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The Tumor Suppressor Function of LECT2 in Human Hepatocellular Carcinoma Makes It a Potential Therapeutic Target

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The Tumor Suppressor Function of LECT2 in Human Hepatocellular Carcinoma Makes It a Potential Therapeutic Target Cancer Gene Therapy (2011) 18, 399–406 r 2011 Nature America, Inc. All rights reserved 0929-1903/11 www.nature.com/cgt ORIGINAL ARTICLE The tumor suppressor function of LECT2 in human hepatocellular carcinoma makes it a potential therapeutic target HT Ong1, PK Tan1, SM Wang1, DT Hian Low1, LL PJ Ooi2 and KM Hui1 1Bek Chai Heah Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, Singapore, Singapore and 2Division of Surgical Oncology, National Cancer Centre, Singapore, Singapore Vascular invasion is one of the clinicopathologic features that are associated with early recurrence of human hepatocellular carcinoma (HCC). In this study, we have employed high-density Affymetrix oligonucleotide GeneChips (Affymetrix, Santa Clara, CA) to compare the expression profiles of HCC with and without vascular invasion. Data mining of the gene expression database established revealed that leukocyte cell-derived chemotaxin-2 (LECT2) transcripts were downregulated in HCC patients with vascular invasion. Expression of LECT2 in human HCC biopsies was significantly reduced (Po0.0001, fold change ¼À7.2) when compared with non-tumorous adjacent liver tissues. The reduction of LECT2 expression was significantly correlated with the early recurrent and poor prognosis of the patient (P ¼ 0.024). To validate the ability of LECT2 to repress the growth of HCC, an adenoviral vector encoding the secreted human LECT2 (AdLECT2) was introduced into the human HCC cell lines Hep3B and PLC/PRF/5, which do not express endogenous LECT2. Over-expression of LECT2 resulted in the significant inhibition of in vitro migration and invasion of the AdLECT2-transfected HCC cells. Additionally, over-expression of AdLECT2 in subcutaneous Hep3B tumor xenografts in athymic nude mice resulted in significant inhibition of tumor growth (Po0.05). In summary, our data not only demonstrated that LECT2 is a candidate prognostic marker of human HCC, but also that therapeutic strategies targeting LECT2 expression is a promising therapy for human HCC. Cancer Gene Therapy (2011) 18, 399–406; doi:10.1038/cgt.2011.5; published online 11 March 2011 Keywords: adenovirus-mediated gene therapy; human hepatocellular carcinoma (HCC); leukocyte cell-derived chemotaxin-2 (LECT2); tumor invasion and metastasis 6–10 Introduction survival. Data-mining studies of a gene expression database that we have established earlier for Hepatitis B 9 Hepatocellular carcinoma (HCC) is the most common virus þ HCC patients revealed that the transcripts of primary malignancy of liver and exhibits a broad the leukocyte cell-derived chemotaxin-2 (LECT2) gene spectrum of clinical behaviors, with considerable mole- were specifically downregulated in the subgroup of HCC cular heterogeneity in tumor development and progres- patients presented with vascular invasion at diagnosis. sion.1 HCC is a difficult disease to manage clinically, LECT2 is a multi-functional protein that involves in and surgical resection and liver transplantation provide chemotaxis, cell proliferation, inflammation, immuno- 11–17 the best options for cure in selected patients.2,3 However, modulation and carcinogenesis. It was originally the long-term clinical outcome for HCC following tumor identified as a novel neutrophil-chemotactic protein by 17 resection and liver transplantation remains unsatisfactory Yamagoe et al. in 1996. LECT2 is a 16-kDa protein that because of the high tumor-recurrence rate.4,5 Although consists of 133 amino acids and three intra-molecular 18,19 various clinicopathologic variables have been described disulfide bonds. The human LECT2 gene consists of 19 as predictive of post-transplant recurrence, the exact four exons and three introns. It has been mapped to molecular mechanism(s) underlying HCC recurrence are chromosome 5q31.1-q32, a cluster harboring several genes still poorly understood. Vascular invasion is one of encoding immuno-regulatory cytokines. These include the clinicopathologic features reported to be strongly interleukin (IL)-3, IL-4, granulocyte macrophage-colony 19 associated with the duration of tumor recurrence and stimulating factor and IL-5. Subsequently, LECT2 has been shown to be synthesized by human hepatocytes20,21 and most hepatocytes show diffuse immune-staining for Correspondence: Dr KM Hui, Division of Cellular and Molecular LECT2 16,20 Research, National Cancer Centre Singapore, 11 