• BMB Reports
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• v.50 no.1
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• pp.1-2
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• 2017

Acquiring a selective growth advantage by breaking the proliferation barrier established by gatekeeper genes is a centrally important event in tumor formation. Removal of the mammalian Hippo kinase Mst1 and Mst2 in hepatocytes leads to rapid hepatocellular carcinoma (HCC) formation, indicating that the Hippo signaling pathway is a critical gatekeeper that restrains abnormal growth in hepatocytes. By rigorous genetic approaches, we identified an interacting network of the Hippo, Wnt/${\beta}$-catenin and Notch signaling pathways that control organ size and HCC development. We found that in hepatocytes, the loss of Mst1/2 leads to the activation of Notch signaling, which forms a positive feedback loop with Yap/Taz (transcription factors controlled by Mst1/2). This positive feedback loop results in severe liver enlargement and rapid HCC formation. Blocking the Yap/Taz-Notch positive feedback loop by Notch inhibition in vivo significantly reduced the Yap/Taz activities, hepatocyte proliferation and tumor formation. Furthermore, we uncovered a surprising inhibitory role of Wnt/${\beta}$-catenin signaling to Yap/Taz activities, which are important in tumor initiation. Genetic removal of ${\beta}$-catenin in the liver of the Mst1/2 mutants significantly accelerates tumoriogenesis. Therefore, Wnt/${\beta}$-catenin signaling, known for its oncogenic property, exerts an unexpected function in restricting Yap/Taz and Notch activities in HCC initiation. The molecular interplay between the three signaling pathways identified in our study provides new insights in developing novel therapeutic strategies to treat liver tumors.

• Journal of Korean Traditional Oncology
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• v.28 no.1
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• pp.45-53
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• 2023

Objectives: To report the reduction of adverse effects of chemotherapy and improvement in the quality of life in recurrent liver metastasis by Korean medicine treatments. Methods: In 2018, a 75-year-old male patient underwent surgery for primary cancer in the ampulla of Vater. In 2021, he was diagnosed with recurrent liver metastasis. Following the failure of tumor treatment with gemcitabine/cisplatin and the development of severe side effects, he decided to discontinue chemotherapy. Subsequently, with a significantly enlarged liver tumor, he resumed capecitabine/oxaliplatin treatment, alongside moxibustion, acupuncture, and herbal prescriptions from August 2021 to August 2023. The changes of chief complaints, abdominal CT, and laboratory findings were investigated. Results: After combined treatment of Korean traditional medicine and chemotherapy, the mass was decreased. Laboratory findings, and chief complaints of hand-foot syndrome, fatigue, abdominal distension, nausea and anorexia were improved. Conclustions: This case study suggests that Korean traditional medicine is effective in enhancing anticancer effects, suppressing the side effects of chemotherapy, and improving general conditions.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4007-4011
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• 2012

Purpose: Retinoblastoma-interacting zinc finger gene (RIZ1) is a tumor suppressor gene which is highly inactivated by promoter hypermethylation in patients with liver fluke-related cholangiocarcinoma (CCA). Epigenetic aberration of this gene might withdraw the ability to restrain tumor cell proliferation and migration. We aimed to define the role of RIZ1 on cell proliferation and migration in CCA cell line. Materials and methods: Small interference RNA (siRNA) was used to knock down the expression of RIZ1 in a CCA-derived cell line in which cell proliferation and cell migration were performed. Results: A predominant nuclear localization of RIZ1 was observed. Reduction of RIZ1 by siRNA augmented cell proliferation and migration. Conclusion: The result suggested that RIZ1 might play a role in regulating cell proliferation and migration in CCA. Reduction of RIZ1 expression may aggravate the progression of CCA.

