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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

NONO-TFE3融合通过靶向NONO-TFE3易位肾细胞癌中的HIF1A促进有氧糖酵解和血管生成

卷 21, 期 8, 2021

发表于: 12 April, 2021

页: [713 - 723] 页: 11

弟呕挨: 10.2174/1568009621666210412115026

价格: $65

摘要

背景：NONO-TFE3 易位肾细胞癌（tRCC）是与 Xp11.2 易位/TFE3 基因融合（Xp11.2 tRCCs）相关的 RCC 之一，涉及 NONO 和 TFE3 之间的 X 染色体倒位，具有核内核的特征。 NONO-TFE3 融合蛋白的聚集。 NONO-TFE3融合的致癌机制尚未完全阐明。 目的：本研究旨在探讨NONO-TFE3融合调控HIF1A的机制以及HIF-1α在缺氧条件下NONO-TFE3 tRCC进展中的作用。 方法：进行免疫组织化学和蛋白质印迹分析以分析 HIF-1α 在肾透明细胞癌 (ccRCC) 或 Xp11.2 tRCC 中的表达。染色质免疫沉淀 (ChIP)、荧光素酶报告基因检测和实时定量 PCR (RT-qPCR) 用于评估 NONO-TFE3 融合对 HIF1A 表达的调节。然后，使用流式细胞术分析、管形成分析和细胞迁移分析以及测量葡萄糖或乳酸水平来确定 HIF-1α 对 NONO-TFE3 tRCC 进展的影响。此外，分析了HIF-1α抑制剂（PX-478）对UOK109细胞的影响。 结果：我们发现HIF1A是NONO-TFE3融合的靶基因。在从 NONO-TFE3 tRCC 样本中分离的 UOK109 细胞中，NONO-TFE3 融合通过在缺氧条件下上调 HIF-1α 的表达来促进有氧糖酵解和血管生成。此外，PX-478 介导的 HIF-1α 抑制抑制了 NONO-TFE3 tRCC 在缺氧条件下的发展。 结论：HIF-1α是缺氧条件下NONO-TFE3 tRCC治疗的潜在靶点。

关键词: NONO-TFE3 融合、HIF-1α、缺氧、血管生成、有氧糖酵解、癌。

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[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]

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