Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths. In the heterogeneous group of HCC, those with embryonic stem cell (ESC)/ progenitor cell gene expression characteristics have the worst prognosis. We report an oncogene in HCC, SALL4, which allows identification of a progenitor HCC subset with worse prognosis, and offers a potential treatment target.
We first screened the expression of SALL4 in primary HCC and carried out clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we carried out in vitro functional and in vivo xenograft assays.
SALL4 is expressed in human fetal liver, silenced in adult liver, but re-expressed in a subgroup of HCC patients with unfavorable prognosis, representing an oncofetal protein. Gene expression analysis reveals the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive HCCs. Loss-of-function studies confirmed that SALL4 is critical for human HCC cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN and inhibited HCC tumor formation in xenograft models in vivo.
Significance of Discovery
SALL4 represents a marker for identifying a progenitor subclass of HCC with aggressive phenotype. The absence of SALL4 expression in normal adult liver enhances the potential of SALL4 as treatment target for HCC.
Figure 1. SALL4 is a novel oncofetal protein in HCC. In healthy humans, SALL4 is expressed in fetal liver but silenced in mature adult liver. In a subgroup of HCC livers, SALL4 is re-activated and plays a functional role in hepatocarcinogenesis by silencing the tumor suppressor PTEN through the recruitment of the NuRD complex. A therapeutic peptide can be used to block the interaction between SALL4 and the NuRD complex, thereby activating PTEN transcription. Upregulation of PTEN expression leads to downregulation of pAKT level and silencing of the PI3K/AKT survival signaling, resulting in decreased HCC cell viability and tumorigenicity. We propose SALL4 to be a novel oncofetal protein that can be specifically targeted for treatment of a subgroup of aggressive HCCs with SALL4 expression.
Kol Jia Yong1,2, Chong Gao3, Joline SJ Lim3,4, Benedict Yan5, Henry Yang1, Todor Dimitrov3, Akira Kawasaki1, Chee Wee Ong1, Kwong-Fai Wong1, Sanghoon Lee1, Sharada Ravikumar1, Supriya Srivastava1, Xi Tian3, Ronnie T. Poon6, Sheung Tat Fan6, John M. Luk1,6,7, Yock Young Dan8, Manuel Salto-Tellez1,9, Li Chai3,*, Daniel G. Tenen1,10,§,*
1Cancer Science Institute ofSingapore, NationalUniversity of Singapore,Singapore
2NUS Graduate School for Integrative Sciences andEngineering,Singapore
3Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
4National University Cancer Institute of Singapore, National University Health System, Singapore
5Department of Pathology,NationalUniversity Health System andNationalUniversity ofSingapore
6Department of Surgery,QueenMaryHospital,Hong Kong
7Department of Pharmacology, NationalUniversity of Singapore,Singapore
8Department of Medicine,NationalUniversity Health System andNationalUniversity ofSingapore
9Centre for Cancer Research and Cell Biology, Queen’s University Belfast, United Kingdom
10Harvard Stem Cell Institute, Harvard Medical School, Boston, MA,
*These authors contributed equally to this work.