Immunoglobulin superfamily member 3 in aggressive hepatocellular carcinoma

Abstract

Abstract of thesis entitled

Immunoglobulin Superfamily Member 3 In Aggressive Hepatocellular Carcinoma

Submitted by

Jiaozi, HE

for the degree of Doctor of Philosophy at The University of Hong Kong in June 2018

Hepatocellular carcinomas (HCCs) together with intrahepatic cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs), collectively classified as liver cancer, is among the top common cancer with high death rate and worse prognosis. Majority (~80% above) of primary liver cancer is HCC. The heterogeneous cell types of HCC that display human embryonic stem cell (hESC) and hepatic progenitor cell (HPC) features is clinically related to unfavourable outcomes. In this study, based on transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset, the investigation of significantly expressed gene in HCC was shed on an oncofetal gene, Immunoglobulin Superfamily Member 3 (IGSF3), an undiscovered marker for a subtype of HCC enriched with embryonic stem cell and hepatic progenitor-like feature and poor survival outcome. IGSF3, an immunoglobulin-like membrane protein, expressed in normal embryogenesis, hepatoblasts, hepatic progenitor cells, human fetal liver and epithelial stem cells, but absent in healthy adult hepatocytes. IGSF3 was found to be significantly upregulated in human HCCs specimens with genomic copy number gain, of which IGSF3 occurred in around 15% of primary HCC tumour tissues (55/364) with a positive correlation to its mRNA expression (R = 0.337; P < 0.0001). Bioinformatics analysis showed that expression of IGSF3 in HCC was associated with significant survival outcome that IGSF3 might be served as an independent prognostic factor. IGSF3-ectopic introduction into human HCC cell lines for gain- and loss-of-function studies in in vitro and in vivo models demonstrated that the aberrant activation of IGSF3 in HCC could promote cell proliferation, tumour formation, migration, invasion, self-renewal and skewed tumour grade towards poorly- to un-differentiation. Gene-set enrichment analysis of clinical HCC specimens indicated that expression of IGSF3 correlated with the expression of stemness-related genes Oct4 and Sox2, HCC CSC markers Sall4, CD133, CD47, EpCAM, CD24, bipotential hepatic progenitor/poorly differentiated HCC markers Sox9 and CK19, typical cancer hallmarks FOXM1, TCF3, CA9 and BMI1. High expression of IGSF3 was also accompanied by the decreased expression of tumour suppressor genes of Acox2, TSC2, and well-differentiated HCC markers of Arg-1 and G6PC. Mechanistically, IGSF3 could promote HCC via NRas-activated signaling pathways with elevated levels of MEK/ERK and PI3K/AKT. In summary, IGSF3 expression in HCC can serve as an indicator of novel subtype with stemness feature and may therefore provide a potential novel target for diagnostic and therapeutic benefits.

An abstract of 376 words

Name: Jiaozi HE