HCC : PE-069 ; C-reactive protein is closely associated with prognosis in hepatocellular carcinoma with pathological portal vein invasion

( Jong Man Kim ),( Choon Hyuck David Kwon ),( Jae Won Joh ),( Jae Berm Park ),( Sung Joo Kim ),( Suk Koo Lee ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background: Hepatocellular carcinoma (HCC) has a high predilection for portal vein invasion. The objective of this study was to investigate clinicopathologic characteristics and outcomes of HCC patients with pathological portal vein invasion. Methods: We retrospectively reviewed the clinicopathologic data and outcomes of 83 HCC patients with portal vein invasion and 1056 patients without portal vein invasion who underwent liver resection. Results: Increased serum alkaline phosphatase (ALP) levels, increased maximum tumor size, and intrahepatic metastasis were predisposing factors for portal vein invasion by multivariate analysis. The median disease-free survival and overall survival of HCC patients with portal vein invasion was 4.5 months and 25 months, respectively. The 1-year, 2-year, and 3-year disease-free survival rates were 30.6%, 26.1%, and 21.2%, respectively, and overall survival rates in HCC patients with portal vein invasion were 68.6%, 54.2%, and 41.6%, respectively. The first detection site was lung in HCC patients with portal vein invasion and liver in HCC patients without portal vein invasion. C-reactive protein (CRP) was a significant independent predictor of tumor recurrence in HCC with portal vein invasion after surgery. Conclusions: Increased ALP levels, increased maximum tumor size, and intrahepatic metastasis were independent predictors of portal vein invasion in HCC. CRP level was closely associated with the predisposing factor of tumor recurrence in HCC patients with portal vein invasion after surgical resection, and lung metastasis was common.

HCC : PE-069 ; C-reactive protein is closely associated with prognosis in hepatocellular carcinoma with pathological portal vein invasion

( Jong Man Kim ),( Choon Hyuck David Kwon ),( Jae Won Joh ),( Jae Berm Park ),( Sung Joo Kim ),( Suk Koo Lee ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Background: Hepatocellular carcinoma (HCC) has a high predilection for portal vein invasion. The objective of this study was to investigate clinicopathologic characteristics and outcomes of HCC patients with pathological portal vein invasion. Methods: We retrospectively reviewed the clinicopathologic data and outcomes of 83 HCC patients with portal vein invasion and 1056 patients without portal vein invasion who underwent liver resection. Results: Increased serum alkaline phosphatase (ALP) levels, increased maximum tumor size, and intrahepatic metastasis were predisposing factors for portal vein invasion by multivariate analysis. The median disease-free survival and overall survival of HCC patients with portal vein invasion was 4.5 months and 25 months, respectively. The 1-year, 2-year, and 3-year disease-free survival rates were 30.6%, 26.1%, and 21.2%, respectively, and overall survival rates in HCC patients with portal vein invasion were 68.6%, 54.2%, and 41.6%, respectively. The first detection site was lung in HCC patients with portal vein invasion and liver in HCC patients without portal vein invasion. C-reactive protein (CRP) was a significant independent predictor of tumor recurrence in HCC with portal vein invasion after surgery. Conclusions: Increased ALP levels, increased maximum tumor size, and intrahepatic metastasis were independent predictors of portal vein invasion in HCC. CRP level was closely associated with the predisposing factor of tumor recurrence in HCC patients with portal vein invasion after surgical resection, and lung metastasis was common.

CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma

Jang, Jae-Woo,Song, Yeonhwa,Kim, Se-Hyuk,Kim, Jin-sun,Kim, Kang mo,Choi, Eun Kyung,Kim, Joon,Seo, Haeng Ran Elsevier 2017 Cancer letters Vol.389 No.-

