Downstream Targets of VHL/HIF-α Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance

被引:34
|
作者
Mazumder, Sonia [1 ]
Higgins, Paul J. [1 ]
Samarakoon, Rohan [1 ]
机构
[1] Albany Med Coll, Dept Regenerat & Canc Cell Biol, Albany, NY 12208 USA
关键词
ccRCC; HIF-alpha; VHL; EGFR; MET; HYPOXIA-INDUCIBLE FACTOR; ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR GENE; TYPE-1; MATRIX-METALLOPROTEINASE; CLINICAL-PRACTICE GUIDELINES; VONHIPPEL-LINDAU DISEASE; CYCLIN D1 EXPRESSION; C-MYC; INTERFERON-ALPHA; FACTOR RECEPTOR;
D O I
10.3390/cancers15041316
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-alpha) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolylhydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-alpha due to increased stability, leading to RCC progression. While HIF-1 alpha acts as a tumor suppressor, HIF-2 alpha promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2 alpha target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2 alpha and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2 alpha targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-alpha, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2 alpha signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions.
引用
收藏
页数:23
相关论文
共 50 条
  • [21] Expression of HIF-α and their association with clinicopathological parameters in clinical renal cell carcinoma
    Sitaram, Raviprakash T.
    Ljungberg, Boerje
    UPSALA JOURNAL OF MEDICAL SCIENCES, 2024, 129 (01)
  • [22] HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma
    Wong, So C.
    Cheng, Weijun
    Hamilton, Holly
    Nicholas, Anthony L.
    Wakefield, Darren H.
    Almeida, Aaron
    Blokhin, Andrei V.
    Carlson, Jeffrey
    Neal, Zane C.
    Subbotin, Vladimir
    Zhang, Guofeng
    Hegge, Julia
    Bertin, Stephanie
    Trubetskoy, Vladimir S.
    Rozema, David B.
    Lewis, David L.
    Kanner, Steven B.
    MOLECULAR CANCER THERAPEUTICS, 2018, 17 (01) : 140 - 149
  • [23] Targeting HIF2α with an RNAi therapeutic for the treatment of clear cell renal cell carcinoma
    Nicholas, A.
    Wong, S.
    Zhu, R.
    Carlson, J.
    Frankiewicz, A.
    Shu, D.
    Hamilton, H.
    Schienebeck, C.
    Andersen, A.
    Fowler-Watters, M.
    Bertin, S.
    Liu, C.
    Li, X.
    Chen, B.
    Schumacher, J.
    Hegge, J.
    Given, B.
    Li, Z.
    EUROPEAN JOURNAL OF CANCER, 2018, 103 : E9 - E9
  • [24] Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy
    Martinez-Saez, Olga
    Borau, Pablo Gajate
    Alonso-Gordoa, Teresa
    Molina-Cerrillo, Javier
    Grande, Enrique
    CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 2017, 111 : 117 - 123
  • [25] A HIF-Regulated VHL-PTP1B-Src Signaling Axis Identifies a Therapeutic Target in Renal Cell Carcinoma
    Suwaki, Natsuko
    Vanhecke, Elsa
    Atkins, Katelyn M.
    Graf, Manuela
    Swabey, Katherine
    Huang, Paul
    Schraml, Peter
    Moch, Holger
    Cassidy, Amy Mulick
    Brewer, Daniel
    Al-Lazikani, Bissan
    Workman, Paul
    De-Bono, Johann
    Kaye, Stan B.
    Larkin, James
    Gore, Martin. E.
    Sawyers, Charles L.
    Nelson, Peter
    Beer, Tomasz M.
    Geng, Hao
    Gao, Lina
    Qian, David Z.
    Alumkal, Joshi J.
    Thomas, Gary
    Thomas, George V.
    SCIENCE TRANSLATIONAL MEDICINE, 2011, 3 (85)
  • [26] Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance
    Caroline Razafinjatovo
    Svenja Bihr
    Axel Mischo
    Ursula Vogl
    Manuela Schmidinger
    Holger Moch
    Peter Schraml
    BMC Cancer, 16
  • [27] GSDMs are potential therapeutic targets and prognostic biomarkers in clear cell renal cell carcinoma
    Yao, Lei
    Li, Juanni
    Xu, Zhijie
    Yan, Yuanliang
    Hu, Kuan
    AGING-US, 2022, 14 (06): : 2758 - 2774
  • [28] Clear Cell Renal Cell Carcinoma: A Comprehensive in silico Study in Searching for Therapeutic Targets
    Naghdibadi, Mohammadjavad
    Momeni, Maryam
    Yavari, Parvin
    Gholaminejad, Alieh
    Roointan, Amir
    KIDNEY & BLOOD PRESSURE RESEARCH, 2023, 48 (01): : 135 - 150
  • [29] Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance
    Razafinjatovo, Caroline
    Bihr, Svenja
    Mischo, Axel
    Vogl, Ursula
    Schmidinger, Manuela
    Moch, Holger
    Schraml, Peter
    BMC CANCER, 2016, 16
  • [30] A Positive Feedback Loop between Inactive VHL-Triggered Histone Lactylation and PDGFRβ Signaling Drives Clear Cell Renal Cell Carcinoma Progression
    Yang, Jiefeng
    Luo, Li
    Zhao, Chongyu
    Li, Xiyuan
    Wang, Zimo
    Zeng, Ziwei
    Yang, Xin
    Zheng, Xiaobin
    Jie, Haiqing
    Kang, Liang
    Li, Shujuan
    Liu, Shuang
    Zhou, Chi
    Liu, Huashan
    INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, 2022, 18 (08): : 3470 - 3483