• Journal of Nutrition and Health
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• v.35 no.2
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• pp.201-206
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• 2002

This study was designed to research the anti-tumor effect of omija (methanol extract(I), malic acid & ethanol extract(II), and water extract (III)) on human liver cancer cell line SNU-398. MTT assay was used in vitro. The longer th\ulcorner exposure time and the higher the concentration of Omija extract, the stronger the anti-tumor effect. When the concentration of (II) was 1,600 $\mu\textrm{g}$/$m\ell$ and the exposure time reached 96 hours, The strongest propagation inhibition effect occurred with the viability rate as low as 5.06%. $IC_{50}$/ value was 363 $\mu\textrm{g}$/$m\ell$. Under the condition of 1,600$\mu\textrm{g}$/$m\ell$ and 96 hours, (I) lowered the rate to 7.75%. $IC_{50}$/ value was 489 $\mu\textrm{g}$/$m\ell$. When it was 1,600$\mu\textrm{g}$/$m\ell$ and 72 hours, (III) the rate decreased to 15.97%. $IC_{50}$/ value was 703 $\mu\textrm{g}$/$m\ell$. In all three cases, the viability of the cancer cell decreased significantly when the exposure time ranged between 24 and 48 hours.

• Environmental Mutagens and Carcinogens
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• v.22 no.4
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• pp.266-273
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• 2002

The dose dependence of the severity of radiation-induced thymic lymphoma in C57BL/6J mice was studied. Mice were exposed to fractionated irradiation at the total doses of 4.0, 6.0 and 8.0 Gy (four irradiations at 8-day intervals) starting from 33 days after birth. Pathological and histological changes of each mouse were observed after periodical sacrifice at day 75, 100, 125, 150, 175, 200, 250, 300 after the first irradiation. The severity of cancers were classified into 4 stages by clinical signs with respect to the enlargement of the thymus, spleen, liver, the progression of the cancer in the thymus, and the metastasis to the spleen, liver, lung and the lymphatic nodes. Among the 490 mice observed, 146 mice had thymic lymphoma. A clear dose-effect relationship was observed as well as the dose-response relationship. Also, periodical observation showed that thymic lymphoma was first induced in mice sacrificed at day 100 (130days old), and metastasize in the order of spleen, lung, liver and then the lymphatic nodes. The results suggest that radiation may be involved not only as a tumor initiator but also as a tumor promoter, and a tumor progression-enhancing agent.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3627-3630
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• 2012

The epithelial cell adhesion molecule (EpCAM) is a pan-epithelial differentiation antigen that is expressed on almost all carcinomas. However, a role in rat liver carcinogenesis has never been reported previously. Thus, its expression was investigated herein in rat liver tumors induced by diethylnitrosamine (DEN). Twenty male 5-week-old F344 rats were used in this experiment. Mini-osmotic pumps containing doses of 47.5 mg of DEN were inserted into the abdominal cavity of each animal to initiate liver carcinogenesis. All animals were sacrificed at 26 weeks after DEN treatment. At necropsy, hepatic masses were processed for histopathological examination, which revealed forty-four hepatocellular adenomas (HCAs) and twenty hepatocellular carcinomas (HCC). Tumors were immunohistochemically analyzed for EpCAM, proliferating cell nuclear antigen (PCNA) and co-localization of the two. EpCAM expression was mainly detected in hepatic tumor cells, showing a cytoplasmic staining pattern. However, expression was also slightly observed in normally-appearing surrounding hepatic cells. PCNA expression was highly detected in tumor cells, showing nuclear staining. Double staining of EpCAM and PCNA in tumors showed many cells with co-localization. Taken together, EpCAM and PCNA expression were increased in DEN-induced tumors and many tumor cells showed co-expression. It is suggested that EpCAM may increase during DEN-induced tumors, possibly associated with cell proliferation.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.9039-9043
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• 2014

There is a continuing need for innovative alternative therapies for liver cancer. DNA vaccines for hormone/growth factor immune deprivation represent a feasible and attractive approach for cancer treatment. We reported a preventive effect of a DNA vaccine based on six copies of the B cell epitope GRP18-27 with optimized adjuvants against H22 hepatocarcinoma. Vaccination with pCR3.1-VS-HSP65-TP-GRP6-M2 (vaccine) elicited much higher level of anti-GRP antibodies and proved efficacious in preventing growth of transplanted hepatocarcinoma cells. The tumor size and weight were significantly lower (p<0.05) in the vaccine subgroup than in the control pCR3.1-VS-TP-HSP65-TP-GRP6, pCR3.1-VS-TP-HSP65-TP-M2 or saline subgroups. In addition, significant reduction of tumor-induced angiogenesis associated with intradermal tumors of H22 cells was observed. These potent effects may open ways towards the development of new immunotherapeutic approaches in the treatment of liver cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.4
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• pp.1597-1602
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• 2014

