Open Access

Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells

  • Authors:
    • Edoardo Abeni
    • Alessandro Salvi
    • Eleonora Marchina
    • Michele Traversa
    • Bruna Arici
    • Giuseppina De Petro
  • View Affiliations

  • Published online on: May 24, 2017     https://doi.org/10.3892/ijo.2017.4019
  • Pages: 128-144
  • Copyright: © Abeni et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Sorafenib is currently used to treat advanced and/or unresectable hepatocellular carcinoma (HCC), but the increase of the median survival was only 3 months. Moreover, sorafenib has severe side effects and patients develop resistance quickly. Epigenetic alterations such as DNA methylation play a decisive role in the development and progression of HCC. To our knowledge, there are no studies that analysed the global DNA methylation changes in HCC cells treated with sorafenib. Using MeDip-chip technologies, we found 1230 differentially methylated genes in HA22T/VGH cells treated with sorafenib compared to untreated cells. Gene ontology and pathway analysis allowed identifying several enriched signaling pathways involved in tumorigenesis and cancer progression. Among the genes differentially methylated we found genes related to apoptosis, angiogenesis and invasion, and genes belonging to pathways known to be deregulated in HCC such as RAF/MEK/ERK, JAK-STAT, PI3K/AKT/mTOR and NF-κB. Generally, we found that oncogenes tended to be hypermethylated and the tumor suppressor genes tended to be hypomethylated after sorafenib treatment. Finally, we validated MeDip-chip results for several genes found differentially methylated such as BIRC3, FOXO3, MAPK3, SMAD2 and TSC2, using both COBRA assay and direct bisulfite sequencing and we evaluated their mRNA expression. Our findings suggest that sorafenib could affect the methylation level of genes associated to cancer-related processes and pathways in HCC cells, some of which have been previously described to be directly targeted by sorafenib.
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July-2017
Volume 51 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Abeni E, Salvi A, Marchina E, Traversa M, Arici B and De Petro G: Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells. Int J Oncol 51: 128-144, 2017
APA
Abeni, E., Salvi, A., Marchina, E., Traversa, M., Arici, B., & De Petro, G. (2017). Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells. International Journal of Oncology, 51, 128-144. https://doi.org/10.3892/ijo.2017.4019
MLA
Abeni, E., Salvi, A., Marchina, E., Traversa, M., Arici, B., De Petro, G."Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells". International Journal of Oncology 51.1 (2017): 128-144.
Chicago
Abeni, E., Salvi, A., Marchina, E., Traversa, M., Arici, B., De Petro, G."Sorafenib induces variations of the DNA methylome in HA22T/VGH human hepatocellular carcinoma-derived cells". International Journal of Oncology 51, no. 1 (2017): 128-144. https://doi.org/10.3892/ijo.2017.4019