Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mounting evidence underlines the role of inducible nitric oxide synthase (iNOS) in hepatocellular carcinoma (HCC) development, but its functional interactions with pathways involved in HCC progression remain uninvestigated. Here, we analyzed in preneoplastic and neoplastic livers from Fisher 344 and Brown Norway rats, possessing different genetic predisposition to HCC, in transforming growth factor-alpha (TGF-alpha) and c-Myc-TGF-alpha transgenic mice, characterized by different susceptibility to HCC, and in human HCC: (i) iNOS function and interactions with nuclear factor-kB (NF-kB) and Ha-RAS/extracellular signal-regulated kinase (ERK) during hepatocarcinogenesis; (ii) influence of genetic predisposition to liver cancer on these pathways and role of these cascades in determining a susceptible or resistant phenotype and (iii) iNOS prognostic value in human HCC. We found progressive iNos induction in rat and mouse liver lesions, always at higher levels in the most aggressive models represented by HCC of rats genetically susceptible to hepatocarcinogenesis and c-Myc-TGF-alpha transgenic mice. iNOS, inhibitor of kB kinase/NF-kB and RAS/ERK upregulation was significantly higher in HCC with poorer prognosis (as defined by patients' survival length) and positively correlated with tumor proliferation, genomic instability and microvascularization and negatively with apoptosis. Suppression of iNOS signaling by aminoguanidine led to decreased HCC growth and NF-kB and RAS/ERK expression and increased apoptosis both in vivo and in vitro. Conversely, block of NF-kB signaling by sulfasalazine or short interfering RNA (siRNA) or ERK signaling by UO126 caused iNOS downregulation in HCC cell lines. These findings indicate that iNOS cross talk with NF-kB and Ha-RAS/ERK cascades influences HCC growth and prognosis, suggesting that key component of iNOS signaling could represent important therapeutic targets for human HCC.
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PMID:Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease. 1857 59

The aim of the current study is to elucidate the mechanism of proline-rich tyrosine kinase 2 (Pyk2)-mediated cell proliferation and invasiveness in hepatocellular carcinoma (HCC) cells. Human HCC cell lines PLC and MHCC97L were stably transfected with either full-length Pyk2 or C-terminal non-kinase region of Pyk2 (PRNK). Functional studies on cell proliferation and invasion were conducted in vitro by colony formation assay, adhesion assay, migration assay and wound-healing assay. For the in vivo study, an orthotopic nude mice liver tumor model was applied to investigate the effects of Pyk2 overexpression on tumor growth and metastasis. Overexpression of Pyk2 in PLC cells resulted in an upregulation of colony formation (P = 0.021) and adhesion toward laminin (P = 0.018). Pyk2 promoted wound recovery by stimulation of actin stress fiber polymerization. In the in vivo study, transfection of PRNK in MHCC97L cells significantly decreased tumor volume (P = 0.001) and the incidence of lung metastasis (P = 0.014). Overexpression of Pyk2 promoted the activation of c-Src, formation of Pyk2/c-Src complex and activated the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)-signaling pathway. Pyk2 upregulated the activation of ERK1/2 that is insensitive to MAPK/ERK kinase (MEK)1/2 inhibition. On the contrary, PRNK overexpression downregulated the activation of c-Src and ERK/MAPK-signaling pathways. Immunofluorescence staining showed that the focal adhesion localization of Pyk2 is a major determinant for c-Src and ERK/MAPK activation. In conclusion, our results showed that Pyk2 promoted cell proliferation and invasiveness by upregulation of the c-Src and ERK/MAPK-signaling pathways.
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PMID:Proline-rich tyrosine kinase 2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation. 1876 15