<P><B>Abstract</B></P> <P>Hepatocellular carcinoma (HCC) is the seventh most common malignant tumor and the third leading cause of cancer-related death in the world. Cancer stem cells (CSCs) are small subpopulation of cells within tumors that drive chemoresistance and tumor recurrence in various cancers. We characterized CSCs in primary HCC and identified CD133 as a CSC surface marker. CD133<SUP>+</SUP> HCC cells displayed more stem cell-like properties, tumor spheroid-forming ability, chemoresistance, migration ability, and tumorigenic capacity than CD133<SUP>-</SUP> HCC cells. The biological function and molecular mechanism of CD133 remain unclear. HCC cell lines with a high level of CD133 expression overexpressed EGFR, which is overexpressed in approximately 70% of conventional HCCs. CD133 depletion destabilized EGFR by augmenting EGFR internalization and thus inhibited EGFR-AKT signaling. CD133 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Furthermore, EGFR-deficient CD133<SUP>+</SUP> HCC cells manifested greater sensitivity to anticancer drugs and less spheroid-formation capacity than control CD133<SUP>+</SUP> HCC cells. Our results strongly indicate that CD133 facilitates CSC-like properties by stabilizing EGFR-AKT signaling in HCC. It might therefore be feasible to use CD133 as a novel target to sensitize HCC cells that manifest resistance to EGFR-targeted therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CD133, a CSC marker is identified in primary HCCs and HCC cell lines. </LI> <LI> The expression of EGFR is correlated with The expression of CD133 in HCC cells. </LI> <LI> CD133 induces CSCs properties through the EGFR stabilization. </LI> <LI> The stabilization of EGFR by CD133 activates EGFR-AKT signaling in HCCs. </LI> <LI> CD133 might be a novel target to sensitize HCC cells that manifest resistance to EGFR-targeted therapy. </LI> </UL> </P>

HCC : Histologic Differentiation Predicts the Survival of Patients with Hepatic Resection for Hepatocellular Carcinoma

( Woong Cheul Lee ),( Jae Young Jang ),( Jin Nyoung Kim ),( Soung Won Jeong ),( Eui Ju Park ),( Byoung Moo Lee ),( Yun Nah Lee ),( Sae Hwan Lee ),( Sang Gyune Kim ),( Sang Woo Cha ),( Young Seok Kim ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: In resection for hepatocellular carcinoma (HCC), patient selection depends on morphological features and liver function. In patients with HCC, we performed a clinico- pathological analysis of risk factors that affected survival after liver resection. Methods: Sixty seven patients with liver resection for HCC were enrolled and data were collected retrospectively. Variables were age, gender, etiology, preoperative alpha-fetoprotein (AFP) levels, Child-Pugh and MELD scores, modified UICC stage, portal vein tumor invasion, and histological differentiation. Results: Sixty seven patients were evaluated and 6 patients were excluded (Three patients with combined hepatocellularcholangiocarcinoma, two patients because of early postoperative death without HCC recurrence and one patient accidental death without HCC recurrence). The mean age of the patients was 57.4±10.5 years. The mean follow-up time was 51.2±34.8 months. The cumulative 1-, 3-, 5-, and 7-year survival rates were 91.3%, 64.5%, 45.0%, and 45.0%, respectively. The 1-, 3-, 5-, and 7-year disease-free survival rates were 80.4%, 50.5%, 12.9%, and 12.9%, respectively. Multivariate analysis showed that modified UICC stage (P=0.005), portal vein tumor invasion (P=0.024) and poor histological differentiation (P=0.012) were independent factors for survival and tumor recurrence. Conclusions: Although morphological stage and liver function are important factors of liver resection, for proper patient selection in liver resection for HCC, prognostic criteria related to tumor histology (especially histological differentiation) should be considered. Poor histological differentiation is indicators of poor prognosis after liver resection for HCC.

TonEBP Promotes Hepatocellular Carcinoma via Promotion of Inflammation

( Jun Ho Lee ),( Neung Hwa Park ),( Hyun Je Kang ),( Jae Hee Suh ),( Chang Jae Kim ),( Hwan Hee Lee ),( Soo Youn Choi ),( Whaseon Lee-kwon ),( Hyug Moo Kwon ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Tonicity-responsive enhancer binding protein (TonEBP) is a key transcription cofactor in pro-inflammatory activation of macrophages. TonEBP is involved in inflammatory diseases such as rheumatoid arthritisand atherosclerosis. Since hepatic inflammation is required for the development of hepatocellular carcinoma (HCC), we asked whether TonEBP played a role in HCC. Methods: We studied liver section and tissue biopsy from patients with HBV-, HCV-, and non-viral-induced HCC, obtained from the University of Ulsan college of Medicine . Levels of protein expression and gene expression was measured by western blot analysis and qRT-PCR. Mice with whole body haplo-deficiency of TonEBP and their wild type littermates (C57BL6 background) were given injection of DEN at 2-week-old age and fed the high fat diet or normal control diet for 30 weeks. Mice of hepatocyte-specific (Albcre +/- or -/- floxed with TonEBP) or myeloid-specific TonEBP deletion(LysM cre +/- or -/- floxed with TonEBP) and their wild type littermates were injected DEN at 8-week-old age for 48 hrs. Results: Here we report that TonEBP haplo-insufficiency is resistant not only to diethylnitrosamine (DEN)-induced HCC but also to DEN/high fat diet induced HCC, through attenuation of COX-2 expression and inflammation. In hepatocytes, TonEBP interacts with transcription factor YY1 and histone acetyltransferase p300. This interaction promotes inflammatory stimuli-induced COX-2 expression. Interestingly, hepatic tumor shows higher expression of TonEBP than non-tumor liver in mice and HCC patients. This regulation is associated with miR-223 which expression is down-regulated upon HCC development. In addition, its expression was significantly associated with poor survival of HCC patients after resection. Conclusions: TonEBP is a novel transcription cofactor in COX-2 regulation through transcription factor YY1. With this mechanism, TonEBP is an independent determinant of HCC and novel target for HCC diagnosis and treatment.

