Hypoxia-Inducible Factor-2-Altered Urothelial Carcinoma: Clinical and Genomic Features

Abstract

Background: Hypoxia is recognized as a key feature of cancer growth and is involved in various cellular processes, including proliferation, angiogenesis, and immune surveillance. Besides hypoxia-inducible factor 1-alpha (HIF-1α), which is the main mediator of hypoxia effects and can also be activated under normoxic conditions, little is known about its counterpart, HIF-2. This study focused on investigating the clinical and molecular landscape of HIF-2-altered urothelial carcinoma (UC). Methods: Publicly available next-generation sequencing (NGS) data from muscle-invasive UC cell lines and patient tumor samples from the MSK/TCGA 2020 cohort (n = 476) were interrogated for the level of expression (mRNA, protein) and presence of mutations, copy number variations, structural variants in the EPAS1 gene encoding HIF-2, and findings among various clinical (stage, grade, progression-free and overall survival) and molecular (tumor mutational burden, enriched gene expression) parameters were compared between altered and unaltered tumors. Results: 19% (7/37) of UC cell lines and 7% (27/380) of patients with muscle-invasive UC display high EPAS1 mRNA and protein expression or/and EPAS1 alterations. EPAS1-altered tumors are associated with higher stage, grade, and lymph node metastasis as well as with shorter PFS (14 vs. 51 months, q = 0.01) and OS (15 vs. 55 months, q = 0.01). EPAS1 mRNA expression is directly correlated with that of its target-genes, including VEGF, FLT1, KDR, DLL4, CDH5, ANGPT1 (q < 0.001). While there is a slightly higher tumor mutational burden in EPAS1-altered tumors (9.9 vs. 4.9 mut/Mb), they are enriched in and associated with genes promoting immune evasion, including ARID5B, SPINT1, AAK1, CLIC3, SORT1, SASH1, and FGFR3, respectively (q < 0.001). Conclusions: HIF-2-altered UC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-preventing genes.

Imbalance of fetal growth factor levels in congenital heart disease pathology: a systematic review to investigate therapeutic potential

“…The correlation between HIF and VEGF, similar to our results, was also shown by Yin, who even considered the increase in angiogenesis to be a protective factor for the fetus, and the level of HIF is a prognostic indicator of CHD(16). Hypoxia-inducible factor (HIF) is the response to low oxygen supply in the body by premetazoans and is a factor that enables angiogenesis and fetal growth during the embryonic period and even in tumors by controlling gene transcription pathways (44,45). Angiogenesis stimulation plays an important role in this process, and in addition to brosis, in ammation, apoptosis and vascular calci cation, it is a highly important factor for the uterus and placenta (46,47).…”

Identification of immune-related biomarkers in peripheral blood of schizophrenia using bioinformatic methods and machine learning algorithms

“…CLIC3 has been found to be expressed in human placenta and fetal membranes ( Money et al, 2007 ), osteoblasts ( Brum et al, 2017 ), and various cancer cells ( Patel et al, 2019 ; Chen et al, 2020 ; Kawai et al, 2020 ). Its rich expression promotes immune evasion in cancer cells ( Vlachostergios et al, 2022 ). Addtionally, it was reported that in hepatitis B virus, CLIC3 promotes classical macrophage activation via the NF-κB pathway ( Liang et al, 2022 ).…”

An Overview of Angiogenesis in Bladder Cancer

“…Activation of the ERK pathway and induction of C–C Motif Chemokine Ligand 2 (CCL2) are responsible for HSP47-induced angiogenesis Wang et al [ 73 ] Mettl3 BC cell lines T24 and UMUC-3 Transgenic mice Ablation of Mettl3 in bladder urothelial cells attenuates the oncogenesis and tumour angiogenesis of BC Abd El-Azeem, Ali and El-Shorbagy [ 74 ] GLUT4 BC tissue samples of radical cystectomies and TUR GLUT4 and fibroblast activation protein (FAP) expression is significantly associated with increased intratumour MVD and adverse clinicopathological factors Mori et al [ 75 ] VCAM-1 Preoperative plasma samples Elevated VCAM-1 is associated with aggressive BC. Preoperative VCAM-1 may serve as a biomarker to help identify patients likely to benefit from multimodal therapy Vlachostergios et al [ 76 ] HIF-2 Publicly available next-generation sequencing (NGS) data from muscle-invasive BC cell lines and patient tumour samples from the MSK/TCGA 2020 cohort were interrogated HIF-2-altered BC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-promoting genes Xia et al [ 77 ] PKM2 Genetically engineered mice BC cell lines RT112, 1376, UMUC3, and T24 and mouse BC cell line MBT2 PKM2 ablation in mouse urothelial cells and/or chemical inhibition of PKM2 reduces complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1α- and VEGF-related angiogenesis Yang et al [ 78 ] Occludin Cell lines T24 and 5637. Human umbilical vein endothelial cells (EA.hy926) and 293 T BC tissue samples Occludin participates in the development of angiogenesis in BCs by activating the IL8/STAT3 pathway via STAT4 CEACAM1 , carcinoembryonic antigen-related cell adhesion molecule-1; DLL4 , delta-like 4; HAS-1 , hyaluronic acid synthase-1; HO-1 , haem oxygenase-1; AT1R , angiotensin II type 1 receptor; BCLA , bladder cancer–specific nuclear matrix protein; VEGFR , VEGF receptor; EDIL-3 , EGF like repeats and discoidin i like domains protein 3; FGFGR , fibroblast growth factor receptor; KLF5 , human Kruppel-like factor 5; BAI-,1 brain-sp...…”