HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models

Abstract

BACKGROUND: HMGA1 is a non-histone nuclear protein that regulates cellular proliferation, invasion and apoptosis and is overexpressed in many carcinomas. In this study we sought to explore the expression of HMGA1 in HCCs and cirrhotic tissues, and its effect in in vitro models. METHODS: We evaluated HMGA1 expression using gene expression microarrays (59 HCCs, of which 37 were matched with their corresponding cirrhotic tissue and 5 normal liver donors) and tissue microarray (192 HCCs, 108 cirrhotic tissues and 79 normal liver samples). HMGA1 expression was correlated with clinicopathologic features and patient outcome. Four liver cancer cell lines with stable induced or knockdown expression of HMGA1 were characterized using in vitro assays, including proliferation, migration and anchorage-independent growth. RESULTS: HMGA1 expression increased monotonically from normal liver tissues to cirrhotic tissue to HCC (P < .01) and was associated with Edmondson grade (P < .01). Overall, 51% and 42% of HCCs and cirrhotic tissues expressed HMGA1, respectively. Patients with HMGA1-positive HCCs had earlier disease progression and worse overall survival. Forced expression of HMGA1 in liver cancer models resulted in increased cell growth and migration, and vice versa. Soft agar assay showed that forced expression of HMGA1 led to increased foci formation, suggesting an oncogenic role of HMGA1 in hepatocarcinogenesis. CONCLUSIONS: HMGA1 is frequently expressed in cirrhotic tissues and HCCs and its expression is associated with high Edmondson grade and worse prognosis in HCC. Our results suggest that HMGA1 may act as oncogenic driver of progression, implicating it in tumor growth and migration potential in liver carcinogenesis.

Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib

“…Protein extraction and western blotting were performed as previously described. 47 Primary antibodies used were: anti- β -Actin (Sigma-Aldrich, St. Louis, MO, USA), anti-PED, 48 anti-Calnexin (CellSignalling Technology, Basel), anti-PED S116 (ThermoFisher Scientific) anti-PED S104 (Cell Signaling Technologies, Danver, MA USA), anti-Caspase-3 (Cell Signaling Technologies, Danver, MA USA), anti-total ERK and anti-phopsho ERK (Cell Signaling Technologies), and anti-HNF4 α (Santacruz Biotechnologies, Heidelberg, Germany for cell lines and Novus Biological, Oxon, England, UK for human samples). Blots were visualized by using the Azure c3000 (Azure Biosystems, Inc., Dublin, CA, USA).…”

“…All cell lines were confirmed negative for mycoplasma infection using the PCR-based Universal Mycoplasma Detection kit (American Type Culture Collection, Manassas, VA, USA) as previously described. 47 …”

High expression of HOXA13 correlates with poorly differentiated hepatocellular carcinomas and modulates sorafenib response in in vitro models

“…SNU-449 and HepG2 cells were grown and expanded in tissue culture flasks as previously described. 40 After reaching 75% confluence, the cells were washed with PBS and detached from the flasks using a short treatment with trypsin/EDTA. 10 000 cells were dispensed into each well of an E-plate 16.…”

TRIM65 triggers β-catenin signaling via ubiquitylation of Axin1 to promote hepatocellular carcinoma

“…HMGA1 is a nonhistone nuclear protein involved in genetic recombination, chromosomal modulation, DNA repair and cell apoptosis (Sumter et al, 2016). Overexpression of HMGA1 in human cancers, such as medulloblastoma, colorectal cancer and HCC, promotes malignant progression via transcriptional regulation of several oncogenes or tumor suppressor genes (Andreozzi et al, 2016;Lau et al, 2012;Liang et al, 2013).…”