Role of Interleukin(IL)-6 in NK Activity to Hypoxic-Induced Highly Invasive Hepatocellular Carcinoma(HCC) Cells

( Hwan Hee Lee ),( Hyojung Kang ),( Hyosun Cho ) 한국미생물생명공학회 2023 Journal of microbiology and biotechnology Vol.33 No.7

Natural killer (NK) cell dysfunctions against hepatocellular carcinoma (HCC) in a hypoxic environment. Many solid tumors are present in a hypoxic condition, which changes the effector function of various immune cells. The transcription of hypoxic-inducible factors (HIFs) in cancer cells make it possible to adapt to their hypoxic environment and to escape the immune surveillance of NK cells. Recently, the correlation between the transcription of HIF-1α and pro-inflammatory cytokines has been reported. Interleukin (IL)-6 is higher in cancers with a highly invasive ability, and is closely related to the metastasis of cancers. This study showed that the expression of HIF-1α in HCC cells was associated with the presence of IL-6 in the environment of HCC-NK cells. Blocking of IL-6 by antibody in the HCC-NK interaction changed the production of several cytokines including TGF-β, IL-1, IL-18 and IL-21. Interestingly, in a co-culture of HIF-1α-expressed HCC cells and NK cells, blocking of IL-6 increased the production of IL-21 in their supernatants. In addition, the absence of IL-6 significantly enhanced the cytotoxic ability and the expression of the activating receptors (NKG2D, NKp44, and NKG2C) in NK cells to HIF-1α-expressed HCC cells. These effects might be made by the decreased expression of HIF-1α in HCC cells through the inhibited phosphorylation of STAT3. In conclusion, the absence of IL- 6 in the interaction of HIF-1α-expressed HCC cells and NK cells could enhance the antitumor activity of NK cells to HCC cells.

