The incidence of hepatocellular carcinoma (HCC) is increasing in the USA. Traditional factors, such as hepatitis C and hepatitis B, along with new emerging trends suggest that the incidence is not only increasing, but is also likely to be under-represented in the current literature. Emerging knowledge of its incidence and epidemiology reflects an increased incidence in younger patients and certain ethnic groups. Without a clear treatment algorithm for this complex cancer, therapy and its utilization remain unclear.
"HCC is the sixth most common malignancy and the third most common cause of cancer-related deaths globally. Mortality rates in the United States are increasing more rapidly than for any other leading cancer, and age-adjusted incidence rates have doubled in the past 30 years, with an increase in early-onset disease in both sexes (Shaw and Shah 2011). "
[Show abstract][Hide abstract] ABSTRACT: Bisphenol A (BPA) is a high production-volume chemical with hormone-like properties that has been implicated as a potential carcinogen. Early life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between BPA exposure and cancer development.
We explored the effects of exposure to BPA during gestation and lactation on adult incidence of hepatic tumors in mice.
Isogenic mice were perinatally exposed to BPA through maternal diets containing one of four environmentally relevant doses (0, 50 ng, 50 µg, or 50 mg of BPA per kg diet) and approximately one male and one female per litter were followed until 10 months of age. Animals were tested for known risk factors for hepatocellular carcinoma, including bacterial and viral infections.
We report dose-dependent incidence of hepatic tumors in exposed 10-month mice. 23% of offspring presented with hepatic tumors or preneoplastic lesions. A statistically significant dose-response relationship was observed, with an odds ratio for neoplastic and preneoplastic lesions of 7.23 (95% CI: 3.23, 16.17) for mice exposed to 50 mg BPA per kg diet compared with unexposed controls. Observed early disease onset, absence of bacterial or viral infection, and lack of characteristic sexual dimorphism in tumor incidence support a non-classical etiology.
To our knowledge, this is the first report of a statistically significant association between BPA exposure and frank tumors in any organ. Our results link early life exposure to BPA with the development of hepatic tumors in rodents, with potential implications for human health and disease.
Environmental Health Perspectives 02/2014; 122(5). DOI:10.1289/ehp.1307449 · 7.98 Impact Factor
"The incidence of hepatocellular carcinoma (HCC) is increasing in the United States and on a global scale, where HCC ranks as the fifth most commonly diagnosed cancer and the third leading cause of cancer-related mortality  . The etiology of HCC is primarily associated with underlying hepatic cirrhosis . "
[Show abstract][Hide abstract] ABSTRACT: Background:
Lysophosphatidic acid (LPA) is a ubiquitously expressed phospholipid that regulates diverse cellular functions. Previously identified LPA receptor subtypes (LPAR1-5) are weakly expressed or absent in the liver. This study sought to determine LPAR expression, including the newly identified LPAR6, in normal human liver (NL), hepatocellular carcinoma (HCC), and non-tumor liver tissue (NTL), and LPAR expression and function in human hepatoma cells in vitro.
We determined LPAR1-6 expression by quantitative reverse transcriptase polymerase chain reaction, Western blot, or immunohistochemistry in NL, NTL, and HCC, and HuH7, and HepG2 cells. Hepatoma cells were treated with LPA in the absence or presence of LPAR1-3 (Ki16425) or pan-LPAR (α-bromomethylene phosphonate) antagonists and proliferation and motility were measured.
We report HCC-associated changes in LPAR1, 3, and 6 mRNA and protein expression, with significantly increased LPAR6 in HCC versus NL and NTL. Analysis of human hepatoma cells demonstrated significantly higher LPAR1, 3, and 6 mRNA and protein expression in HuH7 versus HepG2 cells. Treatment with LPA (0.05-10 μg/mL) led to dose-dependent HuH7 growth and increased motility. In HepG2 cells, LPA led to moderate, although significant, increases in proliferation but not motility. Pretreatment with α-bromomethylene phosphonate inhibited LPA-dependent proliferation and motility to a greater degree than Ki16425.
Multiple LPAR forms are expressed in human HCC, including the recently described LPAR6. Inhibition of LPA-LPAR signaling inhibits HCC cell proliferation and motility, the extent of which depends on LPAR subtype expression.
Journal of Surgical Research 11/2012; 180(1). DOI:10.1016/j.jss.2012.10.054 · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The triterpenoids methylantcinate B (MAB) and antcin B (AB), isolated from the medicinal mushroom Antrodia camphorata , have been identified as strong cytotoxic agents against various type of cancer cells; however, the mechanisms of MAB- and AB-induced cytotoxicity have not been adequately explored. This study investigated the roles of caspase cascades, reactive oxygen species (ROS), DNA damage, mitochondrial disruption, and Bax and Bcl-2 proteins in MAB- and AB-induced apoptosis of hepatocellular carcinoma (HCC) HepG2 cells. Here, we showed that MAB and AB induced apoptosis in HepG2 cells, as characterized by increased DNA fragmentation, cleavage of PARP, sub-G1 population, chromatin condensation, loss of mitochondrial membrane potential, and release of cytochrome c. Increasing the levels of caspase-2, -3, -8, and -9 activities was involved in MAB- and AB-induced apoptosis, and they could be attenuated by inhibitors of specific caspases, indicating that MAB and AB triggered the caspase-dependent apoptotic pathway. Additionally, the enhanced apoptotic effect correlates with high expression of Fas, Fas ligand, as well as Bax and decreased protein levels of Bcl-(XL) and Bcl-2, suggesting that both the extrinsic and intrinsic apoptosis pathways were involved in the apoptotic processes. Incubation of HepG2 cells with antioxidant enzymes superoxide dismutase and catalase and antioxidants N-acetylcysteine and ascorbic acid attenuated the ROS generation and apoptosis induced by MAB and AB, which indicate that ROS plays a pivotal role in cell death. NADPH oxidase activation was observed in MAB- and AB-stimulated HepG2 cells; however, inhibition of such activation by diphenylamine significantly blocked MAB- and AB-induced ROS production and increased cell viability. Taken together, our results provide the first evidence that triterpenoids MAB and AB induced a NADPH oxidase-provoked oxidative stress and extrinsic and intrinsic apoptosis as a critical mechanism of cause cell death in HCC cells.
Journal of Agricultural and Food Chemistry 09/2011; 59(20):10943-54. DOI:10.1021/jf202771d · 2.91 Impact Factor
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