aDepartment of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China bSchool of Materials Science and Engineering, University of Shanghai for Science and Technology, China
Objective: This review aimed to summarize the role of the Hippo signaling pathway in renal cell carcinoma (RCC), a urologic malignancy with subtle initial symptoms and high mortality rates due to metastatic RCC. The Hippo signaling pathway, which regulates tissue and organ sizes, plays a crucial role in RCC progression and metastasis. Understanding the involvement of the Hippo signaling pathway in RCC provides valuable insights for the development of targeted therapies and improved patient outcomes.
Methods: In this review, we explored the impact of the Hippo signaling pathway on RCC. Through an analysis of existing literature, we examined its role in RCC progression and metastasis. Additionally, we discussed potential therapeutic strategies targeting the Hippo pathway for inhibiting RCC cell growth and invasion. We also highlighted the importance of investigating interactions between the Hippo pathway and other signaling pathways such as Wnt, transforming growth factor-beta, and PI3K/AKT, which may uncover additional therapeutic targets.
Results: The Hippo signaling pathway has shown promise as a target for inhibiting RCC cell growth and invasion. Studies have demonstrated its dysregulation in RCC, with altered expression of key components such as yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). Targeting the Hippo pathway has been associated with suppressed tumor growth and metastasis in preclinical models of RCC. Furthermore, investigating crosstalk between the Hippo pathway and other signaling pathways has revealed potential synergistic effects that could be exploited for therapeutic interventions.
Conclusion: Understanding the role of the Hippo signaling pathway in RCC is of paramount importance. Elucidating its functions and molecular interactions contributes to RCC diagnosis, treatment, and the discovery of novel mechanisms. This knowledge informs the development of innovative therapeutic strategies and opens new avenues for research in RCC. Further investigations are warranted to fully comprehend the complex interplay between the Hippo pathway and other signaling pathways, ultimately leading to improved outcomes for RCC patients.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin 2021; 71:209-49.
[2]
Bukavina L, Bensalah K, Bray F, Carlo M, Challacombe B, Karam JA, et al. Epidemiology of renal cell carcinoma: 2022 update. Eur Urol 2022; 82:529-42.
doi: 10.1016/j.eururo.2022.08.019
pmid: 36100483
[3]
Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin 2017; 67:507-24.
[4]
Bakouny Z, El Zarif T, Dudani S, Connor Wells J, Gan CL, Donskov F, et al. Upfront cytoreductive nephrectomy for metastatic renal cell carcinoma treated with immune checkpoint inhibitors or targeted therapy: an observational study from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2023; 83:145-51.
[5]
Bedke J, Albiges L, Capitanio U, Giles RH, Hora M, Lam TB, et al. The 2021 updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibitor-based combination therapies for treatment-naive metastatic clear-cell renal cell carcinoma are standard of care. Eur Urol 2021; 80:393-7.
doi: 10.1016/j.eururo.2021.04.042
pmid: 34074559
[6]
Sung WW, Ko PY, Chen WJ, Wang SC, Chen SL. Trends in the kidney cancer mortality-to-incidence ratios according to health care expenditures of 56 countries. Sci Rep 2021; 11:1479. https://doi.org/10.1038/s41598-020-79367-y.
Wu Z, Guan K. Hippo signaling in embryogenesis and development. Trends Biochem Sci 2021; 46:51-63.
doi: 10.1016/j.tibs.2020.08.008
pmid: 32928629
[9]
Cunningham R, Hansen CG. The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin Sci (Lond) 2022; 136:197-222.
doi: 10.1042/CS20201474
pmid: 35119068
[10]
Akrida I, Bravou V, Papadaki H. The deadly cross-talk between Hippo pathway and epithelial-mesenchymal transition (EMT) in cancer. Mol Biol Rep 2022; 49:10065-76.
doi: 10.1007/s11033-022-07590-z
pmid: 35604626
[11]
Lim YX, Lin H, Seah SH, Lim YP. Reciprocal regulation of Hippo and WBP2 signallingdimplications in cancer therapy. Cells 2021:10.
[12]
Luo J, Yu FX. GPCReHippo signaling in cancer. Cells 2019; 8:426. https://doi.org/10.3390/cells8050426.
[13]
Yu F, Zhao B, Guan K. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 2015; 163:811-28.
[14]
Calses PC, Crawford JJ, Lill JR, Dey A. Hippo pathway in cancer: aberrant regulation and therapeutic opportunities. Trends Cancer 2019; 5:297-307.
doi: S2405-8033(19)30071-8
pmid: 31174842
[15]
Meng Z, Moroishi T, Guan K. Mechanisms of Hippo pathway regulation. Genes Dev 2016; 30:1-17.
