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

NONO-TFE3 Fusion Promotes Aerobic Glycolysis and Angiogenesis by Targeting HIF1A in NONO-TFE3 Translocation Renal Cell Carcinoma

Author(s): Yi Chen, Lei Yang, Ning Liu, Qiancheng Shi, Xiaoqin Yin, Xiaodong Han, Weidong Gan* and Dongmei Li*

Volume 21, Issue 8, 2021

Published on: 12 April, 2021

Page: [713 - 723] Pages: 11

DOI: 10.2174/1568009621666210412115026

Price: $65

Abstract

Background: NONO-TFE3 translocation renal cell carcinoma (tRCC), one of the RCCs that are associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 tRCCs), involves an X chromosome inversion between NONO and TFE3 with the characteristics of endonuclear aggregation of NONO-TFE3 fusion protein. The oncogenic mechanisms of NONO-TFE3 fusion have not yet been fully elucidated.

Objective: This study aimed at investigating the mechanism of NONO-TFE3 fusion regulating HIF1A as well as the role of HIF-1α in the progression of NONO-TFE3 tRCC under hypoxia.

Methods: Immunohistochemistry and Western Blotting assays were performed to profile HIF-1α expression in renal clear cell carcinoma (ccRCC) or in Xp11.2 tRCC. Chromatin immunoprecipitation (ChIP), a luciferase reporter assay, and real-time quantitative PCR (RT-qPCR) were used to evaluate the regulation of HIF1A expression by NONO-TFE3 fusion. Then, the flow cytometry analysis, tube formation assays, and cell migration assays were used as well as glucose or lactic acid levels were measured to establish the impact of HIF-1α on the progression of NONO-TFE3 tRCC. Besides, the effect of HIF-1α inhibitor (PX-478) on UOK109 cells was analyzed.

Results: We found that HIF1A was the target gene of NONO-TFE3 fusion. In UOK109 cells, which were isolated from NONO-TFE3 tRCC samples, NONO-TFE3 fusion promoted aerobic glycolysis and angiogenesis by up-regulating the expression of HIF-1α under hypoxia. Furthermore, the inhibition of HIF-1α mediated by PX-478 suppressed the development of NONO-TFE3 tRCC under hypoxia.

Conclusion: HIF-1α is a potential target for therapy of NONO-TFE3 tRCC under hypoxia.

Keywords: NONO-TFE3 fusion, HIF-1α, hypoxia, angiogenesis, aerobic glycolysis, carcinoma.

