Review: Hepatocellular carcinoma: review of current treatment with a focus on targeted molecular therapies

Olsen, Sonja K.; Brown, Robert S.; Siegel, Abby B.

doi:10.1177/1756283x09346669

Cited by 74 publications

(60 citation statements)

References 82 publications

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“…Despite recent progress in diagnostic and therapeutic management, HCC prognosis remains poor (2). HCC is often diagnosed at an advanced stage when resection, transplantation, percutaneous and transarterial interventions are often of limited efficacy.…”

Section: Introductionmentioning

confidence: 99%

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Yang

Chen

et al. 2012

Int J Oncol

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Abstract. Hepatocellular carcinoma (HCC) is the most common primary malignancy found in the liver. Autophagy is the intracellular bulk degradation process for long-lived proteins and dysfunctional organelles. In this study, we report that autophagy plays a role in HCC cell proliferation in response to ischemia-hypoxia (I/H) and reperfusion and discuss its potential therapeutic implications. By establishing a simulated model in cultured HepG2 (p53 wild-type) and Hep3B (p53 null) hepatoma cells in vitro, we found that exposure to I/H induced a significant increase in microtubule-associated protein 1 light chain 3 (LC3) lipidation and subsequent LC3 puncta formation. While the proliferation of HCC cells was stimulated upon acute I/H exposure compared to that of control, inhibition of autophagy by autophagy-related protein 7 interference abolished it. In addition, the steady-state levels of sequestosome 1 (p62) in both HepG2 and Hep3B cells were reduced following I/H exposure, supporting the notion that acute I/H induces autophagy. Intriguingly, the p62 level further decreased during reperfusion following I/H, accompanied by increased LC3 lipidation. The intracellular reactive oxygen species (ROS) accumulated during acute I/H exposure and persisted through reperfusion in both HepG2 and Hep3B cells and the ROS levels increased at a much faster rate during reperfusion than during I/H periods in both cells. Autophagy functions as a promoter for HCC cell survival during acute I/H and reperfusion and this also points to potential therapy for hepatoma by perturbing the acute I/H-reperfusionautophagy axis. IntroductionHepatocellular carcinoma (HCC) causes almost half a million deaths each year, making HCC the third most common cause of cancer-related mortality (1). Despite recent progress in diagnostic and therapeutic management, HCC prognosis remains poor (2). HCC is often diagnosed at an advanced stage when resection, transplantation, percutaneous and transarterial interventions are often of limited efficacy. Although sorafenib has demonstrated promising results in improving the survival and the time to progression in patients with advanced HCC, HCC is frequently resistant to conventional chemotherapy and radiotherapy (3).Ischemia-hypoxia (I/H) and reperfusion constitute key components of many pathological conditions associated with solid tumors. As the liver is a key metabolic organ in humans, the abnormal vasculature network, high interstitial pressure and high proliferation rate of HCC cells result in different types of hypoxia, such as transient hypoxia and chronic hypoxia (4). In response to I/H, the formation of tumor collateral vessels can induce subsequent reperfusion, resulting in oxidative stress (5). Consistent with the described scenario, HCC cells are reportedly more sensitive to I/H and reperfusion injury than normal liver tissue (6).Transcatheter arterial chemoembolization (TACE) has become one of the most widely used treatments for patients with HCC as a palliative measure (7). However, increased microves...

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Section: Introductionmentioning

confidence: 99%

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Yang

Chen

et al. 2012

Int J Oncol

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“…3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the cell viability according to the manufacturer's instructions (Sigma-Aldrich, St. Louis, MO, USA). Briefly, 1x10 4 cells per well were plated onto 96-well plates and incubated for 3 h. The cells were then treated with wogonoside at the indicated concentrations (1,2,4,8,16,32,64,128,256 and 512 µM, and 1 and 2 mM) for 48 h. Each experiment was performed in triplicate. MTT reagent was added.…”

Section: Methodsmentioning

confidence: 99%

“…Several lines of study demonstrate that the major risk factors of HCC include chronic hepatitis B or C virus infection, diabetes, non-alcoholic fatty liver disease, excessive alcohol consumption and dietary exposure to aflatoxin (2,3). Despite substantial and accelerated research in the area of HCC, the 5-year survival rate for advanced disease remains <10% (4). The first line of therapy consists of ablative therapy, surgical resection and transplantation (5).…”

Section: Introductionmentioning

confidence: 99%

Wogonoside induces apoptosis in Bel-7402, a hepatocellular carcinoma cell line, by regulating Bax/Bcl-2

Chen

et al. 2015

Oncology Letters

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Abstract. The anticancer effect of Scutellaria baicalensis extract has recently become a topic of interest. In this study, the anticancer effects and underlying mechanisms of wogonoside, the main constituent of Scutellaria baicalensis, were investigated in a human hepatocellular carcinoma (HCC) cell line in vitro. The effects of wogonoside on the proliferation, cell cycle progression and apoptosis of hepatocellular carcinoma cells were examined. Western blotting was employed to analyze the proteins associated with the biological effects of wogonoside. Wogonoside exerted anti-proliferation properties in vitro. HCC cell growth was attenuated by wogonoside (8 µM) treatment. Cell cycle progression analysis and DNA ladder assay revealed that apoptosis was enhanced in wogonoside-treated cells and that cell cycle arrest occurred in the G2/M phase. It was also demonstrated that increased apoptosis was accompanied by increased levels of Bax protein and decreased levels of Bcl-2 protein. The results of this study suggest that wogonoside may represent a potential therapeutic agent against HCC.

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“…Some notable kinases include EGFR, VEGFR, PDGFR, IGF1R and MET (3)(4)(5). Even so, response rates of HCC in clinical studies involving such targets remain equivocal.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression

Duan

Wong

Chua

et al. 2015

International Journal of Oncology

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Abstract. While various tyrosine kinases have been associated with the pathogenesis of hepatocellular carcinoma (HCC), the identification of a dominant therapeutic target among them remains a challenge. Here, we investigated the role of Tyro3, a relatively uncharacterized member of the TAM (Tyro3, Axl and Mer) receptor family. The present study aimed to profile and identify potential association between Tyro3 expression in HCC and cancer phenotypes. RNAs obtained from 55 HCC patients were quantified for Tyro3 expression in both cancerous tissue and the adjacent normal tissue. Expression profile was correlated with clinical data. These observations were further substantiated with in vitro HCC cell culture investigations. Tyro3 was strongly upregulated (>2-fold elevation) in the tumor tissue of ~42% of the patients. It was shown that higher expression level of Tyro3 was associated with the key tumor marker AFP, and the tumor diameter and liver injury marker ALT. Subsequent cell culture models indicated high expression in various HCC cell lines, in particular Hep3B. Gene silencing of Tyro3 in Hep3B effectively reduced cell proliferation, ERK phosphorylation and cyclin D1 expression, indicating a key in maintaining the proliferative state of these cells. Notably, silencing also suppressed the transcriptional and translational expression of HCC tumor marker AFP. Overall, these data suggest that Tyro3 contributes significantly to tumor growth, aggressiveness and liver dysfunction. Inhibition of Tyro3 and its aberrant signaling in tumors with high expression could present new opportunities for HCC treatment.

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Review: Hepatocellular carcinoma: review of current treatment with a focus on targeted molecular therapies

Cited by 74 publications

References 82 publications

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Wogonoside induces apoptosis in Bel-7402, a hepatocellular carcinoma cell line, by regulating Bax/Bcl-2

Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression

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