Future of molecular profiling of human hepatocellular carcinoma

National Cancer Institute, Laboratory of Human Carcinogenesis, Center for Cancer Research, NIH, 37 Convent Drive, Bldg. 37, Rm. 3044A, Bethesda, MD 20892-4258, USA.
Future Oncology (Impact Factor: 2.48). 09/2007; 3(4):429-39. DOI: 10.2217/14796694.3.4.429
Source: PubMed


Hepatocellular carcinoma (HCC) is a fatal disease occurring worldwide and developing mainly in chronic liver diseased patients. Despite routine screening of individuals at high risk, most of the patients are diagnosed at late stages of HCC. In addition, the recurrence rate after surgical resection of small tumors is high. Molecular profiling, including expression analysis, comparative genomics and proteomics, provides powerful tools to gain insight into the molecular mechanisms underlying carcinogenesis. Advances in bioinformatics have also allowed for the evaluation of large data sets. Therefore, molecular profiling of HCC using a Biological Expression Network Discovery (BLEND) strategy that integrates global molecular profiling data, including mRNA, miRNA, DNA methylation and DNA copy numbers from both the tumor and the surrounding microenvironment, along with mechanistic studies, may improve the diagnosis, treatment and prognosis of HCC patients. Such an approach will provide mechanistic insight into the pathogenesis of HCC, potentially leading to personalized medicine and the identification of new therapeutic targets.

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    • "In the tumors, hypoxia is an important mechanism that induces proliferation, metastasis, and neovascularization of tumors [9], [13], [14]. HIF-1α is a key molecule in hypoxia [12], and is known to be involved in the proliferation of tumors and survival mechanisms such as angiogenesis and anti-apoptosis [15]. "
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    ABSTRACT: Dimerization of hypoxia-inducible factor-1 beta (HIF-1β) [aryl hydrocarbon receptor nuclear translocator (ARNT)] with HIF-1α is involved in various aspects of cancer biology, including proliferation and survival under hypoxic conditions. We investigated the in vitro mechanism by which silencing of HIF-1β leads to the suppression of tumor cell growth and cellular functions. Various hepatocellular carcinoma (HCC) cell lines (Huh-7, Hep3B, and HepG2) were transfected with small interfering RNA (siRNA) against HIF-1β (siHIF-1β) and cultured under hypoxic conditions (1% O2 for 24 h). The expression levels of HIF-1β, HIF-1α, and growth factors were examined by immunoblotting. Tumor growth was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and tumor activity was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling, tumor cell invasion, and migration assays. Under hypoxic conditions, silencing of HIF-1β expression suppressed tumor cell growth and regulated the expression of tumor growth-related factors, such as vascular endothelial growth factor, epidermal growth factor, and hepatocyte growth factor. Suppression of tumor cell invasion and migration was also demonstrated in HIF-1β-silenced HCC cell lines. Silencing of HIF-1β expression may induce anti-tumor effects under hypoxic conditions in HCC cell lines.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Liver resection and transplantation are currently the main curative therapies for HCC [2], [3]. Unfortunately, there is a high rate of postsurgical recurrence after resection due to metastatic dissemination of the tumor prior to resection or to the development of new neoplastic changes in the remaining cirrhotic liver [4], [5]. Consequently, the long-term prognosis of most patients with HCC is extremely poor [6], [7]. "
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    ABSTRACT: The role of the epithelial-to-mesenchymal transition (EMT) during hepatocellular carcinoma (HCC) progression is well established, however the regulatory mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that transcription factor glioma-associated oncogene 1 (GLI1) modulates EMT through direct up-regulation of SNAI1 and serves as a downstream effector of the transforming growth factor-β1 (TGFβ1) pathway, a well-known regulator of EMT in cancer cells. Overexpression of GLI1 increased proliferation, viability, migration, invasion, and colony formation by HCC cells. Conversely, GLI1 knockdown led to a decrease in all the above-mentioned cancer-associated phenotypes in HCC cells. Further analysis of GLI1 regulated cellular functions showed that this transcription factor is able to induce EMT and identified SNAI1 as a transcriptional target of GLI1 mediating this cellular effect in HCC cells. Moreover, we demonstrated that an intact GLI1-SNAI1 axis is required by TGFβ1 to induce EMT in these cells. Together, these findings define a novel cellular mechanism regulated by GLI1, which controls the growth and EMT phenotype in HCC.
    Full-text · Article · Nov 2012 · PLoS ONE
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    • "Recently, microRNAs (miRNAs), small noncoding RNAs of ∼22 nucleotides (nt) in length, have been implicated in several carcinogenic processes by acting either as tumor suppressors or oncogenes. Studies have shown that miRNAs expression profiles can classify human cancers [1] [2] [3] [4] [5] [6] [7]. Furthermore , some reports also suggest that cell-free circulating miRNAs existed in serum and plasma [8] [9] [10] [11] [12] [13] [14]. "
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    ABSTRACT: It is reported that different microRNA (miRNA) profiles can be detected in the blood of cancer patients. We investigated that whether the key serum miRNAs could discriminate patients with and without breast cancer. This study was divided into three parts: (1) miRNA marker discovery using SOLiD sequencing-based miRNA profiling on cancerous and adjacent noncancerous breast tissue of one breast cancer patient; (2) marker selection and validation by real-time PCR on a small set of serum; (3) gene ontology analysis of the key miRNA target genes. Of genome-wide tissue miRNA expression analysis, five miRNAs were found to be altered more than fivefold by SOLiD sequencing (i.e., miR-29a, miR-23a, miR-23b, miR-192, and miR-21). All the five miRNAs were validated on the 20 breast cancer patients and 20 controls. miR-29a and miR-21 were significantly increased in the serum of breast cancer patients (P < .05). Gene ontology analysis of the target genes revealed enrichment for special biological process categories, that is, signal transduction, development, apoptosis, cell proliferation, and cell adhesion. SOLiD sequencing provides a promising method for cancer-related miRNA profiling. Serum miRNAs may be useful biomarkers for breast cancer detection.
    Full-text · Article · May 2011 · BioMed Research International
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