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( Eiji Miyoshi ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Recent changes in life style have given a big problem, obesity to human being, which is unexpected before 21st century. Numbers of patients with NAFLD (non-alcoholic fatty liver disease) are increasing in many countries. While NAFLD is associated with obesity, the correlation is a little different in each country, which might be dependent on genetic and/or environmental factors. In this symposium, I summarize a difference of obesity and NAFLD in each country and show the importance of biomarker for NAFLD/NASH to prevent HCC. Furthermore, I refer to talk about fucosylated AFP (AFP-L3) as a representative glyco-cancer biomarker for hepatocellular carcinoma.
Noninvasive Diagnostic Method of Nonalcoholic Steatohepatitis
( Eiji Miyoshi ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem and thus discriminating nonalcoholic steatohepatitis(NASH) from NAFLD is of great clinical significance. For NASH diagnosis, liver biopsy-proven histological examination is the currentgold standard, and noninvasive and reliable biomarkers are greatly needed. Recently, we found two glycobiomarkers, fucosylatedhaptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac2bp), are useful independently for NASH diagnosis. Serum Fuc-Hpt issuitable for the prediction of ballooning hepatocytes and serum Mac2bp is suitable for the prediction of liver fibrosis severity.Combination of these 2 glycobiomarkers could make a noninvasive diagnosis of NASH in a large cohort of validation study. Usingreceiver-operating characteristic (ROC) analyses, area under the ROC curve (AUROC), sensitivity, and specificity of these 2 glycobiomarkerscombination was 0.844, with 71.4% and 82.3%, respectively. In addition, we investigated the significance of ourdeveloped NASH diagnosis model in ultrasound-diagnosed NAFLD subjects who received medical health check-ups. Our modelalso could predict NAFLD disease severity in this larger population. Both Mac2-Bp and Hpt are target glycoproteins forfucosylation. Increases in serum fucosylated proteins are associated with hepatic inflammation as well as disrupt of membranetraffic in hepatocytes. In conclusion, the combination of serum Fuc-Hpt and Mac2bp can distinguish NASH from NAFLD patients.Our noninvasive model using two serum glycobiomarkers contributes to a novel NASH diagnostic methodology that could replaceliver biopsy.
Kuwamoto, Kana,Takeda, Yuri,Shirai, Akiko,Nakagawa, Tsutomu,Takeishi, Shunsaku,Ihara, Shinji,Miyamoto, Yasuhide,Shinzaki, Shinichiro,Ko, Jeong Heon,Miyoshi, Eiji D. A. Spandidos 2010 MOLECULAR MEDICINE REPORTS Vol.3 No.4
<P>α2-Heremans-Schmid glycoprotein (human fetuin) is one of numerous serum proteins produced in the liver. Recently, the biological functions of fetuin, such as calcification and insulin resistance, have been clarified. However, these effects appear to be indirect, occurring through binding to other molecules. When equal amounts of fetuin in sera were treated with chymotrypsin, resistance to the protease treatment was observed in patients with pancreatic cancer, but not in normal volunteers. To investigate the molecular mechanism behind this resistance, gel-filtration chromatography was performed. The results revealed that high molecular types of fetuin showed a resistance to protease treatment. When fetuin was purified from sera of patients with pancreatic cancer and normal volunteers, certain types of proteins, including haptoglobin (which binds to fetuin derived from pancreatic cancer patients), were identified using mass spectrometry. Furthermore, the oligosaccharide structures of fetuin analyzed with lectin microarray differed between pancreatic cancer patients and normal volunteers. This macro/micro heterogeneity of fetuin might contribute to pancreatic cancer resistance to chymotrypsin treatment.</P>
Kim, Yong-Sam,Kang, Hye-Yeon,Kim, Jin-Young,Oh, Sejeong,Kim, Cheorl-Ho,Ryu, Chun Jeih,Miyoshi, Eiji,Taniguchi, Naoyuki,Ko, Jeong Heon WILEY-VCH 2006 Proteomics Vol. No.
<P>To gain a better understanding of the mechanism underlying colon cancer and to search for potential markers of colon cancer prognosis, a comparative proteomic analysis of colon cancer WiDr cells was conducted using 2-DE and lectin blot, followed by identification based on ESI-MS. Through these approaches 14 proteins were identified as candidate target proteins for N-acetylglucosaminyl transferase V (GnT-V) that would be expected to be implicated in the progression of colon cancer. We selected protein tyrosine phosphatase kappa (PTPκ) as a model protein to validate this approach to the discovery of novel biomarkers in colon cancer. PTPκ underwent an aberrant glycosylation in GnT-V-overexpressing WiDr cells, and the aberrantly glycosylated PTPκ was vulnerable to proteolytic cleavage. The enhanced cleavage of PTPκ in GnT-V-overexpressing cells was responsible for the mitigation of the homophilic binding capacity, resulting in an increase in cancer cell migration.</P>
Kim, Yong-Sam,Son, Ok Lye,Lee, Ju Yeon,Kim, Sun Hee,Oh, Sejeong,Lee, Yoon Suk,Kim, Cheorl-Ho,Yoo, Jong Shin,Lee, Jeong-Hwa,Miyoshi, Eiji,Taniguchi, Naoyuki,Hanash, Samir M.,Yoo, Hyang Sook,Ko, Jeong H WILEY-VCH Verlag 2008 Proteomics Vol.8 No.16
<P>N-acetylglucosaminyltransferase V (GnT-V) has been reported to be upregulated in malignant cancer cells, and its targets have been sought after with regard to biomarker identification. The low capacity and high false positive rates of 2-DE gel-based lectin blots using phytohemagglutinin-L<SUB>4</SUB> (L-PHA) prompted us to develop a novel protocol for identifying GnT-V targets, in which serum proteins were subjected to immunodepletion, alkylation, and lectin precipitation using L-PHA coupled to avidin–agarose bead complexes, and tryptic digestion. Proteins captured by L-PHA conjugates were analyzed by a nano-LC-FT-ICR/LTQ MS. Here, we report 26 candidate biomarkers for colorectal cancer (CRC) that show 100% specificity and sensitivities of greater than 50%. Not only can these candidate proteins be used as analytes for validation, but the novel protocol described herein can be applied to biomarker discovery in nonCRCs. </P>