• Human hepatocellular carcinomas with “Stemness”-related marker expression: keratin 19 expression and a poor prognosis

    Haeryoung Kim, Gi Hong Choi, Deuk Chae Na, Ei Young Ahn, Gwang Il Kim, Jae Eun Lee, Jai Young Cho, Jeong Eun Yoo, Jin Sub Choi, Young Nyun Park

    There is a recently proposed subtype of hepatocellular carcinoma (HCC) that is histologically similar to usual HCC, but characterized by the expression of “stemness”-related markers. A large-scale study on two different cohorts of HCCs was performed to investigate the clinicopathologic features and epithelial-mesenchymal transition (EMT)-related protein expression status of this subtype of HCCs. The expression status of stemness-related (e.g., keratin 19 [K19], cluster of differentiation [CD]133, epithelial cell adhesion molecule [EpCAM], and c-kit) and EMT-related markers (e.g., snail, S100A4, urokinase plasminogen activator receptor [uPAR], ezrin, vimentin, E-cadherin, and matrix metalloproteinase [MMP]2) were examined using tissue microarrays from cohort 1 HCCs (n = 137). K19 protein expression in cohort 2 HCCs (n = 237) was correlated with the clinicopathologic parameters and messenger RNA (mRNA) levels of K19, uPAR, VIL2, Snail, Slug, and Twist. K19, EpCAM, c-kit, and CD133 positivity were observed in 18.2%, 35.0%, 34.3%, and 24.8%, respectively. K19 was most frequently expressed in combination with at least one other stemness-related marker (92.0%). K19-positive HCCs demonstrated more frequent major vessel invasion and increased tumor size, compared to K19-negative HCCs (P < 0.05). K19 was most significantly associated with EMT-related protein expression (e.g., vimentin, S100A4, uPAR, and ezrin) (P < 0.05) and a poor prognosis (overall survival: P = 0.018; disease-free survival: P = 0.007) in cohort 1. In cohort 2, HCCs with high K19 mRNA levels demonstrated higher mRNA levels of Snail, uPAR, and MMP2 (P < 0.05). K19-positive HCCs demonstrated more frequent microvascular invasion, fibrous stroma, and less tumor-capsule formation, compared to K19-negative HCCs (P < 0.05). K19 expression was a significant independent predictive factor of poor disease-free survival (P = 0.032). Conclusion: K19 was well correlated with clinicopathologic features of tumor aggressiveness, compared to other stemness-related proteins. K19-positive HCCs showed significantly increased EMT-related protein and mRNA expression, suggesting that they may acquire more invasive characteristics, compared to K19-negative HCCs through the up-regulation of EMT-associated genes. (HEPATOLOGY 2011;)

  • A Fibrous Stromal Component in Hepatocellular Carcinoma Reveals a Cholangiocarcinoma-Like Gene Expression Trait and Epithelial-Mesenchymal Transition

    Jae Yeon Seok, Deuk Chae Na, Hyun Goo Woo, Massimo Roncalli, So Mee Kwon, Jeong Eun Yoo, Ei Yong Ahn, Gwang Il Kim, Jin-Sub Choi, Young Bae Kim, and Young Nyun Park

    Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major primary liver cancers in adults. The phenotypic overlap etween HCC and CC has been shown to comprise a continuous liver cancer spectrum. As a proof of this concept, a recent study demonstrated a genomic subtype of HCC that expressed CC-like gene expression traits, such as CC-like HCC, which revealed the common enomic trait of stem-cell–like proper-ties and aggressive clinical outcomes. Scirrhous HCC (S-HCC), a rare variant of HCC, is characterized by abundant fibrous stroma and has been known to express several liver stem/progenitor cell markers. This suggests hat -HCC may harbor common intermediate traits between HCC and CC, including stem-cell traits, which are similar to those of CC-like CC. However, the molecular and pathological characteristics of S-HCC have not been fully evaluated. By performing gene-expression rofiling and immunohistochemical evaluation, we compared the morphological and molecular features of S-HCC with those of CC and HCC. -HCC expresses both CC-like and stem-cell–like genomic traits. In addition, we observed the expression of core epithelial-esenchymal transition (EMT)- related genes, which may contribute to the aggressive behavior of S-HCC. Overexpression of ransforming rowth factor beta (TGF-b) signaling was also found, implying its regula- tory role in the pathobiology of S-HCC. Conclusion: We uggest that the fibrous stromal component in HCC may contribute to the acquisition of CC-like gene-expression traits in HCC. The xpression of stem-cell–like traits and TGF-b/EMT molecules may play a piv- otal role in the aggressive phenotyping of S-HCC. HEPATOLOGY 2012;55:1776-1786)

  • Exploration of ClpC target compounds, as new antibiotic, inhibiting the growth of antibiotic resistant pathogens

    Youn, Chea La

    Since the discovery of penicillin, human beings have used antibiotic for a long time as a human and animal medicine. The antibiotics are indispensable in the field of infectious, but sometimes this results in antibiotic resistance. It is very dangerous because led to serious problems such as death in public health. Recently, The antibiotic resistant microbe is more increasing by poor conditions. Thus WHO can sense a danger of antibiotic resistant bacteria and the WHO was urgently reported to antibiotic resistance in April 2014. According to reports, this serious threat is no longer a prediction in the near future because the infection by antibiotic resistant bacteria. [1] Moreover, The Food and Drug Administration(FDA) was reported to diagnostic device linked to an outbreak of antibiotic resistant bacteria in a UCLA hospital. According to the report, seven people were infected by Carbapenem resistant Enterobacteriaceae (CRE) during endoscopy using a contaminated equipment and two of them died. [2] The typical antibiotic resistant bacterium is Methicillin-resistant Staphylococcus aureus (MRSA) had more occurred by bacterium. At first, MRSA is identified in the 1960s, were observed in the U.S. in the mid 1980s that is responsible for the death in humans. It is strain of Staphylococcus aureus that resistant to beta-lactam antibiotics such as penicillins. The MRSA can invade the bloodstream through damaged skin in hospitals. [3](4) This infection more difficult to therapy because It is not effect by one or more antibiotics. All of the world, The people are nervous that antibiotic resistant bacteria is increasing. Therefore, New antibiotic development need to urgently against the antibiotic resistant bacteria.