Faculty, Staff and Student Publications
Language
English
Publication Date
1-5-2024
Journal
Communications Biology
DOI
10.1038/s42003-023-05736-8
PMID
38182652
PMCID
PMC10770396
PubMedCentral® Posted Date
1-5-2024
PubMedCentral® Full Text Version
Post-print
Abstract
B7-H3 (CD276) has two isoforms (2Ig and 4Ig), no confirmed cognate receptor, and physiological functions that remain elusive. While differentially expressed on many solid tumors correlating with poor survival, mechanisms of how B7-H3 signals in cis (tumor cell) versus in trans (immune cell co-regulator) to elicit pro-tumorigenic phenotypes remain poorly defined. Herein, we characterized a tumorigenic and signaling role for tumor cell-expressed 4Ig-B7-H3, the dominant human isoform, in gynecological cancers that could be abrogated upon CRISPR/Cas9 knockout of B7-H3; tumorigenesis was rescued upon re-expression of 4Ig-B7-H3. Size exclusion chromatography revealed dimerization states for the extracellular domains of both human 4Ig- and murine 2Ig-B7-H3. mEGFP lifetimes of expressed 4Ig-B7-H3-mEGFP fusions determined by FRET-FLIM assays confirmed close-proximity interactions of 4Ig-B7-H3 and identified two distinct homo-FRET lifetime populations, consistent with monomeric and homo-dimer interactions. In live cells, bioluminescence imaging of 4Ig-B7-H3-mediated split luciferase complementation showed dimerization of 4Ig-B7-H3. To separate basal from dimer state activities in the absence of a known receptor, C-terminus (cytosolic) chemically-induced dimerization of 4Ig-B7-H3 increased tumor cell proliferation and cell activation signaling pathways (AKT, Jak/STAT, HIF1α, NF-κβ) significantly above basal expression of 4Ig-B7-H3 alone. These results revealed a new, dimerization-dependent intrinsic tumorigenic signaling role for 4Ig-B7-H3, likely acting in cis, and provide a therapeutically-actionable target for intervention of B7-H3-dependent tumorigenesis.
Keywords
Animals, Humans, Mice, B7 Antigens, Carcinogenesis, Cell Proliferation, Dimerization, Polymers, Protein Isoforms, Signal Transduction, Transcription Factors, Cell signalling, Tumour immunology
Published Open-Access
yes
Recommended Citation
Sutton, Margie N; Glazer, Sarah E; Muzzioli, Riccardo; et al., "Dimerization of the 4Ig Isoform of B7-H3 in Tumor Cells Mediates Enhanced Proliferation and Tumorigenic Signaling" (2024). Faculty, Staff and Student Publications. 6424.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6424
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