Abstract
Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits are modest, and as its mechanisms of action remain elusive, a better understanding of its anticancer effects is needed. Based on our previous study results, we investigated here the implication of the nuclear protein 1 (NUPR1) in HCC and its role in sorafenib treatment. NUPR1 is a stress-inducible protein that is overexpressed in various malignancies, but its role in HCC is not yet fully understood. We found that NUPR1 expression was significantly higher in primary human HCC samples than in the normal liver. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibited the cell growth, migration and invasion of HCC cells, both in vitro and in vivo. Moreover, NUPR1 silencing influenced the expression of RELB and IER3 genes. Unsurprisingly, RELB and IER3 knockdown also inhibited HCC cell viability, growth and migration. Using 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 downregulated gene nodes, and several HCC-related oncogenes were also suppressed. We identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1-regulated gene and demonstrated that RUNX2 gene silencing inhibits HCC cell viability, growth, migration and increased cell sensitivity to sorafenib. We propose that the NUPR1/RELB/IER3/RUNX2 pathway has a pivotal role in hepatocarcinogenesis. The identification of the NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management.
Highlights
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers and is currently the third major cause of cancer-related deaths globally.[1]
Genes involved in endoplasmic reticulum (ER) stress response, such as GRP78, activating transcription factor 4 (ATF4), C/EBP-homologous protein (CHOP) and Tribbles homolog 3 (TRB3) were upregulated (Figures 1a and b), and splicing of X-box-binding protein 1 (XBP1) mRNA was induced (Figures 1c and d)
We present potential molecular mechanisms to explain sorafenib resistance in HCC cells
Summary
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers and is currently the third major cause of cancer-related deaths globally.[1]. NUPR1, a new target in liver cancer MR Emma et al Several reports have indicated that sorafenib may induce cell death signaling pathways via endoplasmic reticulum (ER) stress activation.[8,9,10] Our recent studies analyzing the molecular mechanisms of sorafenib treatment in human HCC cells identified several genes involved in ER stress response modulated by sorafenib.[11] In particular, the stressinducible gene nuclear protein-1 (NUPR1, known as p8/Com-1) was upregulated after sorafenib treatment and its expression was found to be potentiated on treatment with the anti-inflammatory drug celecoxib.[11,12]. As the role of NUPR1 in hepatocarcinogenesis is not yet fully understood, we decided to examine its involvement in the context of sorafenib treatment in HCC cells
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