각종 간질환에 있어서 이상 Prothrombin (des-γ-Carboxyprothrombin)에 관한 연구

이혁우,정경섭,김원호,한광협,정재복,이상인,박인서,최홍재,도윤정,윤홍섭 대한내과학회 1990 대한내과학회지 Vol.38 No.4

The absence of vitamin K or the ingestion of vitamin K antagonists inhibits vitamin K-dependent carboxylase activity in the liver, and an abnormal prothrombin, known as des-y-carboxyprothrombin(DCP) or PIVKA -Ⅱ(a protein induced by vitamin K absence or antagonists-Ⅱ), is released into the blood. In order to evaluate whether abnormal prothrombin levels can be clinically used as an index of hepatocellular dysfunction or as a tumor marker of hepatocellular carcinoma(HHC), DCP levels were determined by a latex agglutination test in 20 normal subjects and in patients with various liver diseases, including 70 hepatocellular carcinoma, sever metastatic liver disease, 45 liver cirrhosis, 13 acute viral hepatitisB, six chronic active hepatitis B, three fatty liver and one liver abscess. The usefulness of the combination assay of DCP and alpha-fetoprotein(AFP) levels to improve the diagnostic value and the effects of vitamin K administration on DCP levels were assessed in the present study. The results obtained were as follows: 1) DCP was detected in 42 out of 70 patients with HCC(60.0%), in three seven patients with metastatic liver disease(42.9%), in 23 out of 45 patients with liver cirrhosis(51.1%), and in one out of six patients with chronic active hepatitisb(16.7%), but there was no detectable DCP among the 20 healthy control subjects or in the 13 acute viral hepatitis B, three fatty liver and one liver abscess cases. 2) The detection rates of DCP according to the size of the HCC were 66.7% in the larger-than 5㎝ size and 44.4% in the 3~5㎝ size, but there was no detection in four patients with smaller-than 3㎝ size. The detection rates of DCP according to Child’s classification of liver cirrhosis were 60% in class C and 25% in class B, but there was no detection in two patients in class A. 3) There was no significant correlation between DCP and AFP levels. However, DCP was also detected 62.5% in less than 400ng/㎖ of AFP, and the positive rates were 91.0% in higher than 400ng/㎖ of AFP or higher than 1:10(+) of DCP in patients with HCC. 4) The detection rate of DCP was 56.8% in liver cirrhosis patients with prolonged prothrombin time(PT). However, 61.4% was detected in HCC patients with normal levels of prothrombin time(PT). 5) On observation of the effectiveness of vitamin K administration on DCP level, are was no effectiveness of vitamin K administration in all patients with 13 HCC, but the DCP level decreased or was not detected in seven out of nine patients with liver cirrhosis after vitamin K administration (p<0.05). Based on these results, DCP determined by a latex agglutination test may be useful as an index of hepatocellular dysfunction. However, due to the lower sensitivity and specificity of the latex agglutination test, it is doubtful whether DCP is a definite tumor marker of HCC. But the combination assay of AFP and DCP is helpful for obtaining an increased diagnostic rate of HCC. We recommended comparison of the effectiveness of vitamin K administration on DCP concentrations during the follow-up observation of chronic liver disease, such as liver cirrhosis, for increasing the diagnostic rate of HCC. Further study utilizing methods such as RIA or ELISA might be needed to evaluate the usefulness of DCP as a tumor marker for HCC.

Gadoxetic Acid (Gd-EOB-DTPA)-Enhanced MRI versus Gadobenate Dimeglumine (Gd-BOPTA)-Enhanced MRI for Preoperatively Detecting Hepatocellular Carcinoma: an Initial Experience

박율리,김성현,김승훈,전용환,이종미,김민주,최동일,이원재,김희정,구지현,임효근 대한영상의학회 2010 Korean Journal of Radiology Vol.11 No.4

Objective: This study was designed to compare the diagnostic performance of gadoxetic acid-enhanced magnetic resonance imaging (MRI) with gadobenate dimeglumine-enhanced MRI for preoperatively detecting hepatocellular carcinoma (HCC). Materials and Methods: Eighteen consecutive patients (17 men and one woman, age range: 31-73 years) with 22 HCCs underwent examinations with gadoxetic acid enhanced MRI and gadobenate dimeglumine-enhanced MRI on a 3.0-Tesla unit. The diagnosis of HCC was established after surgical resection and pathological conformation. Three observers independently reviewed each MR image in a random order on a tumor-by-tumor basis. The diagnostic accuracy of these techniques for the detection of HCC was assessed by performing an alternative free-response receiver operating characteristic (ROC) analysis. The sensitivity and positive predictive values were evaluated. Results: The average value of the area under the ROC curve (Az) for gadoxetic acid enhanced MRI (0.887) was not significantly different from the Az (0.899) for gadobenate dimeglumine-enhanced MRI (p > 0.05). The overall sensitivities of gadoxetic acid enhanced MRI and gadobenate dimeglumine-enhanced MRI were 80% and 83%, respectively, with no significant difference (p > 0.05). The differences of the positive predictive values for the two contrast agents for each observer were not statistically significant (p > 0.05). Conclusion: The diagnostic performance of gadoxetic acid-enhanced MRI and gadobenate dimeglumine-enhanced MRI for preoperatively detecting HCC is quite similar. Objective: This study was designed to compare the diagnostic performance of gadoxetic acid-enhanced magnetic resonance imaging (MRI) with gadobenate dimeglumine-enhanced MRI for preoperatively detecting hepatocellular carcinoma (HCC). Materials and Methods: Eighteen consecutive patients (17 men and one woman, age range: 31-73 years) with 22 HCCs underwent examinations with gadoxetic acid enhanced MRI and gadobenate dimeglumine-enhanced MRI on a 3.0-Tesla unit. The diagnosis of HCC was established after surgical resection and pathological conformation. Three observers independently reviewed each MR image in a random order on a tumor-by-tumor basis. The diagnostic accuracy of these techniques for the detection of HCC was assessed by performing an alternative free-response receiver operating characteristic (ROC) analysis. The sensitivity and positive predictive values were evaluated. Results: The average value of the area under the ROC curve (Az) for gadoxetic acid enhanced MRI (0.887) was not significantly different from the Az (0.899) for gadobenate dimeglumine-enhanced MRI (p > 0.05). The overall sensitivities of gadoxetic acid enhanced MRI and gadobenate dimeglumine-enhanced MRI were 80% and 83%, respectively, with no significant difference (p > 0.05). The differences of the positive predictive values for the two contrast agents for each observer were not statistically significant (p > 0.05). Conclusion: The diagnostic performance of gadoxetic acid-enhanced MRI and gadobenate dimeglumine-enhanced MRI for preoperatively detecting HCC is quite similar.