The purpose of this study was to investigate whether whole-liver radiotherapy plus a tumor-boost dose with concurrent chemotherapy is beneficial for colorectal cancer patients with massive and multiple liver metastases. From January 2007 to December 2012, 19 patients who exhibited massive (with a longest diameter > 5 cm) and invasive liver metastases and multiple metastases were treated with radiotherapy and concurrent chemotherapy. The total radiation dose was 53.4 Gy (range 38.8 Gy-66.3 Gy). All of the patients received a continuous intravenous dose of 5 fluorouracil (5-FU) 225 mg/m2 concurrently with radiation. The median survival time was 19 months. The 1- and 2- year overall survival rates were 78.3% and 14.3%, respectively. Of all of the patients who presented with abdominal pain, 100% experienced a decrease in pain. Decreases in the rates of ascites and jaundice were confirmed by ultrasound and bilirubin levels. No cases of Grade 4 or 5 acute or late toxicity were recorded. There were only two cases of Grade 3 toxicity (elevated bilirubin). These data provide evidence that whole-liver radiotherapy plus a tumor-boost dose with concurrent chemotherapy is beneficial for colorectal cancer patients with massive and multiple liver metastases.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.4
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• pp.1665-1669
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• 2015

Background: The optimal surgical strategy for the treatment of synchronous resectable gastric cancer liver metastases remains controversial. The aims of this study were to analyze the outcome and overall survival of patients presenting with gastric cancer and liver metastases treated by simultaneous resection. Materials and Methods: Between January 1990 and June 2009, 35 patients diagnosed with synchronous hepatic metastases from gastric carcinoma received simultaneous resection of both primary gastric cancer and synchronous hepatic metastases. The clinicopathologic features and the surgical results of the 35 patients were retrospectively analyzed. Results: The 5-year overall survival rate after surgery was 14.3%. Five patients survived for more than 5 years after surgery. No mortality has occurred within 30 days after resection, although two patients (5.7%) developed complications during the peri-operative course. Univariate analysis revealed that patients with the presence of lymphovascular invasion of the primary tumor, bilateral liver metastasis and multiple liver metastases suffered poor survival. Lymphovascular invasion by the primary lesion and multiple liver metastases were significant prognostic factors that influenced survival in the multivariate analysis (p=0.02, p=0.001, respectively). Conclusions: The presence of lymphovascular invasion of the primary tumor and multiple liver metastases are significant prognostic determinants of survival. Gastric cancer patients without lymphovascular invasion and with a solitary synchronous liver metastasis may be good candidates for hepatic resection. Simultaneous resection of both primary gastric cancer and synchronous hepatic metastases may effectively prolong survival in strictly selected patients.

• Investigative Magnetic Resonance Imaging
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• v.20 no.4
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• pp.231-240
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• 2016

Purpose: To determine whether liver stiffness (LS) measured by magnetic resonance elastography (MRE) can predict the outcome of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC) patients. Materials and Methods: A total of 107 patients with Child-Pugh class A liver function who were treated with RFA for single HCC and who had undergone a gradient-echo MRE within 6 months before RFA were included. We evaluated the relationship between the LS values and the ablation volume, local tumor progression (LTP), and intrahepatic distant recurrence (IDR). We also constructed receiver operating characteristic (ROC) curves to examine the role of LS in predicting liver function deterioration, which was defined as an increase of Child-Pugh score by one point or more at 1 year after RFA. Results: There was no significant correlation between LS and ablation volume, and neither time to LTP nor IDR was associated with LS. Among the 66 patients who did not have recurrence 1 year after RFA, 5 patients (7.6%) developed liver function deterioration. A high LS value was significantly associated with development of liver function deterioration after RFA and the area under the ROC curve was 0.764 (95% CI 0.598-0.929, P = 0.003). Conclusion: LS measured by MRE could not predict ablation volume and tumor recurrence. However, high LS values were significantly associated with development of liver function deterioration.