« Previous
Graphical Abstract

[1]
Wang, H.; Jing, H.; Cao, Z.; Liu, Q. Renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusion: Report of 5 cases and literature review. Clin. Nephrol., 2019, 91(3), 192-194.
[http://dx.doi.org/10.5414/CN109619] [PMID: 30371348]
[2]
Wang, Y.; Wang, Y.; Feng, M.; Lian, X.; Lei, Y.; Zhou, H. Renal cell carcinoma associated with Xp11.2 translocation/transcription factor E3 gene fusion: an adult case report and literature review. J. Int. Med. Res., 2020, 48(10), 300060520942095.
[http://dx.doi.org/10.1177/0300060520942095] [PMID: 33026261]
[3]
Mir, M.C.; Trilla, E.; de Torres, I.M.; Panizo, A.; Zlotta, A.R.; Van Rhijn, B.; Morote, J. Altered transcription factor E3 expression in unclassified adult renal cell carcinoma indicates adverse pathological features and poor outcome. BJU Int., 2011, 108(2 Pt 2), E71-E76.
[http://dx.doi.org/10.1111/j.1464-410X.2010.09818.x] [PMID: 21070573]
[4]
Lopez-Beltran, A.; Scarpelli, M.; Montironi, R.; Kirkali, Z. 2004 WHO classification of the renal tumors of the adults. Eur. Urol., 2006, 49(5), 798-805.
[http://dx.doi.org/10.1016/j.eururo.2005.11.035] [PMID: 16442207]
[5]
Moch, H.; Cubilla, A.L.; Humphrey, P.A.; Reuter, V.E.; Ulbright, T.M. The 2016 WHO classification of tumours of the urinary system and male genital organs-Part A: Renal, penile, and testicular tumours. Eur. Urol., 2016, 70(1), 93-105.
[http://dx.doi.org/10.1016/j.eururo.2016.02.029] [PMID: 26935559]
[6]
Xia, Q.Y.; Wang, Z.; Chen, N.; Gan, H.L.; Teng, X.D.; Shi, S.S.; Wang, X.; Wei, X.; Ye, S.B.; Li, R.; Ma, H.H.; Lu, Z.F.; Zhou, X.J.; Rao, Q. Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement. Mod. Pathol., 2017, 30(3), 416-426.
[http://dx.doi.org/10.1038/modpathol.2016.204] [PMID: 27934879]
[7]
Liu, N.; Guo, W.; Shi, Q.; Zhuang, W.; Pu, X.; Chen, S.; Qu, F.; Xu, L.; Zhao, X.; Li, X.; Zhang, G.; Guo, H.; Gan, W.; Li, D. The suitability of NONO-TFE3 dual-fusion FISH assay as a diagnostic tool for NONO-TFE3 renal cell carcinoma. Sci. Rep., 2020, 10(1), 16361.
[http://dx.doi.org/10.1038/s41598-020-73309-4] [PMID: 33004995]
[8]
Clark, J.; Lu, Y.J.; Sidhar, S.K.; Parker, C.; Gill, S.; Smedley, D.; Hamoudi, R.; Linehan, W.M.; Shipley, J.; Cooper, C.S. Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Oncogene, 1997, 15(18), 2233-2239.
[http://dx.doi.org/10.1038/sj.onc.1201394] [PMID: 9393982]
[9]
Argani, P.; Zhong, M.; Reuter, V.E.; Fallon, J.T.; Epstein, J.I.; Netto, G.J.; Antonescu, C.R. TFE3-fusion variant analysis defines specific clinicopathologic associations among Xp11 translocation cancers. Am. J. Surg. Pathol., 2016, 40(6), 723-737.
[http://dx.doi.org/10.1097/PAS.0000000000000631] [PMID: 26975036]
[10]
Kauffman, E.C.; Ricketts, C.J.; Rais-Bahrami, S.; Yang, Y.; Merino, M.J.; Bottaro, D.P.; Srinivasan, R.; Linehan, W.M. Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers. Nat. Rev. Urol., 2014, 11(8), 465-475.
[http://dx.doi.org/10.1038/nrurol.2014.162] [PMID: 25048860]
[11]
La Spina, M.; Contreras, P.S.; Rissone, A.; Meena, N.K.; Jeong, E.; Martina, J.A. MiT/TFE family of transcription factors: An evolutionary perspective. Front. Cell Dev. Biol., 2021, 8, 609683.
[PMID: 33490073]
[12]
