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hepatocellular carcinoma, metformin

Gyuri Kim, Suk-Yong Jang, Eugene Han, Yong-Ho Lee, Se-Young Park, Chung Mo Nam, Eun Seok Kang
Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population-based nested case-control study was conducted within the National Health Insurance Service National Sample Cohort 2002-2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow-up time, and the date of diabetes diagnosis at a five-to-one ratio...
November 7, 2016: International Journal of Cancer. Journal International du Cancer
François Cauchy, Mouniya Mebarki, Benjamin Leporq, Samira Laouirem, Miguel Albuquerque, Simon Lambert, Pierre Bourgoin, Olivier Soubrane, Bernard van Beers, Sandrine Faivre, Pierre Bedossa, Valerie Paradis
Studies suggest that metformin, widely used for treating type 2 diabetes, possesses innate antineoplastic properties. For metabolic syndrome patients with hepatocellular carcinoma, metformin may provide antitumoral effects  We evaluated the impact of metformin on tumor growth and visceral fat composition using relevant preclinical models of metabolic syndrome.  EXPERIMENTAL DESIGN: Studies were performed in three hepatoma cell lines, in HepG2 xenograft mice fed with standard chow-diet (SC), 60% high-fat diet (HFD) or 30% fructose diet (FR), and an ex vivo model of human cultured hepatocellular carcinoma slices...
November 1, 2016: Clinical Science (1979-)
Eun Ho Kim, Mi-Sook Kim, Yoshiya Furusawa, Akiko Uzawa, Soorim Han, Won-Gyun Jung, Sei Sai
The purpose of this study was to investigate the effect of metformin on the responses of hepatocellular carcinoma (HCC) cells to γ-rays (low-linear energy transfer (LET) radiation) and carbon-ion beams (high-LET radiation). HCC cells were pretreated with metformin and exposed to a single dose of γ-rays or carbon ion beams. Metformin treatment increased radiation-induced clonogenic cell death, DNA damage, and apoptosis. Carbon ion beams combined with metformin were more effective than carbon ion beams or γ-rays alone at inducing subG1 and decreasing G2/M arrest, reducing the expression of vimentin, enhancing phospho-AMPK expression, and suppressing phospho-mTOR and phospho-Akt...
October 27, 2016: Oncotarget
Kun-Ming Chan, Chang-Fu Kuo, Jun-Te Hsu, Meng-Jiun Chiou, Yu-Chao Wang, Tsung-Han Wu, Chen-Fang Lee, Ting-Jung Wu, Hong-Shiue Chou, Wei-Chen Lee
BACKGROUND: Hepatocellular carcinoma recurrence following liver resection remains a great concern. The study aims to examine the chemopreventive effect of metformin in patients undergoing liver resection for hepatocellular carcinoma from a population-based study. METHODS: All patients registered as having hepatocellular carcinoma between January 1995 and December 2011 in a nationwide database were retrospectively analysed. Outcomes related to liver resection and the presence of diabetes mellitus were assessed...
October 24, 2016: Liver International: Official Journal of the International Association for the Study of the Liver
Yao-Yao Zhou, Gui-Qi Zhu, Tian Liu, Ji-Na Zheng, Zhang Cheng, Tian-Tian Zou, Martin Braddock, Shen-Wen Fu, Ming-Hua Zheng
Antidiabetic medication may modify the incidence of hepatocellular carcinoma (HCC). We aimed to compare the use of different antidiabetic strategies and the incidence of HCC. PubMed, and Cochrane Library databases were searched up to 31 October 2015 and randomized controlled trials (RCTs), cohort studies or case-control studies were included for our analyses. A total of thirteen studies enrolling 481358 participants with 240678 HCC cases who received at least two different strategies were retrieved in this analysis...
2016: Scientific Reports
Wei Wu, Jun-Ling Yang, Yi-Lang Wang, Han Wang, Min Yao, Li Wang, Juan-Juan Gu, Yin Cai, Yun Shi, Deng-Fu Yao
AIM: To interfere with the activation of nuclear factor-κB (NF-κB) with metformin and explore its effect in reversing multidrug resistance (MDR) of hepatocellular carcinoma (HCC) cells. METHODS: Expression of P-glycoprotein (P-gp) and NF-κB in human HepG2 or HepG2/adriamycin (ADM) cells treated with pCMV-NF-κB-small interference RNA (siRNA) with or without metformin, was analyzed by Western blot or fluorescence quantitative PCR. Cell viability was tested by CCK-8 assay...
August 18, 2016: World Journal of Hepatology
Chuan Shen, Chenghong Peng, Baiyong Shen, Zhecheng Zhu, Ning Xu, Tao Li, Junjie Xie
Immunosuppressive agents used postoperatively after liver transplantation (LT) for hepatocellular carcinoma (HCC) favor recurrence and metastasis. Therefore, new effective immunosuppressants are needed. This retrospective study assessed combined sirolimus and metformin on survival of HCC patients after LT. In 2001-2013, 133 HCC patients with LT were divided into four groups: sirolimus and metformin combination (Sir+Met), sirolimus monotherapy (Sir), other immunosuppressants in diabetes mellitus (DM) patients without metformin (No Sir with DM), and other immunosuppressants in patients without DM (No Sir without DM)...