We examined the effects of gemcitabine, a pyrimidine analogue, on hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) cells. After HCC cells (HepG2, Hep3B, HLF and PLC/PRF/5) and CCC cells (HuCCT-1) were treated with gemcitabine, cellular growth, cell cycle, nuclear morphology and activity of signaling molecules were evaluated by WST-8 assays, flow cytometry analysis, Hoechst 33258 staining and Western blotting, respectively. We found that gemcitabine significantly inhibited the growth of HCC and CCC cells in a dose- and time-dependent manner. Gemcitabine induced cell cycle arrest at the G1 phase, however, the sub-G1 fraction was not observed and nuclear morphology did not indicate the induction of apoptosis. Gemcitabine induced differential activation of checkpoint kinases, Chk2 and Chk1, in HCC and CCC cells, respectively and gemcitabine activated extracellular signal-regulated kinase (ERK)1/2 in both cell types. After the cells were pretreated with a MEK inhibitor U0126, activations of these checkpoint kinases were abrogated and the cell death was enhanced. These results demonstrate that gemcitabine inhibited the growth of HCC and CCC cells by cell cycle arrest without apoptosis and that the ERK/Chk1/2 signaling pathway was in part responsible for the resistance to gemcitabine. Our findings shed light on treating patients with HCC and CCC by gemcitabine, especially when combined with a MEK inhibitor and Chk1/2 inhibitors.
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PMID:The growth inhibition of hepatocellular and cholangiocellular carcinoma cells by gemcitabine and the roles of extracellular signal-regulated and checkpoint kinases. 1881 28

Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of this complex disease and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived growth factor receptor, and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time-to-progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug responsiveness will lead to a more personalized medicine.
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PMID:Molecular targeted therapies in hepatocellular carcinoma. 1882 91

Studies on rodents and humans demonstrate an inherited predisposition to hepatocellular carcinoma (HCC). Analysis of the molecular alterations involved in the acquisition of a phenotype resistant or susceptible to hepatocarcinogenesis showed a deregulation of G1 and S phases in HCC of genetically susceptible F344 rats and a G1-S block in lesions of resistant Brown norway (BN) rats. Unrestrained extracellular signal-regulated kinase (ERK) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (DUSP1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex occurs in more aggressive HCC of F344 rats and humans. This mechanism is less active in HCC of BN rats and human HCC with better prognosis. Upregulation of iNos cross-talk with IKK/NF-kappaB and RAS/ERK pathways occurs in rodent liver lesions at higher levels in the most aggressive models represented by HCC of F344 rats and c-Myc-TGF-alpha transgenic mice. iNOS, IKK/NF-kappaB, and RAS/ERK upregulation is highest in human HCC with a poorer prognosis and positively correlates with tumor proliferation, genomic instability and microvascularization, and negatively with apoptosis. Thus, cell cycle regulation and the activity of signal transduction pathways seem to be modulated by HCC modifier genes, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.
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PMID:Interaction of major genes predisposing to hepatocellular carcinoma with genes encoding signal transduction pathways influences tumor phenotype and prognosis. 1903 60

Unresectable hepatocellular carcinoma (HCC) has a poor therapeutic outcome. We report here on a 40-year-old male HCC patient who had undergone partial hepatectomy and was refractory to therapeutic embolization. In addition, the tumour expressed phosphorylated extracellular signal-regulated kinase and CD34. Sorafenib was administered as salvage treatment and resulted in a rapid decline in alpha-fetoprotein (AFP) levels. However, this was accompanied by a grade 3 skin reaction, which improved as sorafenib dosage was gradually reduced. Unfortunately, reducing the dose of sorafenib also resulted in a rebound in AFP levels and portal vein thrombosis was noted thereafter. Sorafenib 800 mg/day was resumed, but the tumour failed to respond. Intensity-modulated radiation therapy (IMRT) combined with sorafenib was administered, resulting in marked tumour shrinkage and causing recurrence of the systemic skin reaction and development of photosensitivity. The patient survived for 20 months after the start of sorafenib treatment. This case suggests that the combination of sorafenib and IMRT might provide clinical benefits in patients with HCC who express potential targets but fail to respond to sorafenib; however, skin reactions should be monitored.
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PMID:Combination of sorafenib and intensity modulated radiotherapy for unresectable hepatocellular carcinoma. 1906 76

Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high due to multicentric carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is 'clonal deletion' therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state. Retinoids, a group of structural and functional analogs of vitamin A, exert their biological function primarily through two distinct nuclear receptors, retinoic acid receptors and retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various cancers, including HCC. In particular, a malfunction of RXRalpha due to phosphorylation by the Ras-mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the extracellular signal-regulated kinase and RXRalpha proteins. In conclusion, the inhibition of RXRalpha phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and clonal deletion. Acyclic retinoid, which targets phosphorylated RXRalpha, may thus play a critical role in preventing the development of multicentric HCC.
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PMID:Strategy and mechanism for the prevention of hepatocellular carcinoma: phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention. 1906 86

Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. We show here that expression of TRbeta1 in hepatocarcinoma and breast cancer cells reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice. In cultured cells, TRbeta1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-I, and transforming growth factor beta, and regulates expression of genes that play a key role in tumorigenicity and metastatic growth. The receptor disrupts the mitogenic action of growth factors by suppressing activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways that are crucial for cell proliferation and invasiveness. Furthermore, increased aggressiveness of skin tumors is found in genetically modified mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression. These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer.
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PMID:Thyroid hormone receptor beta1 acts as a potent suppressor of tumor invasiveness and metastasis. 1914 63

Metastasis is considered to be the major cause of death in patients with cancers, and hepatocellular carcinoma (HCC) is a highly metastatic cancer. Ganoderma lucidum , a well-known mushroom with various biological effects, is a functional food known to contain lucidenic acid. The objectives of this study were to investigate the anti-invasion effect of a lucidenic acid-rich G. lucidum extract (GLE) on human hepatoma HepG2 cells as well as the antiproliferative and antimetastatic effects of GLE in human hepatoma cells implanted into ICR-nu/nu mice. Phorbol-12-myristate-13-acetate (PMA)-induced invasion and matrix metalloproteinase (MMP)-9 expression levels of HepG2 cells were reduced by GLE treatment in a dose-dependent manner. The inhibitory effects of GLE on MMP-9 expression proceeded by inhibiting the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and protein kinase B in the cytosol as well as reducing activator protein-1 and nuclear factor-kappa B levels in the nucleus of HepG2 cells. In a human tumor xenograft model, a dose-response inhibition was observed in the average size, volume, and weight of tumors upon oral administration of GLE. The number of metastatic tumor-bearing mice, the number of affected organs, and the number of tumor foci as well as the MMP-2 and -9 activities in serum of mice were also significantly suppressed by oral administration of GLE. These results suggest that the lucidenic acid-rich GLE could serve as a chemopreventive agent for the tumorigenesis and metastasis of highly invasive hepatoma cells.
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PMID:Inhibitory effects of ganoderma lucidum on tumorigenesis and metastasis of human hepatoma cells in cells and animal models. 1942 27

Comparative analysis of hepatocellular carcinoma (HCC) in rat strains that are either susceptible or resistant to the induction of HCC has allowed the mapping of genes responsible for inherited predisposition to HCC. These studies show that the activity of several low penetrance genes and a predominant susceptibility gene regulate the development of hepatocarcinogenesis in rodents. These studies shed light on the epidemiology of human HCC. The identified genes regulate resistance to hepatocarcinogenesis by affecting the capacity of the initiated cells to grow autonomously and to progress to HCC. Analysis of the molecular alterations showed highest iNos cross-talk with IKK/NF-kB and RAS/ERK pathways in most aggressive liver lesions represented by HCC in the susceptible F344 rats. Unrestrained extracellular signal-regulated kinase (Erk) activity linked to proteasomal degradation of dual-specificity phosphatase 1 (Dusp1), a specific ERK inhibitor, by the CKS1-SKP2 ubiquitin ligase complex was highest in more aggressive HCC of genetically susceptible rats. Furthermore, deregulation of G1 and S phases of the cell cycle occurs in HCC of susceptible F344 rats, leading to pRb hyperphosphorylation and elevated DNA synthesis, whereas a block to G1-S transition is present in the HCC of resistant BN rats. Importantly, similar alterations in the signaling pathways that regulate cell cycle progression were found in human HCC with poorer prognosis (as defend by patients' survival length), whereas human HCC with better prognosis had molecular characteristics similar to the lesions in the HCC of resistant rat strains. This review discusses the role of molecular alterations involved in the acquisition of resistance or susceptibility to HCC and the importance of genetically susceptible and resistant rat models for the identification of prognostic markers, and chemopreventive or therapeutic targets for the biological network therapy of human disease.
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PMID:Genetic and epigenetic control of molecular alterations in hepatocellular carcinoma. 1942 55


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