The identification and application of the Von Hippel-Lindau(VHL)gene is a seminal breakthrough in kidney cancer research.VHL and its protein p VHL are the root cause of most kidney cancers,and the cascading pathway be...The identification and application of the Von Hippel-Lindau(VHL)gene is a seminal breakthrough in kidney cancer research.VHL and its protein p VHL are the root cause of most kidney cancers,and the cascading pathway below them is crucial for understanding hypoxia,in addition to the aforementioned tumorigenesis routes and treatments.We reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor(HIF),their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a transcription factor,respectively,as well as their non-canonical functions revealed recently.Additionally,we discussed how their dysregulation promotes tumorigenesis:beginning with chromosome 3 p-arm(3p)loss/epigenetic methylation,followed by two-allele knockout,before the loss of complimentary tumor suppressor genes leads cells down predictable oncological paths.These different pathways can ultimately determine the grade,outcome,and severity of the deadliest genitourinary cancer.We finished by investigating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma(cc RCC)by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor(VEGF)inhibitors,mammalian target of rapamycin complex 1(mTORC1)inhibitors,small molecule HIF inhibitors,immune checkpoint blockade therapy,and synthetic lethality.展开更多
基金supported by the Cancer Prevention and Research Institute of Texas(CPRIT,RR190058)the American Cancer Society(ACS)Research Scholar Award(RSG-18059-01-TBE)+2 种基金the National Cancer Institute(R01CA211732)the Department of Defense Kidney Cancer Research Program(KCRP)Idea Development Award(W81XWH1910813)supported by Developmental Research Program from Kidney Cancer Specialized Program of Research Excellence(SPORE)at UTSW sponsored by NCI(P50CA196516)。
文摘The identification and application of the Von Hippel-Lindau(VHL)gene is a seminal breakthrough in kidney cancer research.VHL and its protein p VHL are the root cause of most kidney cancers,and the cascading pathway below them is crucial for understanding hypoxia,in addition to the aforementioned tumorigenesis routes and treatments.We reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor(HIF),their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a transcription factor,respectively,as well as their non-canonical functions revealed recently.Additionally,we discussed how their dysregulation promotes tumorigenesis:beginning with chromosome 3 p-arm(3p)loss/epigenetic methylation,followed by two-allele knockout,before the loss of complimentary tumor suppressor genes leads cells down predictable oncological paths.These different pathways can ultimately determine the grade,outcome,and severity of the deadliest genitourinary cancer.We finished by investigating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma(cc RCC)by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor(VEGF)inhibitors,mammalian target of rapamycin complex 1(mTORC1)inhibitors,small molecule HIF inhibitors,immune checkpoint blockade therapy,and synthetic lethality.