Borreguero-Munõz N, Fletcher GC, Aguilar-Aragon M, Elbediwy A, Vincent-Mistiaen ZI, Thompson BJ. The Hippo pathway integrates PI3KeAkt signals with mechanical and polarity cues to control tissue growth. PLoS Biol 2019; 17:e3000509. https://doi.org/10.1371/journal.pbio.3000509.
[20]
Yu F, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, et al. Regulation of the HippoeYAP pathway by G-protein-coupled receptor signaling. Cell 2012; 150:780-91.
[21]
Holden JK, Cunningham CN. Targeting the Hippo pathway and cancer through the TEAD family of transcription factors. Cancers 2018; 10:81. https://doi.org/10.3390/cancers10030081.
[22]
Huh HD, Kim DH, Jeong HS, Park HW. Regulation of TEAD transcription factors in cancer biology. Cells 2019; 8:600. https://doi.org/10.3390/cells8060600.
[23]
Xu J, Kausalya PJ, Ong AGM, Goh CMF, Mohamed Ali S, Hunziker W. ZO-2/Tjp2 suppresses Yap and Wwtr1/Tazmediated hepatocyte to cholangiocyte transdifferentiation in the mouse liver. NPJ Regen Med 2022; 7:55. https://doi.org/10.1038/s41536-022-00251-6.
[24]
Pavel M, Park SJ, Frake RA, Son SM, Manni MM, Bento CF, et al. a-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation. Nat Commun 2021; 12:1703. https://doi.org/10.1038/s41467-021-21882-1.
[25]
Park JA, Kwon YG. HippoeYAP/TAZ signaling in angiogenesis. BMB Rep 2018; 51:157-62.
[26]
Giampietro C, Disanza A, Bravi L, Barrios-Rodiles M, Corada M, Frittoli E, et al. The actin-binding protein EPS8 binds VEcadherin and modulates YAP localization and signaling. J Cell Biol 2015; 211:1177-92.
doi: 10.1083/jcb.201501089
pmid: 26668327
[27]
Gu Y, Wang Y, Sha Z, He C, Zhu Y, Li J, et al. Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a therapeutic target in YAP/TAZ-active cancers. Cell Rep 2022; 40:111296. https://doi.org/10.1016/j.celrep.2022.111296.
[28]
Ooki T, Murata-Kamiya N, Takahashi-Kanemitsu A, Wu W, Hatakeyama M. High-molecular-weight hyaluronan is a Hippo pathway ligand directing cell density-dependent growth inhibition via PAR1b. Dev Cell 2019; 49:590-604. e9. https://doi.org/10.1016/j.devcel.2019.04.018.
doi: S1534-5807(19)30299-0
pmid: 31080060
[29]
Shalhout SZ, Yang PY, Grzelak EM, Nutsch K, Shao S, Zambaldo C, et al. YAP-dependent proliferation by a small molecule targeting annexin A2. Nat Chem Biol 2021; 17:767-75.
doi: 10.1038/s41589-021-00755-0
pmid: 33723431
[30]
Ma B, Cheng H, Gao R, Mu C, Chen L, Wu S, et al. Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-b signalling pathways. Nat Commun 2016; 7:11123. https://doi.org/10.1038/ncomms11123.
[31]
Mo JS, Meng Z, Kim YC, Park HW, Hansen CG, Kim S, et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol 2015; 17:500-10.
[32]
Luo M, Meng Z, Moroishi T, Lin KC, Shen G, Mo F, et al. Heat stress activates YAP/TAZ to induce the heat shock transcriptome. Nat Cell Biol 2020; 22:1447-59.
doi: 10.1038/s41556-020-00602-9
pmid: 33199845
[33]
Panda DK, Bai X, Zhang Y, Stylianesis NA, Koromilas AE, Lipman ML, et al. SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis. J Clin Invest 2022; 132:e153943. https://doi.org/10.1172/JCI153943.
[34]
Schroeder MC, Halder G. Regulation of the Hippo pathway by cell architecture and mechanical signals. Semin Cell Dev Biol 2012; 23:803-11.
doi: 10.1016/j.semcdb.2012.06.001
pmid: 22750148
[35]
Li Z, Chen S, Cui H, Li X, Chen D, Hao W, et al. Tenascin-Cmediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis. Ann Rheum Dis 2021; 80:891-902.
