| Autor: |
Xin Wei Wang, Snorri S. Thorgeirsson, Xiaoling Luo, Gary A. Mitchell, Jinqiu Chen, Lun-Xiu Qin, Hu-Liang Jia, Qing-Hai Ye, Katie Powell, Xiaolin Wu, Rachel Bagni, Ji Luo, Dana A. Dominguez, Sean P. Martin, Subreen Khatib, Naoki Oishi, Hien Dang, Atsushi Takai |
| Rok vydání: |
2023 |
| Popis: |
Hepatocellular carcinoma (HCC) is a genetically heterogeneous disease for which a dominant actionable molecular driver has not been identified. Patients with the stem cell–like EpCAM+AFP+ HCC subtype have poor prognosis. Here, we performed a genome-wide RNAi screen to identify genes with a synthetic lethal interaction with EpCAM as a potential therapeutic target for the EpCAM+AFP+ HCC subtype. We identified 26 candidate genes linked to EpCAM/Wnt/β-catenin signaling and HCC cell growth. We further characterized the top candidate PMPCB, which plays a role in mitochondrial protein processing, as a bona fide target for EpCAM+ HCC. PMPCB blockage suppressed EpCAM expression and Wnt/β-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suppression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM+ HCC subpopulations.Significance:This study identifies PMPCB as critical to mitochondrial homeostasis and a synthetic lethal candidate that selectively kills highly resistant EpCAM+ HCC tumors by inactivating the Wnt/β-catenin signaling pathway. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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