Abstract
Aptamers are small synthetic oligonucleotides that bind to target proteins with high specificity and affinity. AS1411 is an aptamer that binds to nucleolin, which is overexpressed in the cytoplasm and occurs on the surface of cancer cells. We investigated the therapeutic potential of aptamers in hepatocellular carcinoma (HCC) by evaluating anti-tumor effects and confirming the affinity and specificity of AS1411- and modified AS1411-aptamers in HCC cells. Cell growth was assessed using the MTS assay, and cell death signaling was explored by immunoblot analysis. Fluorescence-activated cell sorting was performed to evaluate the affinity and specificity of AS1411-aptamers in SNU-761 HCC cells. We investigated the in vivo effects of the AS1411-aptamer using BALB/c nude mice in a subcutaneous xenograft model with SNU-761 cells. Treatment with a modified AS1411-aptamer significantly decreased in vitro (under normoxic [P = 0.035] and hypoxic [P = 0.018] conditions) and in vivo (under normoxic conditions, P = 0.041) HCC cell proliferation compared to control aptamers. AS1411- and control aptamers failed to control HCC cell proliferation. However, AS1411- and the modified AS1411-aptamer did not induce caspase activation. Decrease in cell growth by AS1411 or modified AS1411 was not prevented by caspase or necrosis inhibitors. In a microarray, AS1411 significantly enhanced galectin-14 expression. Suppression of HCC cell proliferation by the modified AS1411-aptamer was attenuated by galectin-14 siRNA transfection. Modified AS1411-aptamer suppressed HCC cell growth in vitro and in vivo by up-regulating galectin-14 expressions. Modified AS1411-aptamers may have therapeutic potential as a novel targeted therapy for HCC.
Highlights
Hepatocellular carcinoma is complex, with a heterogeneous tumor biology [1]
Because AS1411-aptamer targets nucleolin on the cell surface, we evaluated nucleolin expression on the cell surface in SNU-761 hepatocellular carcinoma (HCC) cells
To find the main mechanism of anti-tumor activity, we evaluated whether the PI3K/Akt or ERK1/2-mitogen-activated protein kinase (MAPK) pathways were activated by AS1411- or modified AS1411-aptamers, as these are key survival signaling pathways in HCC cells [14]
Summary
Hepatocellular carcinoma is complex, with a heterogeneous tumor biology [1]. Several genomic alterations, such as Ras/extracellular signal-regulated kinases, epidermal growth factor receptor (EGFR), phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, and Hedgehog signaling, limit the therapeutic efficacy of systemic molecular targeted chemotherapy, including sorafenib [2,3,4]. Targeted treatment with high affinity to specific receptors on HCC cells is essential [5]. Aptamers within drugencapsulated polymer particles have cell-specific anti-tumor effects. Combining targeted-delivery with controlled drug release leads to cytotoxicity in targeted tumor cells and spares surrounding noncancerous cells from toxicity, which is an ideal strategy for cancer treatment
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