Hideo Suzuki1, Motoyuki Kohjima1,2, Masatake Tanaka1,3, Takeshi Goya1, Shinji Itoh4, Tomoharu Yoshizumi4, Masaki Mori4, Mariko Tsuda1, Motoi Takahashi1, Miho Kurokawa1, Koji Imoto1, Shigeki Tashiro1, Akifumi Kuwano1, Masaki Kato1,5, Seiji Okada3, Makoto Nakamuta2, Yoshihiro Ogawa1,6. 1. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 2. Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, 1-8-1 Zigyohama, Chuo-ku, Fukuoka 810-8563, Japan. 3. Department of Pathophysiology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 4. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 5. Graduate School of Nutritional Sciences, Nakamura Gakuen University, 5-7-1 Befu, Jounan-ku, Fukuoka 814-0198, Japan. 6. CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
Abstract
Objective: Metabolic alteration is widely considered as one of the hallmarks of cancer. Hepatocellular carcinoma (HCC) presents a unique pathological feature in which lipid accumulation is common in well-differentiated HCC and rare in poorly differentiated HCC; however, the underlying mechanism remains unclear. Methods: Tissue samples were obtained from 103 HCC patients who had undergone hepatic resection and 12 living donors of liver transplantation. We evaluated metabolic gene expressions in cancer tissues as well as background noncancer tissues and compared the expressions by the degree of cancer differentiation and by liver disease states. Besides, the metabolomics was evaluated and integrated to gene expressions in nonalcoholic steatohepatitis (NASH)-HCC model mice. Results: In cancer tissues, the expression levels of enzymes related to glycolysis, pentose phosphate pathway (PPP), and fatty acid (FA) synthesis were increased and that of tricarboxylic acid (TCA) cycle and β-oxidation were suppressed. Same metabolic alterations were observed in noncancer tissue as the liver disease progresses from healthy liver to chronic hepatitis, cirrhosis, and HCC. Similar alterations of metabolic genes were detected in NASH-HCC mice, which were consistent with the results of metabolomics. As the degree of cancer differentiation decreased, glycolysis and PPP were accelerated; however, FA synthesis and uptake were diminished. Conclusions: The metabolic alterations including glycolysis, PPP, TCA cycle, and β-oxidation became more prominent as liver disease progresses from normal, chronic hepatitis, cirrhosis, well-, moderately, and poorly differentiated HCC. FA synthesis and uptake were highest in well-differentiated HCC, which could explain the lipid accumulation.
Objective: Metabolic alteration is widely considered as one of the hallmarks of cancer. Hepatocellular carcinoma (HCC) presents a unique pathological feature in which lipid accumulation is common in well-differentiated HCC and rare in poorly differentiated HCC; however, the underlying mechanism remains unclear. Methods: Tissue samples were obtained from 103 HCCpatients who had undergone hepatic resection and 12 living donors of liver transplantation. We evaluated metabolic gene expressions in cancer tissues as well as background noncancer tissues and compared the expressions by the degree of cancer differentiation and by liver disease states. Besides, the metabolomics was evaluated and integrated to gene expressions in nonalcoholic steatohepatitis (NASH)-HCC model mice. Results: In cancer tissues, the expression levels of enzymes related to glycolysis, pentose phosphate pathway (PPP), and fatty acid (FA) synthesis were increased and that of tricarboxylic acid (TCA) cycle and β-oxidation were suppressed. Same metabolic alterations were observed in noncancer tissue as the liver disease progresses from healthy liver to chronic hepatitis, cirrhosis, and HCC. Similar alterations of metabolic genes were detected in NASH-HCCmice, which were consistent with the results of metabolomics. As the degree of cancer differentiation decreased, glycolysis and PPP were accelerated; however, FA synthesis and uptake were diminished. Conclusions: The metabolic alterations including glycolysis, PPP, TCA cycle, and β-oxidation became more prominent as liver disease progresses from normal, chronic hepatitis, cirrhosis, well-, moderately, and poorly differentiated HCC. FA synthesis and uptake were highest in well-differentiated HCC, which could explain the lipid accumulation.
Authors: Heather R Christofk; Matthew G Vander Heiden; Marian H Harris; Arvind Ramanathan; Robert E Gerszten; Ru Wei; Mark D Fleming; Stuart L Schreiber; Lewis C Cantley Journal: Nature Date: 2008-03-13 Impact factor: 49.962
Authors: Weiwei Yang; Yan Xia; Yu Cao; Yanhua Zheng; Wen Bu; Lin Zhang; M James You; Mei Yee Koh; Gilbert Cote; Kenneth Aldape; Yi Li; Inder M Verma; Paul J Chiao; Zhimin Lu Journal: Mol Cell Date: 2012-11-01 Impact factor: 17.970
Authors: J Rowles; S W Scherer; T Xi; M Majer; D C Nickle; J M Rommens; K M Popov; R A Harris; N L Riebow; J Xia; L C Tsui; C Bogardus; M Prochazka Journal: J Biol Chem Date: 1996-09-13 Impact factor: 5.157