Slade, L.; Pulinilkunnil, T. The MiTF/TFE family of transcription factors: Master regulators of organelle signaling, metabolism, and stress adaptation. Mol. Cancer Res., 2017, 15(12), 1637-1643.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0320] [PMID: 28851811]
[13]
Pogenberg, V.; Ballesteros-Álvarez, J.; Schober, R.; Sigvaldadóttir, I.; Obarska-Kosinska, A.; Milewski, M.; Schindl, R.; Ögmundsdóttir, M.H.; Steingrímsson, E.; Wilmanns, M. Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif. Nucleic Acids Res., 2020, 48(2), 934-948.
[http://dx.doi.org/10.1093/nar/gkz1104] [PMID: 31777941]
[14]
Dong, B.; Horowitz, D.S.; Kobayashi, R.; Krainer, A.R. Purification and cDNA cloning of HeLa cell p54nrb, a nuclear protein with two RNA recognition motifs and extensive homology to human splicing factor PSF and Drosophila NONA/BJ6. Nucleic Acids Res., 1993, 21(17), 4085-4092.
[http://dx.doi.org/10.1093/nar/21.17.4085] [PMID: 8371983]
[15]
Xie, R.; Chen, X.; Cheng, L.; Huang, M.; Zhou, Q.; Zhang, J.; Chen, Y.; Peng, S.; Chen, Z.; Dong, W.; Huang, J.; Lin, T. NONO inhibits lymphatic metastasis of bladder cancer via alternative splicing of SETMAR. Mol. Ther., 2021, 29(1), 291-307.
[http://dx.doi.org/10.1016/j.ymthe.2020.08.018] [PMID: 32950106]
[16]
Yin, X.; Wang, B.; Gan, W.; Zhuang, W.; Xiang, Z.; Han, X.; Li, D. TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas. J. Exp. Clin. Cancer Res., 2019, 38(1), 119.
[http://dx.doi.org/10.1186/s13046-019-1101-7] [PMID: 30849994]
[17]
Anglard, P.; Trahan, E.; Liu, S.; Latif, F.; Merino, M.J.; Lerman, M.I.; Zbar, B.; Linehan, W.M. Molecular and cellular characterization of human renal cell carcinoma cell lines. Cancer Res., 1992, 52(2), 348-356.
[PMID: 1345811]
[18]
Watts, E.R.; Walmsley, S.R. Inflammation and hypoxia: HIF and PHD isoform selectivity. Trends Mol. Med., 2019, 25(1), 33-46.
[http://dx.doi.org/10.1016/j.molmed.2018.10.006] [PMID: 30442494]
[19]
Ke, Q.; Costa, M. Hypoxia-inducible factor-1 (HIF-1). Mol. Pharmacol., 2006, 70(5), 1469-1480.
[http://dx.doi.org/10.1124/mol.106.027029] [PMID: 16887934]
[20]
Fong, G.H.; Takeda, K. Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ., 2008, 15(4), 635-641.
[http://dx.doi.org/10.1038/cdd.2008.10] [PMID: 18259202]
[21]
Semenza, G.L. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol., 2014, 9, 47-71.
[http://dx.doi.org/10.1146/annurev-pathol-012513-104720] [PMID: 23937437]
[22]
Glover, L.E.; Lee, J.S.; Colgan, S.P. Oxygen metabolism and barrier regulation in the intestinal mucosa. J. Clin. Invest., 2016, 126(10), 3680-3688.
[http://dx.doi.org/10.1172/JCI84429] [PMID: 27500494]
[23]
Maxwell, P.H.; Ferguson, D.J.; Nicholls, L.G.; Iredale, J.P.; Pugh, C.W.; Johnson, M.H.; Ratcliffe, P.J. Sites of erythropoietin production. Kidney Int., 1997, 51(2), 393-401.
[http://dx.doi.org/10.1038/ki.1997.52] [PMID: 9027712]
[24]
Spencer, J.A.; Ferraro, F.; Roussakis, E.; Klein, A.; Wu, J.; Runnels, J.M.; Zaher, W.; Mortensen, L.J.; Alt, C.; Turcotte, R.; Yusuf, R.; Côté, D.; Vinogradov, S.A.; Scadden, D.T.; Lin, C.P. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature, 2014, 508(7495), 269-273.
[http://dx.doi.org/10.1038/nature13034] [PMID: 24590072]
[25]
Macklin, P.S.; McAuliffe, J.; Pugh, C.W.; Yamamoto, A. Hypoxia and HIF pathway in cancer and the placenta. Placenta, 2017, 56, 8-13.
[http://dx.doi.org/10.1016/j.placenta.2017.03.010] [PMID: 28330647]
[26]
