Dataset Information

Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro.

ABSTRACT: Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multikinase inhibitors, regorafenib (Stivarga) and sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration, and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1-1 µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multikinase inhibitor concentrations thus modulate several aspects of HCC cell biology.

SUBMITTER: Carr BI

PROVIDER: S-EPMC3582757 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro.

Carr Brian I BI D'Alessandro Rosalba R Refolo Maria G MG Iacovazzi Palma A PA Lippolis Catia C Messa Caterina C Cavallini Aldo A Correale Mario M Di Carlo Antonio A

Journal of cellular physiology 20130601 6

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multikinase inhibitors, regorafenib (Stivarga) and sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration, and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at ...[more]

PMID: 23169148

Similar Datasets

Project description:Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits is modest, also because its mechanism of action remains elusive, therefore, a better understanding of its molecular action and molecular targets are needed. On the basis of our previous studies, here, we investigated the role of the nuclear protein 1 (NUPR1) in HCC and its role in the context of sorafenib treatment. NUPR1 is a stress-inducible protein over-expressed in different malignancies, however, its role in HCC is not yet fully understood. We found that NUPR1, is over-expressed in 53% of primary human HCC samples. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibits cell growth, migration and invasion of HCC cells in vitro and tumorigenicity in vivo. Moreover, NUPR1 silencing influenced expression of target genes RelB and IER3. Unsurprisingly, RelB and IER3 knockdown also inhibited HCC cells viability, growth and migration. By gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-ÎºB and ERK as down-regulated gene nodes, and several genes known to be involved in hepatocarcinogenesis were also suppressed. In addition, we identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1 down-regulated gene. We also demonstrated that RUNX2 gene silencing inhibited HCC cells viability, growth, migration and increased cell sensitivity to sorafenib. Conclusion: We propose that NUPR1/RELB/IER3/RUNX2 pathway play pivotal role in hepatocarcinogenesis. The identification of NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management. To better understand the molecular mechanisms of NUPR1 gene action in ovarian HCC cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon NUPR1 suppression in HCC cells. We compared the gene expression of the previously selected shRNA-mediated NURP1-knockdown Hep3B clone against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for the NUPR1-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.

Project description:Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits is modest, also because its mechanism of action remains elusive, therefore, a better understanding of its molecular action and molecular targets are needed. On the basis of our previous studies, here, we investigated the role of the nuclear protein 1 (NUPR1) in HCC and its role in the context of sorafenib treatment. NUPR1 is a stress-inducible protein over-expressed in different malignancies, however, its role in HCC is not yet fully understood. We found that NUPR1, is over-expressed in 53% of primary human HCC samples. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibits cell growth, migration and invasion of HCC cells in vitro and tumorigenicity in vivo. Moreover, NUPR1 silencing influenced expression of target genes RelB and IER3. Unsurprisingly, RelB and IER3 knockdown also inhibited HCC cells viability, growth and migration. By gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as down-regulated gene nodes, and several genes known to be involved in hepatocarcinogenesis were also suppressed. In addition, we identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1 down-regulated gene. We also demonstrated that RUNX2 gene silencing inhibited HCC cells viability, growth, migration and increased cell sensitivity to sorafenib. Conclusion: We propose that NUPR1/RELB/IER3/RUNX2 pathway play pivotal role in hepatocarcinogenesis. The identification of NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management.

Dataset Information

Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro.

Publications

Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets