CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers

Abstract

Background: Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1) is a critical metabolic enzyme of melatonin. Although melatonin has been identified to exhibit tumor suppressing activity, the role and mechanism of the clinical and immunological characteristics of CYP1B1 in cancer remain unclear. Methods: In this study, RNA expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) across 33 solid tumors. The expression, survival, immune subtype, molecular subtype, tumor mutation burden (TMB), microsatellite instability (MSI), biological pathways, and function in vitro and vivo were evaluated. The predictive value of CYP1B1 in immune cohorts was further explored. Results: We found the dysregulated expression of CYP1B1 was associated with the clinical stage and tumor grade. Immunological correlation analysis showed CYP1B1 was positively correlated with the infiltration of lymphocyte, immunomodulator, chemokine, receptor, and cancer-associated fibroblasts (CAFs) in most cancer. Meanwhile, CYP1B1 was involved in immune subtype and molecular subtype, and was connected with TMB, MSI, neoantigen, the activation of multiple melatonergic and immune-related pathways, and therapeutic resistance. Conclusions: Together, this study comprehensively revealed the role and mechanism of CYP1B1 and explored the significant association between CYP1B1 expression and immune activity. These findings provide a promising predictor and molecular target for clinical immune treatment.

Human Adult Renal Progenitor Cells Prevent Cisplatin-Nephrotoxicity by Inducing CYP1B1 Overexpression and miR-27b-3p Down-Regulation through Extracellular Vesicles

“…To assess the expression of CYP1B1 ex vivo, we performed immunohistochemistry assays on biopsies of healthy human kidney tissue and cisplatin-treated renal cell carcinoma (RCC) ( Figure 5 A,B). As expected [ 26 ], CYP1B1 is highly expressed in renal carcinoma ( Figure 5 B), whereas healthy kidney tissue displays a low expression of this protein ( Figure 5 A). In order to detect the possible involvement of tARPC in CYP1B1 expression, we performed an immunofluorescence assay on RCC biopsies for CD133 and CYP1B1 ( Figure 5 D–F).…”

“…However, CYP1B1’s precise role in drug resistance remains obscure. Regarding CYP1B1 significance at the tumor level, CYP1B1 was associated both with protective overall survival in skin cutaneous melanoma and sarcoma, whereas its expression correlates with tumor stage in bladder urothelial carcinoma and other tumors [ 26 ]. Here, we found a co-localization between the CYP1B1 and CD133 marker in RCC biopsies of cisplatin-treated patients, confirming the hypothesis of a potential renoprotective role of this enzyme during chemotherapy.…”

Cytochrome P450 and Other Drug-Metabolizing Enzymes As Therapeutic Targets

“…While P450 isoforms in the CYP1, CYP2 and CYP3 subfamilies are generally more regarded for their roles in xenobiotic metabolism, a number of these enzymes have also been evaluated as possible drug targets. Both CYP1A1 and CYP1B1 have been shown to activate procarcinogens as well as to catalyze the metabolism of estrogen and 17β-estradiol (Napoli et al, 2005) with the prevalence of various cancers (Watanabe et al, 2000;Androutsopoulos et al, 2009;Gajjar et al, 2012;Rodriguez and Potter, 2013;Alsubait et al, 2020;Al-Saraireh et al, 2021;Yuan et al, 2022). While much of the research surrounding CYP1A1 and CYP1B1 as therapeutic targets has centered on their ability to activate prodrugs, additional approaches including chemical inhibitors, immunotherapy and antisense oligonucleotides have all been described in the literature (McFadyen and Murray, 2005;Luby, 2008;Mescher and Haarmann-Stemmann, 2018;Carrera et al, 2020).…”

Design and Synthesis of Novel Near-Infrared Fluorescence Probes Based on an Open Conformation of a Cytochrome P450 1B1 Complex for Molecular Imaging of Colorectal Tumors

“…CYP1B1 is considered as a potential tumor biomarker not only because of its selective overexpression in various cancers but also because it is associated with clinical stage and tumor grade of cancers. Data analysis consisting of 33 cancers showed positive correlation between high expression of CYP1B1 and clinical stage of tumors, including blade urothelial carcinoma, kidney renal clear cell carcinoma, skin cutaneous melanoma, and others . Likewise, CYP1B1 is significantly expressed in the late stages of the disease (100% in grades III and IV) .…”

“…Data analysis consisting of 33 cancers showed positive correlation between high expression of CYP1B1 and clinical stage of tumors, including blade urothelial carcinoma, kidney renal clear cell carcinoma, skin cutaneous melanoma, and others. 32 Likewise, CYP1B1 is significantly expressed in the late stages of the disease (100% in grades III and IV). 20 In addition, the relationship between CYP1B1 and drug resistance is gradually being explored.…”