Abstract
Introduction
Hepatitis C is the most significant risk factor for development of hepatocellular carcinoma. Inflammation, fibrosis, and liver cell proliferation may contribute to cancer development either through malignant hepatocyte transformation or extracellular matrix remodeling within the tumor microenvironment. The study objective was to investigate differences in gene expression between patients with Hepatitis C (± cancer) and normal that might explain the increased cancer risk.
Methods
Liver tissue was collected from three patient groups: 1) healthy patients, 2) Hepatitis C patients without cancer, 3) patients with Hepatitis C and hepatocellular carcinoma. Microarray analysis was performed on samples from each group. Western blot and real-time polymerase chain reaction (PCR) analyses corroborated the microarray data. A p value of 0.05 was set as significant.
Results
Microarray analysis showed overexpression of autotaxin in patients with cancer versus hepatitis patients or normal patients. Rho GTPase binding proteins (Cdc42s) associated with lysophosphatidic acid signaling were also overexpressed in cancer patients. Real-time polymerase chain reaction showed overexpression of several factors associated with autotaxin in patients with Hepatitis C (± cancer) versus normal patients.
Conclusions
Patients with Hepatitis C and hepatocellular carcinoma show differential expression of various components of the autotaxin pathway versus normal patients. This merits further investigation in the context of early diagnosis.
Similar content being viewed by others
References
Stracke ML, Krutzsch HC, Unsworth EJ, Arestad A, Cioce V, Schiffmann E, Liotta LA. Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein. J Biol Chem 1992;267(4):2524–2529.
Kishi Y, Okudaira S, Tanaka M, Hama K, Shida D, Kitayama J, Yamori T, Aoki J, Fujimaki T, Arai H. Autotaxin is overexpressed in glioblastoma multiform and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. J Biol Chem 2006;281(25):17492–17500.
Black EJ, Clair T, Delrow J, Neiman P, Gillespie DAF. Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by c-Jun. Oncogene 2004;23(13):2357–2366.
Hama KAJ, Fukaya M, Kishi Y, Sakai T, Suzuki R, Ohta H, Yamori T, Watanabe M, Chun J, Arai H. Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. J Biol Chem 2004;279(17):17634–17639.
Goding JW, Grobben B, Slegers H. Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Biochim Biophys Acta 2003;1638(1):1–19.
Nam SWCT, Campo CK, Lee HY, Liotta LA, Stracke ML. Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells. Oncogene 2000;19:241–247.
Moolenaar WH. Bioactive lysophospholipids and their G protein-coupled receptors. Exp Cell Res 1999;253(1):230–238.
Fukui K, Tamura S, Wada A, Kamada Y, Sawai Y, Imanaka K, Kudara T, Shimomura I, Hayashi N. Expression and prognostic role of RhoA GTPases in hepatocellular carcinoma. J Cancer Res Clin Oncol 2006;132(10):627–633.
Stam JC, Michiels F, van der Kammen RA, Moolenaar WH, Collard JG. Invasion of T-lymphoma cells: Cooperation between Rho family GTPases and lysophospholipid receptor signaling. EMBO J 1998;17(14):4066–4074.
Moolenaar WH, van Meeteren LA, Giepmans BNG. The ins and outs of lysophosphatidic acid signaling. Bioessays 2004;26(8):870–881.
Xu YSZ, Wiper DW, Wu M, Morton RE, Elson P, Kennedy AW, Belinson J, Markman M, Casey G. Lysophosphatidic Acid as a Potential Biomarker for Ovarian and Other Gynecologic Cancers. JAMA 1998;280(8):719–723.
Yamashita H, Kitayama J, Shida D, Ishikawa M, Hama K, Aoki J, Arai H, Nagawa H. Differential expression of lysophosphatidic acid receptor-2 in intestinal and diffuse type gastric cancer. J Surg Oncol 2006;93(1):30–35.
Di Bisceglie AM, Simpson LH, Lotze MT, Hoofnagle JH, Di Bisceglie AM, Simpson LH, Lotze MT, Hoofnagle JH. Development of hepatocellular carcinoma among patients with chronic liver disease due to hepatitis C viral infection. J Clin Gastroenterol 1994;19(3):222–226.
Zhang G, Zhao Z, Xu S, Ni L, Wang X. Expression of autotaxin mRNA in human hepatocellular carcinoma. Chin Med J 1999;112(4):330–332.
Conflicts of Interest/Disclosures
There are no conflicts of interest or financial disclosures relevant to this paper for any of the authors.
Grant Support
This project was supported by a grant from the NIH (K22-CA111393).
Author information
Authors and Affiliations
Corresponding author
Additional information
DISCUSSION
Paul Kwo, M.D. (Indianapolis, IN): Congratulations, Dr. Cooper and Dr. Maluccio. The relationship of hepatitis C and hepatocellular carcinoma, those of you who are practicing know, is one of the largest clinical conundrums we face, with a half million people in the United States with hepatitis C-related cirrhosis. Alpha fetoprotein, which is the one tumor marker that we historically have used (yet frustrates us), is no longer recommended as a screening test. Whereas many of us still use it to some degree in practice, your work here with autotaxin, if confirmed in larger studies, I think would be a major advance in the ability to have serum markers to screen for hepatoma.
One of the issues is that with hepatitis C, there is a diverse range of disease, ranging from little fibrosis to a large amount of fibrosis or cirrhosis, and indeed I think this may explain why you had so much variability in the hepatitis C group compared to the hepatocellular carcinoma group, where I think the fibrosis distribution is relatively uniform, that is, they are all stage 3 or stage 4 fibrosis, at least advanced fibrosis. My questions are the following.
As you move forward with your future studies, how do you think are you going to need to stratify for not only fibrosis but perhaps for other diseases? For instance, hepatitis C patients drink, they are heavy, they smoke, and all of these factors I think are going to have to be differentiated as you try and differentiate the role of autotoxin in hepatoma screening. And lastly, if you can sort this out and find a role for this, do you plan on pursuing the role of autotaxin in other diseases? For instance, hepatitis C therapies will probably be largely refined in the next 10 years. Steatosis and cirrhosis caused by obesity is the next big epidemic that we are all going to be dealing with, and I would think if the role of autotoxin be defined in one disease such as hepatitis C, it would be nice to determine its role in other chronic liver diseases.
Amanda Cooper, M.D. (Indianapolis, IN): I agree. I think definitely things that we know to be significant predictors of future development of hepatocellular carcinoma such as degree of fibrosis are certainly things that we would like to stratify in future studies with larger sample sizes. In addition, we do hope in future studies to be able to look at patients with NASH and see if we see these same changes in levels of expression. Hepatitis C happened to be the most convenient large sample size that we had readily available.
Dr. Kwo: Fatty liver is rapidly catching up.
Dr. Cooper: Yes.
Rights and permissions
About this article
Cite this article
Cooper, A.B., Wu, J., Lu, D. et al. Is Autotaxin (ENPP2) the Link between Hepatitis C and Hepatocellular Cancer?. J Gastrointest Surg 11, 1628–1635 (2007). https://doi.org/10.1007/s11605-007-0322-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11605-007-0322-9