Genomic Amplification of TBC1D31 Promotes Hepatocellular Carcinoma Through Reducing the Rab22A‐Mediated Endolysosomal Trafficking and Degradation of EGFR

• Published in: Advanced science Vol. 11; no. 40; pp. e2405459 - n/a
• Main Authors: Cao, Pengbo, Chen, Hongxia, Zhang, Ying, Zhang, Qi, Shi, Mengting, Han, Huihui, Wang, Xiaowen, Jin, Liang, Guo, Bingqian, Hao, Rongjiao, Zhao, Xi, Li, Yuanfeng, Gao, Chengming, Liu, Xinyi, Wang, Yahui, Yang, Aiqing, Yang, Chenning, Si, Anfeng, Li, Hua, Song, Qingfeng, He, Fuchu, Zhou, Gangqiao
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.10.2024; John Wiley and Sons Inc; Wiley
• Subjects: 8q24.13 amplification; Clinical outcomes; Datasets; epidermal growth factor receptor (EGFR) trafficking; Gene expression; hepatocellular carcinomas (HCCs); Kinases; lenvatinib; Liver cancer; Medical prognosis; Mutation; Proteins; Rab22A; TBC1D31; hepatocellular carcinomas (HCCs); epidermal growth factor receptor (EGFR) trafficking; TBC1D31; lenvatinib; 8q24.13 amplification; Rab22A
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202405459

Hepatocellular carcinomas (HCCs) are characterized by a vast spectrum of somatic copy number alterations (CNAs); however, their functional relevance is largely unknown. By performing a genome‐wide survey on prognosis‐associated focal CNAs in 814 HCC patients by an integrative computational framework based on transcriptomic data, genomic amplification is identified at 8q24.13 as a promising candidate. Further evidence is provided that the 8q24.13 amplification‐driven overexpression of Rab GTPase activating protein TBC1D31 exacerbates HCC growth and metastasis both in vitro and in vivo through activating Epidermal growth factor receptor (EGFR) signaling. Mechanistically, TBC1D31 acts as a Rab GTPase activating protein to catalyze GTP hydrolysis for Rab22A and then reduces the Rab22A‐mediated endolysosomal trafficking and degradation of EGFR. Notably, overexpression of TBC1D31 markedly increases the resistance of HCC cells to lenvatinib, whereas inhibition of the TBC1D31‐EGFR axis can reverse this resistance phenotype. This study highlights that TBC1D31 at 8q24.13 is a new critical oncogene, uncovers a novel mechanism of EGFR activation in HCC, and proposes the potential strategies for treating HCC patients with TBC1D31 amplification or overexpression. Epidermal growth factor receptor (EGFR), rarely driven by oncogenic mutations (<5%) in hepatocellular carcinoma (HCC), soars in protein levels (> 60%). Here, TBC1D31 is identified as a novel Rab GTPase activating protein to catalyze GTP hydrolysis for Rab22A, which mediates endolysosomal trafficking and degradation of EGFR, and proposes TBC1D31 as a novel actionable target for HCC patients with 8q24.13 amplification.