August 25, 2016: Oncotarget
Koji Fujita, Hisakazu Iwama, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects...
July 21, 2016: World Journal of Gastroenterology: WJG
Mamatha Bhat, Akiko Yanagiya, Tyson Graber, Nataliya Razumilava, Steve Bronk, Domenick Zammit, Yunhao Zhao, Chadi Zakaria, Peter Metrakos, Michael Pollak, Nahum Sonenberg, Gregory Gores, Maritza Jaramillo, Masahiro Morita, Tommy Alain
Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). Metformin has also been shown to induce apoptosis in this cancer. Here, we investigate whether metformin-induced apoptosis in HCC is mediated by the downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during metformin treatment negatively regulate translation of the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) mRNA...
July 18, 2016: Oncotarget
Mary-Anne Doyle, Joel Singer, Terry Lee, Miriam Muir, Curtis Cooper
BACKGROUND: Approximately 180 million people worldwide, (3 % of the world's population) are infected with hepatitis C (HCV). Insulin resistance (IR) and type 2 diabetes (T2DM) are common extrahepatic manifestations of chronic HCV infection and associated with poor treatment and liver-related outcomes. The presence of these metabolic complications have been associated with poor response to interferon-based HCV antiviral therapy and increased risk of liver-related outcomes. Metformin, an insulin sensitizer is known to improve HCV treatment response and has been associated with a reduced risk of developing hepatocellular carcinoma (HCC)...
July 20, 2016: Trials
Nadine Gehrke, Marcus A Wörns, Yvonne Huber, Moritz Hess, Beate K Straub, Nadine Hövelmeyer, Ari Waisman, Yong Ook Kim, Detlef Schuppan, Peter R Galle, Jörn M Schattenberg
BACKGROUND & AIMS: The pathomechanisms underlying non-alcoholic fatty liver disease (NAFLD) and the involved molecular regulators are incompletely explored. The nuclear factor-kappa B (NF-κB)-cofactor gene B cell leukemia-3 (Bcl-3) plays a critical role in altering the transcriptional capacity of NF-κB - a key inducer of inflammation - but also of genes involved in cellular energy metabolism. METHODS: To define the role of Bcl-3 in non-alcoholic steatohepatitis (NASH), we developed a novel transgenic mouse model with hepatocyte-specific overexpression of Bcl-3 (Bcl-3(Hep)) and employed a high-fat, high-carbohydrate dietary feeding model...
December 2016: Journal of Hepatology
Hong-Wu Xin, Chenwi M Ambe, Tyler C Miller, Jin-Qiu Chen, Gordon W Wiegand, Andrew J Anderson, Satyajit Ray, John E Mullinax, Danielle M Hari, Tomotake Koizumi, Jessica D Godbout, Paul K Goldsmith, Alexander Stojadinovic, Udo Rudloff, Snorri S Thorgeirsson, Itzhak Avital
BACKGROUND & AIMS: Recently, we reported that liver Label Retaining Cancer Cells (LRCC) can initiate tumors with only 10 cells and are relatively resistant to the targeted drug Sorafenib, a standard of practice in advanced hepatocellular carcinoma (HCC). LRCC are the only cancer stem cells (CSC) isolated alive according to a stem cell fundamental function, asymmetric cell division. Metformin has been reported to preferentially target many other types of CSC of different organs, including liver...
2016: Journal of Cancer
Yu Tian, Bo Tang, Chengye Wang, Deguang Sun, Rixin Zhang, Nan Luo, Zhao Han, Rui Liang, Zhenming Gao, Liming Wang
Metformin plays an anti-proliferative role in tumor cells in many types of cancer. However, the correlation between metformin and sensitivity to chemotherapeutic agents in hepatocellular carcinoma (HCC) and the relevant mechanism are unclear. The present study showed that HCC patients with type 2 diabetes mellitus benefited from metformin administration, with a longer overall survival. Metformin resensitized Bel-7402/5-fluorouracil (Bel/Fu) cells to 5-fluorouracil (5-Fu) in vitro and in vivo, and the combination of metformin and 5-Fu inhibited cell proliferation, promoted cell apoptosis and induced G0/G1 cell cycle arrest in the Bel/Fu cells...
June 15, 2016: Oncotarget
Yunpeng Sun, Chonglin Tao, Xiaming Huang, Han He, Hongqi Shi, Qiyu Zhang, Huanhuan Wu
The antidiabetic drug metformin has been shown to possess antitumor functions in many types of cancers. Although studies have revealed its beneficial effects on the prognosis of hepatocellular carcinoma (HCC), the detailed molecular mechanism underlying this event remains largely unknown. In this work, we showed that miR-23a was significantly induced upon metformin treatment; inhibition of miR-23a abrogated the proapoptotic effect of metformin in HepG2 cells. We next established forkhead box protein A1 (FOXA1) as the functional target of miR-23a, and silencing FOXA1 mimicked the effect of metformin...
