摘要：肾细胞癌 （renal cell caricinoma, RCC） 作为最常见的肾脏恶性肿瘤，约占肾脏恶性肿瘤的 90%。肾癌 发病率近年来有上升趋势，早期肾癌患者可以通过手术达到良好的治疗效果，晚期患者由于缺乏有效的治疗手 段，预后较差。靶向治疗是晚期肾癌的一线治疗方案，但长期的靶向治疗容易出现耐药以及带来副反应。因此， 需要探索新的肾癌特异性治疗靶点来优化晚期肾癌治疗方案。蛋白激酶 B （protein kinase B, AKT） 作为磷脂 酰肌醇 3-激酶 （phosphatidylinositol 3-kinase, PI3K） 在 PI3K/AKT/mTOR信号通路中的效应分子，一旦激 活，能调节许多下游蛋白的功能，这些下游蛋白涉及细胞生存、增殖、迁移、凋亡等，AKT信号通路在各种癌 症的发病机制中起着重要作用。以往的研究发现 AKT与肾癌的发生发展关系密切，对肾癌的诊疗工作及新型靶 向治疗药物的研发中具有巨大的潜在价值。论文对AKT在肾细胞癌中表达及其作用的研究进展统一综述。

[1] SIEGEL RL, MILLER KD, JEMAL A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020,70(1):7-30

[2] PATEL HD, GUPTA M, JOICE GA, et al. Clinical Stage Migration and Survival for Renal Cell Carcinoma in the United States [J]. Eur Urol Oncol, 2019,2(4):343-348

[3] LJUNGBERG B, ALBIGES L, ABU- GHANEM Y, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update [J]. Eur Urol, 2019,75(5): 799-810

[4] BELLACOSA A, FRANKE TF, GONZALEZ- PORTAL ME, et al. Structure, expression and chromosomal mapping of c-akt: relationship to v-akt and its implications [J]. Oncogene, 1993,8(3):745-754

[5] AOKI M, FUJISHITA T. Oncogenic Roles of the PI3K/ AKT/mTOR Axis [J]. Curr Top Microbiol Immunol, 2017,407:153-189

[6] SONG G, OUYANG G, BAO S. The activation of Akt/ PKB signaling pathway and cell survival [J]. J Cell Mol Med, 2005,9(1):59-71

[7] REVATHIDEVI S, MUNIRAJAN AK. Akt in cancer: Mediator and more [J]. Semin Cancer Biol, 2019,59:80-91

[8] DATTA SR, BRUNET A, GREENBERG ME. Cellular survival: a play in three Akts [J]. Genes Dev, 1999,13(22): 2905-2927

[9] ALESSI DR, JAMES SR, DOWNES CP, et al. Characterization of a 3- phosphoinositide- dependent protein kinase which phosphorylates and activates protein kinase Balpha [J]. Curr Biol, 1997,7(4):261-269

[10] ALESSI DR, ANDJELKOVIC M, CAUDWELL B, et al. Mechanism of activation of protein kinase B by insulin and IGF-1[J]. EMBO J, 1996,15(23):6541-6551

[11] HORNBECK PV, KORNHAUSER JM, TKACHEV S, et al. PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally deter- mined post- translational modifications in man and mouse [J]. Nucleic Acids Res, 2012,40(Database issue):D261- D270

[12] FRESNO VJ, CASADO E, DE CASTRO J, et al. PI3K/Akt signalling pathway and cancer [J]. Cancer Treat Rev, 2004,30(2):193-204

[13] LIAO SY, KUO IY, CHEN YT, et al. AKT- mediated phosphorylation enhances protein stability and transcription activity of ZNF322A to promote lung cancer progression [J]. Oncogene, 2019,38(41):6723-6736

[14] NAKATANI K, THOMPSON DA, BARTHEL A, et al. Up- regulation of Akt3 in estrogen receptor- deficient breast cancers and androgen- independent prostate cancer lines [J]. J Biol Chem, 1999,274(31):21528-21532

[15] CRISTIANO BE, CHAN JC, HANNAN KM, et al. A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)- M phase transition [J]. Cancer Res, 2006,66(24):11718-11725

[16] SLATTERY ML, MULLANY LE, SAKODA LC, et al. The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer [J]. Mol Carcinog, 2018,57(2):243-261

[17] VANDAMME T, BEYENS M, BOONS G, et al. Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms [J]. Endocr Relat Cancer, 2019, 26(1):1-12

[18] CARPTEN JD, FABER AL, HORN C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer [J]. Nature, 2007,448(7152):439-444

