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- Title
Effect of Sortilin1 on promoting angiogenesis and systemic metastasis in hepatocellular carcinoma via the Notch signaling pathway and CD133.
- Authors
Ahn, Hye Ri; Kim, Sujin; Baek, Geum Ok; Yoon, Moon Gyeong; Kang, Minji; Ng, Jestlin Tianthing; Go, Yunjin; Lim, Su Bin; Yoon, Jung Hwan; Jeong, Jee-Yeong; Han, Ji Eun; Kim, Soon Sun; Cheong, Jae Youn; Eun, Jung Woo; Cho, Hyo Jung
- Abstract
Hepatocellular carcinoma (HCC) is known to be lethal disease. However, its prognosis remains poor, primarily because the precise oncogenic mechanisms underlying HCC progression remain elusive, thus hampering effective treatment. Here, we aimed to identify the potential oncogenes in HCC and elucidate the underlying mechanisms of their action. To identify potential candidate genes, an integrative analysis of eight publicly available genomic datasets was performed, and the functional implications of the identified genes were assessed in vitro and in vivo. Sortilin 1 (SORT1) was identified as a potential candidate oncogene in HCC, and its overexpression in HCC cells was confirmed by analyzing spatial transcriptomic and single-cell data. Silencing SORT1 in Huh-7 and Hep3B cells significantly reduced HCC progression in vitro and in vivo. Functional analyses of oncogenic pathways revealed that SORT1 expression regulated the Notch signaling pathway activation and CD133 expression. Furthermore, analysis of epigenetic regulation of the candidate gene and its clinical implications using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) and our HCC cohort (AJOU_HCC cohort) data demonstrated an inverse correlation between the methylation status of the SORT1 promoter region, specifically at the cg16988986 site, and SORT1 mRNA expression, indicating the epigenetic regulation of SORT1 in HCC. In addition, the distinct methylation status of cg16988986 was significantly associated with patient survival. In conclusion, SORT1 plays a pivotal role in HCC by activating the Notch signaling pathway and increasing CD133 expression. These findings suggest SORT1 as a promising therapeutic target for HCC.
- Publication
Cell Death & Disease, 2024, Vol 15, Issue 8, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-024-07016-7