2016: OncoTargets and Therapy
Young-Seok Seo, Yun-Jung Kim, Mi-Sook Kim, Kyung-Suk Suh, Sang Bum Kim, Chul Ju Han, Youn Joo Kim, Won Il Jang, Shin Hee Kang, Ha Jin Tchoe, Chan Mi Park, Ae Jung Jo, Hyo Jeong Kim, Jin A Choi, Hyung Jin Choi, Michael N Polak, Min Jung Ko
Many preclinical reports and retrospective population studies have shown an anticancer effect of metformin in patients with several types of cancer and comorbid type 2 diabetes mellitus (T2DM). In this work, the anticancer effect of metformin was assessed in hepatocellular carcinoma (HCC) patients with T2DM who underwent curative resection.A population-based retrospective cohort design was used. Data were obtained from the National Health Insurance Service and Korea Center Cancer Registry in the Republic of Korea, identifying 5494 patients with newly diagnosed HCC who underwent curative resection between 2005 and 2011...
April 2016: Medicine (Baltimore)
Aneta Rogalska, Agnieszka Sliwinska, Jacek Kasznicki, Jozef Drzewoski, Agnieszka Marczak
Type 2 diabetes mellitus patients are at increased risk of many forms of malignancies, especially of the pancreas, colon and hepatocellular cancer. Unfortunately, little is known of the possible interaction between antidiabetic drugs and anticancer agents. The present study investigates the influence of metformin (MET) and sitagliptin (SITA) on the in vitro anticancer activity of the microtubule depolymerization inhibitor agent epothilone A (EpoA). Hepatocellular liver carcinoma cell line (HepG2) viability and apoptosis were determined by the MTT test and by double staining with PO-PRO-1 and 7-aminoactinomycin D, respectively, after treatment with EpoA, metformin or sitagliptin...
2016: Asian Pacific Journal of Cancer Prevention: APJCP
Laure Elkrief, Pierre-Emmanuel Rautou, Shiv Sarin, Dominique Valla, Valérie Paradis, Richard Moreau
Disorders of glucose metabolism, namely glucose intolerance and diabetes, are frequent in patients with chronic liver diseases. In patients with cirrhosis, diabetes can be either a classical type 2 diabetes mellitus or the so-called hepatogenous diabetes, i.e. a consequence of liver insufficiency and portal hypertension. This review article provides an overview of the possible pathophysiological mechanisms explaining diabetes in patients with cirrhosis. Cirrhosis is associated with portosystemic shunts as well as reduced hepatic mass, which can both impair insulin clearance by the liver, contributing to peripheral insulin resistance through insulin receptors down-regulation...
July 2016: Liver International: Official Journal of the International Association for the Study of the Liver
Abin You, Manqing Cao, Zhigui Guo, Bingfeng Zuo, Junrong Gao, Hongyuan Zhou, Huikai Li, Yunlong Cui, Feng Fang, Wei Zhang, Tianqiang Song, Qiang Li, Xiaolin Zhu, Haifang Yin, Huichuan Sun, Ti Zhang
BACKGROUND: Sorafenib is recognized as a standard treatment for advanced hepatocellular carcinoma (HCC). However, many patients have to adopt dose reduction or terminate the use of sorafenib because of side effects. In addition, a large number of patients are resistant to sorafenib. Thus, it is essential to investigate the underlying mechanisms of the resistance to sorafenib and seek potential strategy to enhance its efficacy. METHODS: The protein expression of hypoxia-inducible factors (HIF)-2α, 30-kDa HIV Tat-interacting protein (TIP30), E-cadherin, N-cadherin, and pAMPK was detected by Western blot...
2016: Journal of Hematology & Oncology
Chen Shen, Sun-O Ka, Su Jin Kim, Ji Hye Kim, Byung-Hyun Park, Ji Hyun Park
NANOG, a marker of stemness, impacts tumor progression and therapeutic resistance in cancer cells. In human hepatocellular carcinoma (HCC), upregulation of NANOG is associated with metastasis and a low survival rate, while its downregulation results in a lower colony formation rate and enhanced chemosensitivity. Metformin, an agent widely used for diabetes treatment, and AICAR, another AMP-activated protein kinase (AMPK) activator, have been reported to inhibit the growth of several types of cancer. Although inhibitory effects of metformin on NANOG in pancreatic cancer cells and of AICAR in mouse embryonic stem cells have been described, the underlying molecular mechanisms remain uncertain in HCC...
August 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Danielle K DePeralta, Lan Wei, Sarani Ghoshal, Benjamin Schmidt, Gregory Y Lauwers, Michael Lanuti, Raymond T Chung, Kenneth K Tanabe, Bryan C Fuchs
BACKGROUND: Hepatocellular carcinoma (HCC)-associated mortality is increasing at an alarming rate, and there is a readily identifiable cohort of at-risk patients with cirrhosis, viral hepatitis, nonalcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention because it is inexpensive, has a favorable safety profile, and is well tolerated over long time periods. METHODS: The authors studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, in which tumors develop in the setting of chronic inflammation and cirrhosis...
April 15, 2016: Cancer
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