Reduced expression of low-density lipoprotein receptor in hepatocellular carcinoma with paraneoplastic hypercholesterolemia.
OBJECTIVE
Hepatocellular carcinoma (HCC) is frequently associated with paraneoplastic hypercholesterolemia. In familial hypercholesterolemia, genetic mutation of the low-density lipoprotein (LDL) receptor gene has been recognized as being a pathogenesis of the disease. We investigate the expression of a LDL receptor protein and gene abnormalities of a LDL receptor in HCC cells in cases with paraneoplastic hypercholesterolemia.


METHODS
Eleven patients with HCC associated with paraneoplastic hypercholesterolemia and seven patients with HCC who did not have hypercholesterolemia were studied. Paraffin-embedded tissues were obtained at operative resection, autopsy, or biopsy. Immunohistochemistry was performed using a monoclonal antibody against human LDL receptors. Confocal laser-scanning microscopy was used to observe the FITC-labeled LDL receptor. DNA samples were extracted from paraffin-embedded tissues. Since a LDL receptor gene is located on chromosome 19p13.2, a microsatellite marker, D19S413, was used to analyze the chromosomes.


RESULTS
Immunoreactive LDL receptors were observed all over the surface of non-tumorous hepatocytes. However, expression of the LDL receptor was significantly decreased in all HCC cells derived from the 11 patients with hypercholesterolemia. In contrast, the expression was retained in the HCC cells of all patients without hypercholesterolemia. In two patients with hypercholesterolemia, DNA analysis revealed a loss of heterozygosity on chromosome 19p13.2.


CONCLUSIONS
We demonstrated reduced expression of the LDL receptor in HCC cases with paraneoplastic hypercholesterolemia. LDL receptor genes with genomic disorders may cause decreased expression of the LDL receptor protein, leading to feed-back failure of the cholesterol regulation system, as seen in familial hypercholesterolemia. This is the first report considering the mechanism behind the development of paraneoplastic hypercholesterolemia in HCC.
Sohda
Tetsuro
T
Department of Gastroenterology and Medicine, Fukuoka University School of Medicine, Fukuoka, Japan. tetsuro@fukuoka-u.ac.jp
Iwata
Kaoru
K
Kitamura
Yuji
Y
Suzuki
Norihisa
N
Takeyama
Yasuaki
Y
Irie
Makoto
M
Anan
Akira
A
Nakane
Hidetoshi
H
Yoshikane
Makoto
M
Watanabe
Hiroshi
H
Sakisaka
Shotaro
S
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D002888:Chromosomes, Human, Pair 19; D002895:Chromosomes, Human, Pair 5; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010257:Paraneoplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000032:analysis* / Q000235:genetics