[36]
Shen J, Cao B, Wang Y, Ma C, Zeng Z, Liu L, et al. Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer. J Exp Clin Cancer Res 2018; 37:175. https://doi.org/10.1186/s13046-018-0850-z.
doi: 10.1186/s13046-018-0850-z
pmid: 30055645
[37]
Claude-Taupin A, Isnard P, Bagattin A, Kuperwasser N, Roccio F, Ruscica B, et al. The AMPKeSirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells. Nat Commun 2023; 14:8056. https://doi.org/10.1038/s41467-023-43775-1.
doi: 10.1038/s41467-023-43775-1
pmid: 38052799
[38]
Fernando RN, Cotter L, Perrin-Tricaud C, Berthelot J, Bartolami S, Pereira JA, et al. Optimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway. Nat Commun 2016; 7:12186. https://doi.org/10.1038/ncomms12186.
doi: 10.1038/ncomms12186
pmid: 27435623
[39]
Cao JJ, Zhao XM, Wang DL, Chen KH, Sheng X, Li WB, et al. YAP is overexpressed in clear cell renal cell carcinoma and its knockdown reduces cell proliferation and induces cell cycle arrest and apoptosis. Oncol Rep 2014; 32:1594-600.
[40]
Schütte U, Bisht S, Heukamp LC, Kebschull M, Florin A, Haarmann J, et al. Hippo signaling mediates proliferation, invasiveness, and metastatic potential of clear cell renal cell carcinoma. Transl Oncol 2014; 7:309-21.
doi: 10.1016/j.tranon.2014.02.005
pmid: 24913676
[41]
Xu S, Zhang H, Chong Y, Guan B, Guo P. YAP promotes VEGFA expression and tumor angiogenesis though Gli2 in human renal cell carcinoma. Arch Med Res 2019; 50:225-33.
doi: S0188-4409(19)30216-4
pmid: 31518897
[42]
Yang WH, Ding CKC, Sun T, Rupprecht G, Lin CC, Hsu D, et al. The Hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep 2019; 28:2501-8. e4. https://doi.org/10.1016/j.celrep.2019.07.107.
[43]
Xu T, Wei D, Yang Z, Xie S, Yan Z, Chen C, et al. ApoM suppresses kidney renal clear cell carcinoma growth and metastasis via the HippoeYAP signaling pathway. Arch Biochem Biophys 2023; 743:109642. https://doi.org/10.1016/j.abb.2023.109642.
[44]
Chen X, Zhang X, Jiang Y, Zhang X, Liu M, Wang S, et al. YAP1 activation promotes epithelialemesenchymal transition and cell survival of renal cell carcinoma cells under shear stress. Carcinogenesis 2022; 43:301-10.
[45]
Meng K, Hu Y, Wang D, Li Y, Shi F, Lu J, et al. EFHD1, a novel mitochondrial regulator of tumor metastasis in clear cell renal cell carcinoma. Cancer Sci 2023; 114:2029-40.
[46]
Xiao J, Shi Q, LiW, Mu X, Peng J, Li M, et al. ARRDC1 and ARRDC3 act as tumor suppressors in renal cell carcinoma by facilitating YAP1 degradation. Am J Cancer Res 2018; 8:132-43.
doi: <空>
pmid: 29416926
[47]
Kumar B, Ahmad R, Giannico GA, Zent R, Talmon GA, Harris RC, et al. Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation. J Exp Clin Cancer Res 2021; 40:77.
doi: 10.1186/s13046-021-01870-5
pmid: 33622361
[48]
Liu S, Yang Y, Wang W, Pan X. Long noncoding RNA TUG1 promotes cell proliferation and migration of renal cell carcinoma via regulation of YAP. J Cell Biochem 2018; 119:9694-706.
doi: 10.1002/jcb.27284
pmid: 30132963
[49]
Zhang W, Liu R, Zhang L, Wang C, Dong Z, Feng J, et al. Downregulation of miR-335 exhibited an oncogenic effect via promoting KDM3A/YAP 1 networks in clear cell renal cell carcinoma. Cancer Gene Ther 2022; 29:573-84.
[50]
Wu S, He H, Huang J, Jiang S, Deng X, Huang J, et al. FMR1 is identified as an immune-related novel prognostic biomarker for renal clear cell carcinoma: a bioinformatics analysis of TAZ/YAP. Math Biosci Eng 2022; 19:9295-320.
doi: 10.3934/mbe.2022432
pmid: 35942760
[51]
Yuan N, Li G. Comprehensive analysis reveals the involvement of hsa_circ_0037858/miR-5000-3p/FMR1 axis in malignant metastasis of clear cell renal cell carcinoma. Aging (Albany NY) 2023; 15:5399-411.