[19] YANG WL, WANG J, CHAN CH, et al. The E3 ligase TRAF6 regulates Akt ubiquitination and activation [M ]. 2009

[20] DOWNWARD J. Targeting RAS signalling pathways in cancer therapy [J]. Nat Rev Cancer, 2003,3(1):11-22

[21] JONASCH E, GAO J, RATHMELL WK. Renal cell carcinoma[J]. BMJ, 2014,349:g4797

[22] SPIRINA LV, KONDAKOVA IV, YURMAZOV ZA, et al. VHL Expression in Kidney Cancer: Relation to Metastasis Development, Transcription and Growth Factors and Component of Akt/m- TOR Signaling Pathway [J]. Bull Exp Biol Med, 2019,167(5):671-675

[23] MAXWELL PH, WIESENER MS, CHANG GW, et al. The tumour suppressor protein VHL targets hypoxia- inducible factors for oxygen- dependent proteolysis [J]. Nature, 1999,399(6733):271-275

[24] JONASCH E, FUTREAL PA, DAVIS IJ, et al. State of the science: an update on renal cell carcinoma [J]. Mol Cancer Res, 2012,10(7):859-880

[25] GUO H, GERMAN P, BAI S, et al. The PI3K/AKT Pathway and Renal Cell Carcinoma [J]. J Genet Genomics, 2015,42(7):343-353

[26] LIAN JH, WANG WH, WANG JQ, et al. MicroRNA- 122 promotes proliferation, invasion and migration of renal cell carcinoma cells through the PI3K/Akt signaling pathway [J]. Asian Pac J Cancer Prev, 2013,14(9):5017-5021

[27] LIU Y, CHEN JB, ZHANG M, et al. SGK2 promotes renal cancer progression via enhancing ERK 1/2 and AKT phosphorylation [J]. Eur Rev Med Pharmacol Sci, 2019,23 (7):2756-2767

[28] ZHAO Z, ZHANG M, DUAN X, et al. TRPM7 Regulates AKT/FOXO1- Dependent Tumor Growth and Is an Independent Prognostic Indicator in Renal Cell Carcinoma [J]. Mol Cancer Res, 2018,16(6):1013-1023

[29] MIAO C, LIANG C, TIAN Y, et al. Overexpression of CAPN2 promotes cell metastasis and proliferation via AKT/mTOR signaling in renal cell carcinoma [J]. Oncotarget, 2017,8(58):97811-97821

[30] YANG Y, DONG MH, HU HM, et al. LncRNA FGD5- AS1/miR- 5590- 3p axis facilitates the proliferation and metastasis of renal cell carcinoma through ERK/AKT signalling [J]. Eur Rev Med Pharmacol Sci, 2020,24(17): 8756-8766

[31] JIANGQIAO Z, TAO Q, ZHONGBAO C, et al. Antisilencing function 1B histone chaperone promotes cell proliferation and migration via activation of the AKT pathway in clear cell renal cell carcinoma [J]. Biochem Biophys Res Commun, 2019,511(1):165-172

[32] ZHU Q, ZHONG AL, HU H, et al. Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3β signalling pathway in renal cell carcinoma [J]. J Hematol Oncol, 2020,13(1):2.

[33] ZHAI W, ZHU R, MA J, et al. A positive feed-forward loop between LncRNA- URRCC and EGFL7/P- AKT/ FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma [J]. Mol Cancer, 2019,18(1): 81

[34] AKHTAR M, AL- BOZOM IA, AL HT. Papillary Renal Cell Carcinoma (PRCC): An Update [J]. Adv Anat Pathol, 2019,26(2):124-132

[35] TWARDOWSKI PW, MACK PC, LARA PJ. Papillary renal cell carcinoma: current progress and future directions [J]. Clin Genitourin Cancer, 2014,12(2):74-79

[36] ISAACS JS, JUNG YJ, MOLE DR, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability [J]. Cancer Cell, 2005,8(2):143-153

[37] DAVIS CF, RICKETTS CJ, WANG M, et al. The somatic genomic landscape of chromophobe renal cell carcinoma [J]. Cancer Cell, 2014,26(3):319-330

[38] ANDJELKOVIC M, ALESSI DR, MEIER R, et al. Role of translocation in the activation and function of protein kinase B [J]. J Biol Chem, 1997,272(50):31515-31524

[39] HAGER M, HAUFE H, KEMMERLING R, et al. Increased activated Akt expression in renal cell carcinomas and prognosis [J]. J Cell Mol Med, 2009,13(8B):2181- 2188

