Biology subjects

Parrotta, R.

Publications and source records attributed to Parrotta, R..

3 recordsLinked to original sources

bioRxiv2025

Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer. Loss of von Hippel-Lindau (VHL) and the consequent activation of hypoxia-inducible factor- (HIF, especially HIF2) plays an essential role in ccRCC initiation and progression. The approved HIF2 inhibitor belzutifan faces the challenge of resistance, presenting an opportunity of co-targeting HIF2 and another vulnerability. This study elucidates the synthetic essentiality of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in VHL-deficient ccRCC, uncovering a novel reciprocal regulation between HIF2 and TRAIL. TRAIL was identified as a direct transcriptional target of HIF2 and paradoxically found to be crucial for cell proliferation, primarily by activating the p38 MAPK pathway and facilitating G1/S phase transition. Depletion of endogenous TRAIL or inhibition of HIF2 with belzutifan sensitizes ccRCC cells to recombinant TRAIL, presenting a promising avenue for combination therapy to overcome both TRAIL resistance and belzutifan resistance in treating ccRCC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/621197v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1d603b9org.highwire.dtl.DTLVardef@18e6dc7org.highwire.dtl.DTLVardef@1c953cdorg.highwire.dtl.DTLVardef@9cd144_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Extrachromosomal circular DNA promotes inflammation and hepatocellular carcinoma development

Two decades after the initial report on increased micronuclei in human chronic liver disease (CLD) and hepatocellular carcinoma (HCC), their role in HCC development is still poorly understood. Here we show that micronuclei in hepatocytes trigger hepatic immune response and promote HCC development via an increased level of extrachromosomal circular DNA (eccDNA). Livers from a CLD model (Mcl1{Delta}hep mice) show increased micronuclei in parallel to eccDNA. Circular sequencing confirms higher eccDNA levels in micronuclei compared to primary nuclei. We developed nuclei-segregated DNA fiber (NuSeF) assay to show that micronuclei are more susceptible to replication stress, showing increased replication fork slowing. By comparing different murine liver disease models, high eccDNA is correlated with increased tumor incidence. EccDNA is a strong immunostimulant and promotes a crosstalk between hepatocytes and immune cells through the cGAS-STING pathway. Deletion of Sting1 in Mcl1{Delta}hep mice reduces immune cell chemotaxis, as well as tumor incidence. Our findings suggest that eccDNA from micronuclei mediates inflammation-driven liver carcinogenesis in CLD.

cancer biology↗

bioRxiv2023

A HEV ORF2 protein-mediated mechanism of hepatitis E associated kidney disease.

Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN developed in parallel with increasing glomerular deposition of a noninfectious form of HEV open reading frame 2 (ORF2, capsid) protein secreted in excess. HEV particles or RNA, however, were not detectable. Patients with acute hepatitis E displayed similar but less pronounced deposits. Our results elucidate an immunologic mechanism by which this hepatotropic virus causes variable renal manifestations and establish a link between the HEV ORF2 protein and hepatitis E-associated GN. They directly provide a tool for etiology-based diagnosis of HEV-associated GN as a distinct entity and suggest therapeutic implications.

pathology↗