Grimm, C.; Willmann, G. Hypoxia in the eye: a two-sided coin. High Alt. Med. Biol., 2012, 13(3), 169-175.
[http://dx.doi.org/10.1089/ham.2012.1031] [PMID: 22994516]
[27]
Nagao, A.; Kobayashi, M.; Koyasu, S.; Chow, C.C.T.; Harada, H. HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int. J. Mol. Sci., 2019, 20(2), E238.
[http://dx.doi.org/10.3390/ijms20020238] [PMID: 30634433]
[28]
Moldogazieva, N.T.; Mokhosoev, I.M.; Terentiev, A.A. Metabolic heterogeneity of cancer cells: An interplay between HIF-1, GLUTs, and AMPK. Cancers (Basel), 2020, 12(4), E862.
[http://dx.doi.org/10.3390/cancers12040862] [PMID: 32252351]
[29]
Hong, M.; Shi, H.; Wang, N.; Tan, H.Y.; Wang, Q.; Feng, Y. Dual effects of chinese herbal medicines on angiogenesis in cancer and ischemic stroke treatments: Role of HIF-1 network. Front. Pharmacol., 2019, 10, 696.
[http://dx.doi.org/10.3389/fphar.2019.00696] [PMID: 31297056]
[30]
Jing, X.; Yang, F.; Shao, C.; Wei, K.; Xie, M.; Shen, H.; Shu, Y. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol. Cancer, 2019, 18(1), 157.
[http://dx.doi.org/10.1186/s12943-019-1089-9] [PMID: 31711497]
[31]
Arriagada, C.; Silva, P.; Torres, V.A. Role of glycosylation in hypoxia-driven cell migration and invasion. Cell Adhes. Migr., 2019, 13(1), 13-22.
[http://dx.doi.org/10.1080/19336918.2018.1491234] [PMID: 30015560]
[32]
Luo, W.; Wang, Y. Hypoxia mediates tumor malignancy and therapy resistance. Adv. Exp. Med. Biol., 2019, 1136, 1-18.
[http://dx.doi.org/10.1007/978-3-030-12734-3_1] [PMID: 31201713]
[33]
Lu, Y.; Wang, B.; Shi, Q.; Wang, X.; Wang, D.; Zhu, L. Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells. Sci. Rep., 2016, 6, 39123.
[http://dx.doi.org/10.1038/srep39123] [PMID: 27982118]
[34]
Wang, B.; Yin, X.; Gan, W.; Pan, F.; Li, S.; Xiang, Z.; Han, X.; Li, D. PRCC-TFE3 fusion-mediated PRKN/parkin-dependent mitophagy promotes cell survival and proliferation in PRCC-TFE3 translocation renal cell carcinoma. Autophagy, 2020, 22, 1-19.
[PMID: 33019842]
[35]
Zhang, Y.; Ren, H.; Li, J.; Xue, R.; Liu, H.; Zhu, Z.; Pan, C.; Lin, Y.; Hu, A.; Gou, P.; Cai, J.; Zhou, J.; Zhu, W.; Shi, X. Elevated HMGB1 expression induced by hepatitis B virus X protein promotes epithelial-mesenchymal transition and angiogenesis through STAT3/miR-34a/NF-κB in primary liver cancer. Am. J. Cancer Res., 2021, 11(2), 479-494.
[PMID: 33575082]
[36]
Huang, Q.; Sun, Y.; Ma, X.; Gao, Y.; Li, X.; Niu, Y.; Zhang, X.; Chang, C. Androgen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma. Nat. Commun., 2017, 8(1), 918.
[http://dx.doi.org/10.1038/s41467-017-00701-6] [PMID: 29030639]
[37]
Zhao, J.; Du, F.; Shen, G.; Zheng, F.; Xu, B. The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis., 2015, 6, e1600.
[http://dx.doi.org/10.1038/cddis.2014.565] [PMID: 25590810]
[38]
Argani, P.; Lui, M.Y.; Couturier, J.; Bouvier, R.; Fournet, J.C.; Ladanyi, M. A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene, 2003, 22(34), 5374-5378.
[http://dx.doi.org/10.1038/sj.onc.1206686] [PMID: 12917640]
[39]
Huang, W.; Goldfischer, M.; Babayeva, S.; Mao, Y.; Volyanskyy, K.; Dimitrova, N.; Fallon, J.T.; Zhong, M. Identification of a novel PARP14-TFE3 gene fusion from 10-year-old FFPE tissue by RNA-seq. Gen. Chromo. Can., 2015, 54(8), 500-505.
[http://dx.doi.org/10.1002/gcc.22261] [PMID: 26032162]
[40]