[52]
White SM, Avantaggiati ML, Nemazanyy I, Di Poto C, Yang Y, Pende M, et al. YAP/TAZ inhibition induces metabolic and signaling rewiring resulting in targetable vulnerabilities in NF2-deficient tumor cells. Dev Cell 2019; 49:425-43.e9. https://doi.org/10.1016/j.devcel.2019.04.014.
doi: S1534-5807(19)30284-9
pmid: 31063758
[53]
Zhu Z, Wei D, Xa Li, Wang F, Yan F, Xing Z, et al. RNA-binding protein QKI regulates contact inhibition via Yes-associate protein in ccRCC. Acta Biochim Biophys Sin 2019; 51:9-19.
[54]
Matsuura K, Nakada C, Mashio M, Narimatsu T, Yoshimoto T, Tanigawa M, et al. Downregulation of SAV1 plays a role in pathogenesis of high-grade clear cell renal cell carcinoma. BMC Cancer 2011; 11:523. https://doi.org/10.1186/1471-2407-11-523.
doi: 10.1186/1471-2407-11-523
pmid: 22185343
[55]
Kai T, Tsukamoto Y, Hijiya N, Tokunaga A, Nakada C, Uchida T, et al. Kidney-specific knockout of Sav1 in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway. J Pathol 2016; 239:97-108.
[56]
Guan Y, Gong Z, Xiao T, Li Z. Knockdown of miR-572 suppresses cell proliferation and promotes apoptosis in renal cell carcinoma cells by targeting the NF2/Hippo signaling pathway. Int J Clin Exp Pathol 2018; 11:5705-14.
[57]
Baumgartner R, Poernbacher I, Buser N, Hafen E, Stocker H. The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev Cell 2010; 18:309-16.
doi: 10.1016/j.devcel.2009.12.013
pmid: 20159600
[58]
Schelleckes K, Schmitz B, Ciarimboli G, Lenders M, Pavenst?dt HJ, Herrmann E, et al. Promoter methylation inhibits expression of tumor suppressor KIBRA in human clear cell renal cell carcinoma. Clin Epigenet 2017; 9:109.
[59]
Miao D, Wang Q, Shi J, Lv Q, Tan D, Zhao C, et al. N6- methyladenosine-modified DBT alleviates lipid accumulation and inhibits tumor progression in clear cell renal cell carcinoma through the ANXA2/YAP axis-regulated Hippo pathway. Cancer Commun 2023; 43:480-502.
[60]
Yin L, Li W, Xu A, Shi H, Wang K, Yang H, et al. SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating Hippo/TEAD1-Twist1 pathway. EBioMedicine 2020; 51:102596. https://doi.org/10.1016/j.ebiom.2019.12.005.
[61]
Yu Z, Li Q, Zhang G, Lv C, Dong Q, Fu C, et al. PLEKHO1 knockdown inhibits RCC cell viability in vitro and in vivo, potentially by the Hippo and MAPK/JNK pathways. Int J Oncol 2019; 55:81-92.
doi: 10.3892/ijo.2019.4819
pmid: 31180521
[62]
Peng Q, Wang L, Zhao D, Lv Y, Wang H, Chen G, et al. Overexpression of FZD1 is associated with a good prognosis and resistance of sunitinib in clear cell renal cell carcinoma. J Cancer 2019; 10:1237-51.
doi: 10.7150/jca.28662
pmid: 30854133
[63]
Jiang Y, Zhang Y, Leung JY, Fan C, Popov KI, Su S, et al. MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression. Nat Commun 2019; 10:1515. https://doi.org/10.1038/s41467-019-09233-7.
doi: 10.1038/s41467-019-09233-7
pmid: 30944303
[64]
Fine SW, Argani P, DeMarzo AM, Delahunt B, Sebo TJ, Reuter VE, et al. Expanding the histologic spectrum of mucinous tubular and spindle cell carcinoma of the kidney. AmJ Surg Pathol 2006; 30:1554-60.
[65]
Reuter VE, Argani P, Zhou M, Delahunt B. Best practices recommendations in the application of immunohistochemistry in the kidney tumors: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol 2014; 38:e35-49.
