Award Date

12-1-2022

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Health Physics and Diagnostic Sciences

First Committee Member

Yu Kuang

Second Committee Member

Steen Madsen

Third Committee Member

Janice Pluth

Fourth Committee Member

Daniel Young

Abstract

Primary liver cancer hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. In the US, primary liver cancer is the most rapidly increasing type of cancer due to increases in hepatitis B and C and the continued trend of greater and greater percentages of the population suffering from obesity, diabetes mellitus and metabolic syndrome. The prognosis for this disease is poor, with a 5-year survival rate of 26% as compared to only 2% when the cancer is metastatic. Unfortunately, current strategies for early detection of HCC, including routine CT imaging or alpha-fetoprotein biomarker, are suboptimal and tend to underestimate disease burden and extent, exposing patients to unnecessary morbidity, risks, and expense. There is an urgent need to identify specific early biomarkers, such as lipid molecular species, specific to various liver disease. We hypothesize that lipid species will be different between liver disease states (steatosis, nonalcoholic steatohepatitis, chronic fibrosis, HCC and surrounding hepatic tissues), as well as normal tissues, and that we can use these findings to identify potential biomarker (s) for early identification of liver cancer.In this study, a lipidomics profiling technology and a statistical analysis method were used to quantify the lipid molecular species from mouse liver tissue. Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and ultra-performance liquid chromatography tandem mass spectrometer (UPLC-MS/MS) were used to identify and quantify individual lipid molecular species concentrations (signal (m/z) intensity per milligram dry tissue weight) in tissues from a nonalcoholic steatohepatitis (NASH) stelic animal model (STAM™) of HCC (five different disease stages of STAM liver tissues including steatosis (n=10), nonalcoholic steatohepatitis (n=10), chronic fibrosis (n=10), HCC (n=9) and hepatic tissues surrounding HCC (a.k.a surrounding hepatic tissues) (n=10), as well as normal liver tissues (n=10)). Differences in concentrations of lipid molecular species between five liver disease states, as well as normal tissues, were analyzed with ANOVA, followed by Bonferroni’s post-hoc test. Lipid molecular species exhibited significant differences in concentration between various fatty liver disease states, as well as normal tissues. A total of 263 lipid species concentrations, which include complex lipids (glycerophospholipids and sphingolipids) and triacylglycerol species, were included for tissue comparison. All diseased tissues displayed a large number of significantly different concentrations of distinct lipid molecular species compared to normal tissues (i.e., on average 32 and 57 different complex lipid and 57 triacyclglycerols species, respectively) . In paired comparisons of all disease tissues (e.g., 10 pair-wise comparisons), HCC tissues compared to steatosis tissues exhibited the greatest number of distinct lipid molecular species with significant concentration differences (i.e., 30 species, including ether-linked phosphatidylethanolamine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and triacylglycerols subspecies). Given there were a number of differences between the various disease tissue and normal tissue, we sought to reduce the study to a more manageable and informative comparison to allow identification of a potential biomarker. As genetic variation can influence lipid metabolism, we decided to focus on identifying significant differences in the concentrations of lipid species between HCC tissues and the same mouse surrounding hepatic tissues to eliminate genetic variation effects and provide a smaller subset to define an informative biomarker for HCC. HCC tissues, compared to surrounding hepatic tissues had 15 lipid molecular species with significantly different concentrations. All TAG and complex lipids species had significantly higher concentrations in HCC as compared to surrounding hepatic tissues, except for ether-linked lipids. Furthermore, three lipid species, phosphatidylethanolamine (36:1), phosphatidylserine (38:4), and TAG (16:0/18:0/18:1), may serve as potential biomarkers for HCC as they had significant different concentrations as compared to both normal tissues and surrounding hepatic tissues. We believe HCC development requires the buildup of the three specific lipid species. These findings, although preliminary, will provide data for further investigation and more complex statistical analysis to determine if additional biomarkers for other disease states prior to HCC can be identified to diagnose and/or treat HCC and pre-HCC diseases.

Keywords

Glycerophospholipid; Liver Cancer; Mass Spectrometry; Nonalcoholic fatty liver disease; Sphingolipids; Triacylglycerols

Disciplines

Biophysics | Nuclear

File Format

pdf

File Size

1629 KB

Degree Grantor

University of Nevada, Las Vegas

Language

English

Rights

IN COPYRIGHT. For more information about this rights statement, please visit http://rightsstatements.org/vocab/InC/1.0/

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