조기 간암에서의 동맥치료: 완화법에서 완치법으로

오정석 ( Jung Suk Oh ),천호종 ( Ho Jong Chun ) 대한간암학회 2012 대한간암학회지 Vol.12 No.2

Early stage hepatocellular carcinoma (HCC) based on BCLC staging system can be curatively treated by liver transplantation, surgical resection or percutaneous ablation. However, transarterial approaches, including transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), are standard of care for intermediate stage HCC and can be an alternative treatment in the patients with early stage HCC which are unresectable, unsuitable for percutaneous ablation, or not eligible for liver transplantation. Many previous TACE studies in early stage HCC revealed that the overall survival rate was competitive with those of curative therapies considering their operation risks, but recurrence-free survival rate was significantly lower than curative therapies. Moreover, the histopathologic reports about TACE in early stage HCC demonstrated that only 38% of the HCC nodules were completely necrotic after TACE and only 81% of the nodules with complete response by EASL criteria showed complete necrosis. Although there is no long-term survival data about TARE in early stage HCC, a histopathologic report about TARE showed that 73% of the HCC nodules were completely necrotic after TARE and 100% of the nodules with complete response by EASL criteria showed complete necrosis. In conclusion, TACE is now limited to be categorized into a curative therapy in early stage HCC, according to the previous data about TACE. However, new recent technologies including C-arm CT, superselective embolization technique, drug-eluting bead (DEB) may sufficiently improve the survival data of TACE to prove its curative role. Considering its RFA-comparable histopathologic tumor response, TARE may prove to be a potential curative therapeutic for early stage HCC.

Association between PNPLA3 rs738409 polymorphism and hepatocellular carcinoma risk: an updated meta-analysis

Li Zhang,Chuanmiao Liu,Kuihua Xu,Jiasheng Chen 한국유전학회 2016 Genes & Genomics Vol.38 No.9

Hepatocellular carcinoma (HCC) is a common malignant tumor and the leading cause of cancer-related death worldwide. The protein encoded by patatin-like phospholipase domain-containing protein 3 (PNPLA3) plays important roles in liver fatty metabolism. Recent studies have indicated associations of PNPLA3 rs738409 with various liver diseases, including HCC. This metaanalysis was performed to investigate and update the association between rs738409 polymorphism and the risk of HCC, and to test the association between rs738409 and HCC specifically in patients within chronic hepatitis B and/ or C infection, alcoholic liver disease, or other diseases. Studies were searched from the literature database up to March 31, 2016. The meta-analysis was conducted based on statement of preferred reporting items for systematic reviews and meta-analyses. Pooled odds ratios (OR) and 95 % confidence intervals (CI) were estimated the strength of associations between rs738409 polymorphism and HCC risk. Fifteen published studies, consisting of 2264 HCC patients (case) and 5802 without HCC individuals (control), were included in the present study. Meta-analysis revealed that rs738409 polymorphism contributed to HCC risk under the allelic effect model (C vs. G: OR 1.73; 95 % CI 1.53–1.96), the dominant effect model (CC vs. CG?GG: OR 1.61; 95 % CI 1.44–1.81), and the recessive effect model (CC?CG vs. GG: OR 2.66; 95 % CI 2.28–3.11). Furthermore, the effect of rs738409 G allele on liver oncogenesis was higher in alcoholic liver disease (OR 2.55), compared to chronic hepatitis C/B (OR 1.32) and other diseases (OR 2.27). The results suggested that rs738409 polymorphism was significantly associated with HCC risk and it could be used as one risk factor for HCC.