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Abstract
BackgroundGalectins are beta-galactose specific binding proteins. In human cancers, including hepatocellular carcinoma (HCC), galectin-1 (Gal-1) is often found to be overexpressed. In order to combat the dismal diagnosis and death rates of HCC, gene silencing and targeted inhibition of Gal-1 was investigated for its improved therapeutic potential.MethodsCellular and secretory Gal-1 levels were analyzed using HCC clinical samples. The study of Gal-1 was carried by both knockdown and overexpression approaches. The stable clones were tested by in vitro assays and in vivo experiments. Mass spectrometry was used to identify downstream targets of Gal-1. The upstream regulator of Gal-1, microRNA-22 (miR-22) was characterized by functional assays. The therapeutic effect of inhibiting Gal-1 was also analyzed.ResultsGal-1 overexpression was observed in HCC and correlated with aggressive clinicopathological features and poorer survival. The loss of Gal-1 resulted in hindered cell migration, invasion and anchorage independent growth. This was also observed in the animal models, in that when Gal-1 was knocked down, there were fewer lung metastases. Proteomic profiling of control and Gal-1 knockdown cells identified that the level of retention in endoplasmic reticulum 1 (RER1) was suppressed when Gal-1 level was reduced. The cell motility of Gal-1 knockdown cells was enhanced upon the rescue of RER1 expression. In HCC tissues, Gal-1 and RER1 expressions displayed a significant positive correlation. The upstream regulator of Gal-1, miR-22 was observed to be underexpressed in HCC tissues and negatively correlated with Gal-1. Silencing of miR-22 resulted in the upregulation of Gal-1 and enhanced cell growth, migration and invasion. However, such enhancement was abolished in cells treated with OTX008, an inhibitor of Gal-1. Combinational treatment of OTX008 and sorafenib significantly reduced tumor growth and size.ConclusionsGal-1 overexpression was detected in HCC and this played a role in promoting tumorigenic processes and metastasis. The function of Gal-1 was found to be mediated through RER1. The correlations between miR-22, Gal-1 and RER1 expressions demonstrated the importance of miR-22 regulation on Gal-1/RER1 oncogenic activity. Lastly, the combinational treatment of OTX008 and sorafenib proved to be an improved therapeutic option compared to when administering sorafenib alone.
Highlights
Gal-1 overexpression was detected in hepatocellular carcinoma (HCC) and this played a role in promoting tumorigenic processes and metastasis
The correlations between miR-22, Gal-1 and retention in endoplasmic reticulum 1 (RER1) expressions demonstrated the importance of miR-22 regulation on Gal-1/RER1 oncogenic activity
The combinational treatment of OTX008 and sorafenib proved to be an improved therapeutic option compared to when administering sorafenib alone
Summary
Clinical HCC samples HCC paired patient samples were obtained upon surgical resection from Queen Mary Hospital, Hong Kong. A HCC tissue microarray consisting of 97 paired tumorous and nontumorous cases was used for analyzing Gal-1 expression using immunohistochemistry. To establish Gal-1 knockdown stable clones, shRNA against Gal-1 was transfected into 293FT cells using the FuGene® 6 transfection reagent (Promega) for the generation of viral particles. For the reduction of miR-22, lentiviral particles inhibitor for miR-22 (GeneCopoeia) was transfected with GeneCopoeia Lenti-PacTM HIV expression packaging system into 293FT cells before viral transduction into HCC cell lines. Tumor growth in the liver was monitored weekly for up to 6 weeks via bioluminescent imaging. This was carried out by anaesthetizing the animal and injecting it with D-luciferin (Xenogen, Hopkinton, MA, USA), which is required for bioluminescent signaling. A P-value of less than 0.05 is considered statistically significant
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