# Extracellular-Vesicle-Associated UBE2NL and HIST2H3PS2 Promote Tumor Aggressiveness and Metastasis in Gynecologic Cancer

## TL;DR

This study identifies UBE2NL and HIST2H3PS2 as proteins in extracellular vesicles that promote aggressive tumor growth and metastasis in gynecologic cancers.

## Contribution

The study discovers UBE2NL and HIST2H3PS2 as novel extracellular vesicle cargo proteins linked to tumor aggressiveness in gynecologic cancers.

## Key findings

- UBE2NL and HIST2H3PS2 are overexpressed in aggressive ovarian cancer cells and stromal progenitor cells.
- High expression of these proteins correlates with advanced tumor stages and poor survival in epithelial and endometrial ovarian cancers.
- Knockdown of UBE2NL reduces tumor invasiveness and improves survival in mouse models.

## Abstract

Extracellular vesicles (EVs) play pivotal roles in tumor progression and metastasis by mediating intercellular communication within the tumor microenvironment. In this study, we identified two novel EX cargo proteins—UBE2NL and HIST2H3PS2—derived from highly aggressive epithelial ovarian cancer (EOC) cells and mesenchymal-type ovarian stromal progenitor cells (MSC-OCSPCs) but absent in less aggressive SKOV3 cells. Quantitative proteomic profiling via LC-MS/MS and TCGA-integrated analysis revealed that high expression of these genes correlated with advanced tumor stages and poor overall survival in EOC, and high HIST2H3PS2 expression predicted poor survival in endometrial cancer (EC). Functionally, UBE2NL and HIST2H3PS2 overexpression promoted EOC cell invasiveness, which was further enhanced by EX-mediated autocrine and paracrine effects. In contrast, the knockdown of UBE2NL reduced cell invasiveness and prolonged mouse survival in vivo. Moreover, HIST2H3PS2-enriched EXs significantly increased peritoneal dissemination and ascites in murine models. These findings suggest that EX-packaged UBE2NL and HIST2H3PS2 drive tumor aggressiveness and metastasis in gynecologic cancers, highlighting their potential as prognostic biomarkers and therapeutic targets.