[40] ZHAI W, SUN Y, GUO C, et al. LncRNA- SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA- 143- 3p signals [J]. Cell Death Differ, 2017,24(9):1502-1517

[41] HORIGUCHI A, OYA M, UCHIDA A, et al. Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma [J]. J Urol, 2003,169(2):710-713

[42] PANTUCK AJ, SELIGSON DB, KLATTE T, et al. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy [J]. Cancer, 2007,109(11):2257-2267

[43] FAN D, LIU Q, WU F, et al. Prognostic significance of PI3K/AKT/ mTOR signaling pathway members in clear cell renal cell carcinoma [J]. Peer J, 2020,8:e9261

[44] LI P, JAHNKE J, PETTIT AR, et al. Comparative Survival Associated With Use of Targeted vs Nontargeted Therapy in Medicare Patients With Metastatic Renal Cell Carcinoma [J]. JAMA Netw Open, 2019,2(6):e195806

[45] 陈莉,汪涌,祝广峰,等.2020年欧洲泌尿协会肾癌诊断和治疗指 南概要[J].现代泌尿外科杂志,2020,25(10):927-932

[46] 吴海欧,于常华.转移性肾癌靶向治疗和免疫治疗的现状与进展 [J].现代肿瘤医学,2019,27(21):3920-3922

[47] PORTA C, PAGLINO C, MOSCA A. Targeting PI3K/ Akt/mTOR Signaling in Cancer [J]. Front Oncol, 2014,4:64

[48] ZHU H, MAO JH, WANG Y, et al. Dual inhibition of BRD4 and PI3K- AKT by SF2523 suppresses human renal cell carcinoma cell growth [J]. Oncotarget, 2017,8(58): 98471-98481

[49] XU M, WANG Y, ZHOU LN, et al. The therapeutic value of SC66 in human renal cell carcinoma cells [J]. Cell Death Dis, 2020,11(5):353

[50] NITULESCU GM, MARGINA D, JUZENAS P, et al. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review) [J]. Int J Oncol, 2016,48(3):869-885. 

李钻,李伟. 蛋白激酶B在肾细胞癌中表达及其功能的研究进展[J]. 泌尿外科杂志（电子版）,2021,13(2):85-91. DOI:10.3969/j.issn.1674-7410.2021.02.019.

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肾癌是泌尿系最常见的恶性肿瘤之一，发病率 仅次于前列腺癌和膀胱癌。根据美国最新统计， 2020 年美国新发肾癌患者 73 750 例，预计将导致 14 830例患者死亡[1] 。根据分期与生存期研究统计， 有 70%左右的患者被诊断为早期肾癌。早期肾癌患 者的 5年总体生存率有 82.4%，由于晚期患者缺乏有 效的治疗手段，5年生存率偏低，约 5%~20%[2] 。在 2006 年引入靶向治疗之前转移性肾细胞癌 （metastatic renal cell carcinoma, mRCC） 的一线疗法是 细胞因子治疗，如干扰素-α和白细胞介素-2。在靶 向药物治疗时代，晚期患者病情得以控制并延长了 生存时间[3] 。但药物耐药性和副反应问题并没有得到 解决，部分肾癌患者仍不能获得长期缓解，因此探 索新的治疗靶点是现阶段肾癌研究的热点。蛋白激 酶 B （protein kinase B, AKT） 是一种丝氨酸/苏氨 酸激酶，是许多信号通路的中心节点，在正常细胞 生理和癌症发病机制中都发挥着不同的作用[4] ，被认 为是癌症治疗中很有应用前景的一个潜在靶点。因 此，本文就 AKT 的功能及对肾癌的潜在诊疗价值进 行综述。

1 AKT 结构及活化过程

2 AKT 在实体肿瘤中的致癌作用

3 AKT 及其相关通路与肾癌发生发展的关系

4 AKT 在肾癌诊疗中的运用

5 结语

5 结语 

mRCC 的一线治疗是靶向治疗，能明显延长患 者生存期，但仍面临耐药这一巨大挑战，肾癌的靶 向治疗药物种类有限，因此寻找需要新的靶点研制 新型靶向药物一直是肾癌研究的热点。AKT 在细胞 代谢生长、存活和凋亡等过程起着重要作用，同时 与肾癌的发生发展关系密切，是多种信号通路的核 心，也是目前研究最广泛的信号网络之一，这些都 使得 AKT 在肾癌靶向治疗药物研发中具有巨大潜在 价值，但现有的研究只是对 AKT 与肾癌发生发展等 相关作用的初步研究，仍需深入的分子生物学基础 研究提供重要理论和实验依据。

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