Argani, P.; Zhang, L.; Reuter, V.E.; Tickoo, S.K.; Antonescu, C.R. RBM10-TFE3 renal cell carcinoma: A potential diagnostic pitfall due to cryptic intrachromosomal Xp11.2 inversion resulting in false-negative TFE3 FISH. Am. J. Surg. Pathol., 2017, 41(5), 655-662.
[http://dx.doi.org/10.1097/PAS.0000000000000835] [PMID: 28296677]
[41]
Pivovarcikova, K.; Grossmann, P.; Alaghehbandan, R.; Sperga, M.; Michal, M.; Hes, O. TFE3-fusion variant analysis defines specific clinicopathologic associations amog Xp11 translocation cancers. Am. J. Surg. Pathol., 2017, 41(1), 138-140.
[http://dx.doi.org/10.1097/PAS.0000000000000730] [PMID: 27631518]
[42]
Weterman, M.A.; Wilbrink, M.; Geurts van Kessel, A. Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Proc. Natl. Acad. Sci. USA, 1996, 93(26), 15294-15298.
[http://dx.doi.org/10.1073/pnas.93.26.15294] [PMID: 8986805]
[43]
Ellis, C.L.; Eble, J.N.; Subhawong, A.P.; Martignoni, G.; Zhong, M.; Ladanyi, M.; Epstein, J.I.; Netto, G.J.; Argani, P. Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage. Mod. Pathol., 2014, 27(6), 875-886.
[http://dx.doi.org/10.1038/modpathol.2013.208] [PMID: 24309327]
[44]
Lee, H.J.; Shin, D.H.; Kim, S.Y.; Hwang, C.S.; Lee, J.H.; Park, W.Y.; Choi, K.U.; Kim, J.Y.; Lee, C.H.; Sol, M.Y.; Rha, S.H.; Park, S.W. TFE3 translocation and protein expression in renal cell carcinoma are correlated with poor prognosis. Histopathology, 2018, 73(5), 758-766.
[http://dx.doi.org/10.1111/his.13700] [PMID: 29968390]
[45]
Tamura, R.; Tanaka, T.; Akasaki, Y.; Murayama, Y.; Yoshida, K.; Sasaki, H. The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications. Med. Oncol., 2019, 37(1), 2.
[http://dx.doi.org/10.1007/s12032-019-1329-2] [PMID: 31713115]
[46]
Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med., 1971, 285(21), 1182-1186.
[http://dx.doi.org/10.1056/NEJM197111182852108] [PMID: 4938153]
[47]
Apte, R.S.; Chen, D.S.; Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell, 2019, 176(6), 1248-1264.
[http://dx.doi.org/10.1016/j.cell.2019.01.021] [PMID: 30849371]
[48]
Pascale, R.M.; Calvisi, D.F.; Simile, M.M.; Feo, C.F.; Feo, F. The Warburg effect 97 years after its discovery. Cancers (Basel), 2020, 12(10), E2819.
[http://dx.doi.org/10.3390/cancers12102819] [PMID: 33008042]
[49]
Tarade, D.; Ohh, M. The HIF and other quandaries in VHL disease. Oncogene, 2018, 37(2), 139-147.
[http://dx.doi.org/10.1038/onc.2017.338] [PMID: 28925400]
[50]
Ooi, A. Advances in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) research. Semin. Cancer Biol., 2020, 61, 158-166.
[http://dx.doi.org/10.1016/j.semcancer.2019.10.016] [PMID: 31689495]
[51]
Baba, M.; Furuya, M.; Motoshima, T.; Lang, M.; Funasaki, S.; Ma, W.; Sun, H.W.; Hasumi, H.; Huang, Y.; Kato, I.; Kadomatsu, T.; Satou, Y.; Morris, N.; Karim, B.O.; Ileva, L.; Kalen, J.D.; Wilan Krisna, L.A.; Hasumi, Y.; Sugiyama, A.; Kurahashi, R.; Nishimoto, K.; Oyama, M.; Nagashima, Y.; Kuroda, N.; Araki, K.; Eto, M.; Yao, M.; Kamba, T.; Suda, T.; Oike, Y.; Schmidt, L.S.; Linehan, W.M. TFE3 Xp11.2 Translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. Mol. Cancer Res., 2019, 17(8), 1613-1626.
[http://dx.doi.org/10.1158/1541-7786.MCR-18-1235] [PMID: 31043488]

Rights & Permissions Print Cite
Article Metrics
28
1
© 2024 Bentham Science Publishers | Privacy Policy