[66]
Mehra R, Vats P, Cieslik M, Cao X, Su F, Shukla S, et al. Biallelic alteration and dysregulation of the Hippo pathway in mucinous tubular and spindle cell carcinoma of the kidney. Cancer Discov 2016; 6:1258-66.
pmid: 27604489
[67]
Ren Q, Wang L, Al-Ahmadie HA, Fine SW, Gopalan A, Sirintrapun SJ, et al. Distinct genomic copy number alterations distinguish mucinous tubular and spindle cell carcinoma of the kidney from papillary renal cell carcinoma with overlapping histologic features. Am J Surg Pathol 2018; 42:767-77.
doi: 10.1097/PAS.0000000000001038
pmid: 29462091
[68]
Karakiewicz PI, Hutterer GC, Trinh QD, Pantuck AJ, Klatte T, Lam JS, et al. Unclassified renal cell carcinoma: an analysis of 85 cases. BJU Int 2007; 100:802-8.
doi: 10.1111/j.1464-410X.2007.07148.x
pmid: 17822461
[69]
Lopez-Beltran A, Kirkali Z, Montironi R, Blanca A, Algaba F, Scarpelli M, et al. Unclassified renal cell carcinoma:a report of 56 cases. BJU Int 2012; 110:786-93.
[70]
Crispen PL, Tabidian MR, Allmer C, Lohse CM, Breau RH, Blute ML, et al. Unclassified renal cell carcinoma: impact on survival following nephrectomy. Urology 2010; 76:580-6.
doi: 10.1016/j.urology.2009.12.037
pmid: 20223503
[71]
Sirohi D, Smith SC, Agarwal N, Maughan BL. Unclassified renal cell carcinoma: diagnostic difficulties and treatment modalities. Res Rep Urol 2018; 10:205-17.
doi: 10.2147/RRU.S154932
pmid: 30510921
[72]
Chen Y, Xu J, Skanderup AJ, Dong Y, Brannon AR, Wang L, et al. Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets. Nat Commun 2016; 7:13131. https://doi.org/10.1038/ncomms13131.
[73]
Malouf GG, Flippot R, Dong Y, Dinatale RG, Chen Y, Su X, et al. Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers. Sci Rep 2020; 10:701. https://doi.org/10.1038/s41598-020-57534-5.
doi: 10.1038/s41598-020-57534-5
pmid: 31959902
[74]
Duong NX, Le MK, Kondo T, Mitsui T. Heterogeneity of Hippo signalling activity in different histopathologic subtypes of renal cell carcinoma. J Cell Mol Med 2023; 27:66-75.
[75]
Zhang B, Chu W, Wen F, Zhang L, Sun L, Hu B, et al. Dysregulation of long non-coding RNAs and mRNAs in plasma of clear cell renal cell carcinoma patients using microarray and bioinformatic analysis. Front Oncol 2020; 10:559730. https://doi.org/10.3389/fonc.2020.559730.
[76]
Islam MS, Afrin S, Singh B, Jayes FL, Brennan JT, Borahay MA, et al. Extracellular matrix and Hippo signaling as therapeutic targets of antifibrotic compounds for uterine fibroids. Clin Transl Med 2021; 11:e475. https://doi.org/10.1002/ctm2.475.
doi: 10.1002/ctm2.475
pmid: 34323413
[77]
MudiantoT, CampbellKM, WebbJ, ZolkindP, SkidmoreZL, RileyR, et al. Yap1 mediates trametinib resistance in head and neck squamous cell carcinomas. Clin Cancer Res 2021; 27:2326-39.
doi: 10.1158/1078-0432.CCR-19-4179
pmid: 33547198
[78]
Barrette AM, Ronk H, Joshi T, Mussa Z, Mehrotra M, Bouras A, et al. Anti-invasive efficacy and survival benefit of the YAPTEAD inhibitor verteporfin in preclinical glioblastoma models. Neuro Oncol 2022; 24:694-707.
[79]
Pancholi NJ. AACR Virtual Annual Meeting II: insights into cancer metastasis reveal potential therapeutic strategies. https://www.aacr.org/blog/2020/08/21/aacr-virtual-annualmeeting-ii-insights-into-cancer-metastasis-reveal-potentialtherapeutic-strategies/. [Accessed 29 December 2023].
Luis G. Medina, Randall A. Lee, Valeria Celis, Veronica Rodriguez, Jaime Poncel, Aref S. Sayegh, Rene Sotelo. Robotic management of urinary fistula[J]. Asian Journal of Urology, 2024, 11(3): 357
-365
.
