li Z, et al. The hippo transducer TAZ promotes epithelial to mesenchymal transition and cancer stem cell maintenance in oral cancer. Mol Oncol. 2015;9:1091–105. https://doi.org/10.1016/j.molonc.2015.01.007.CrossRefPubMedPubMedCentral

60.

Tang Y, Weiss SJ. Snail/slug-YAP/TAZ complexes cooperatively regulate mesenchymal stem cell function and bone formation. Cell Cycle. 2017;16:399–405. https://doi.org/10.1080/15384101.2017.1280643.CrossRefPubMedPubMedCentral

61.

Lea MA, Kim H, Des BC. Effects of Biguanides on Growth and Glycolysis of Bladder and Colon Cancer Cells. Anticancer Res. 2018;38:5003–11. https://doi.org/10.21873/anticanres.12819.CrossRefPubMed

62.

Xian S, Shang D, Kong G, Tian Y. FOXJ1 promotes bladder cancer cell growth and regulates Warburg effect. Biochem Biophys Res Commun. 2018;495:988–94. https://doi.org/10.1016/j.bbrc.2017.11.063.CrossRefPubMed

63.

Chen J, Cao L, Li Z, Li Y. SIRT1 promotes GLUT1 expression and bladder cancer progression via regulation of glucose uptake. Hum Cell. 2019;32:193–201. https://doi.org/10.1007/s13577-019-00237-5.CrossRefPubMed

64.

Liberti MV, Locasale JW. The Warburg effect: how does it benefit Cancer cells? Trends Biochem Sci. 2016;41:211–8. https://doi.org/10.1016/j.tibs.2015.12.001.CrossRefPubMedPubMedCentral

65.

Shi Y, et al. Rac1-mediated DNA damage and inflammation promote Nf2 tumorigenesis but also limit cell-cycle progression. Dev Cell. 2016;39:452–65. https://doi.org/10.1016/j.devcel.2016.09.027.CrossRefPubMedPubMedCentral

66.

Yoshino H, et al. Aberrant expression of microRNAs in bladder cancer. Nat Rev Urol. 2013;10:396–404. https://doi.org/10.1038/nrurol.2013.113.CrossRefPubMed

67.

Zhang Y, et al. MiR-942 decreased before 20 weeks gestation in women with preeclampsia and was associated with the pathophysiology of preeclampsia in vitro. Clin Exp Hypertens. 2017;39:108–13. https://doi.org/10.1080/10641963.2016.1210619.CrossRefPubMed

Title: A positive feedback loop between TAZ and miR-942-3p modulates proliferation, angiogenesis, epithelial-mesenchymal transition process, glycometabolism and ROS homeostasis in human bladder cancer
Authors: Feifan Wang
Mengjing Fan
Xuejian Zhou
Yanlan Yu
Yueshu Cai
Hongshen Wu
Yan Zhang
Jiaxin Liu
Shihan Huang
Ning He
Zhenghui Hu
Guoqing Ding
Xiaodong Jin
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01846-5

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