Hospital Drive, within the cytoplasm. Singapore, 169610, Singapore. LECT2 is involved in many pathologic conditions. E-mail: [email protected] Recently, LECT2 has been identified as one of the 22,23 Received 18 May 2010; revised 4 October 2010; accepted 26 proteins associated with human systemic amyloidosis. November 2010; published online 11 March 2011 LECT2 amyloid was discovered in a patient who had LECT2 inhibits growth of human HCC cells HT Ong et al 400 nephritic syndrome and slowly progressive renal failure (Affymetrix, Santa Clara, CA) as per the manufacturer’s over a number of years.22 However, clinical and instructions. The HCC profiling data sets can be obtained pathological features of earlier phases of this type of using E-MEXP-84 and E-TABM-292 at ArrayExpress, amyloidosis have yet to be determined. Kameoka et al.11 European Bioinformatics Institutes of the European reported a polymorphism of the human LECT2 gene in Molecular Biology Laboratory.9 the Japanese population associated with a severe form of rheumatoid arthritis that leads to progressive joint Real-time PCR destruction. Using the concanavalin A-induced hepatic HCC specimens with and without vascular invasion were injury model, Segawa et al.15 reported that LECT2 expres- selected randomly and subjected to real-time PCR sion in the mouse liver was inversely regulated by TNF-a amplification. Each sample was amplified in duplicates and/or IFN-g. Saito et al.14 observed severe liver injury in using Rotor-Gene 2000 Real Time Cycler (Corbett LECT2À/À knockout mice compared with wild-type mice, Research, Mortlake, VIC, Australia). Gene expression following treatment with concanavalin A and correlated was normalized against the corresponding 18S mRNA with the significant increase of natural killer T cells in the expression level. liver of the LECT2À/À knockout mice. These authors concluded that the increase of hepatic natural killer T cells Adenoviral vector expressing recombinant could result from the excessive expression of IL-4 and Fas human LECT2 ligand in these mice, suggesting that LECT2 might All adenovirus vectors used in this study were replication regulate the homeostasis of natural killer T cells in the deficient (E1/E3 deleted) and based on the serotype-5 liver.14 Using immunohistochemistry, Uchida et al.16 adenovirus genome.26 The cDNA of human LECT2 or demonstrated the reduction in LECT2 expression with firefly luciferase were cloned into a transfer plasmid, with the progression of hepatocarcinogenesis and its expres- expression driven by an human cytomegalovirus immediate sion was abrogated in malignant HCC cells. Despite these early gene region promoter/enhancer, and mRNA stability observations, the direct function of LECT2 in hepato- and polyadenylation directed by a rabbit b-globin intron/ carcinogenesis has not been well studied and its role in polyadenylation signal. The expression cassettes were intro- vascular invasion of human HCC has not been reported. duced into a bacterial plasmid-borne adenovirus genome, In this study, we showed that re-expression of LECT2 using a recombination in bacteria.27,28 The resulting adeno- significantly reduced the migration and invasion of virus genomes (AdLECT2 and AdLuc) were linearized with human HCC cells in vitro and significantly reduced their SpeI enzyme, transfected into E1-complementing human growth in vivo. embryonic kidney 293 cells and were maintained in Dulbecco’s modified Eagle’s medium (DMEM) (Invitro- gen, Grand Island, NY) until a cytophathic effect was apparent 5–7d post-transfection. Cells were collected and Materials and methods subjected to four freeze/thaw cycles. The supernatant was Patients and tissue specimens stored at À80 1C as crude viral lysate. An inoculum was Human HCC tissues and some of the corresponding distal added to 293 cells and the cycle was repeated three times noncancerous liver tissues were obtained from patients to amplify the virus. The resulting recombinant Ad who had undergone partial hepatectomy at the National vectors were propagated in 293 cells and purified using Cancer Centre, Singapore, with informed consent and AdenoPACK (Sartorius Stedium Biotech, Epsom, UK). conducted in accordance with the policies of the Institu- Vector stocks were frozen at À80 1C until use. Quantifica- tional Review Board. This study consisted of specimens tion of viruses was based on protein content,29 using the from vascular invasive (N ¼ 29) and non-invasive (N ¼ 51) conversion 1 mg of viral protein ¼ 3.4  1012 viral parti- HCC. As a control, histologically normal liver tissues cles (vp).30 Typical vector stock titers were 1012vp/ml with (NN) from colorectal patients with liver metastases a 1:100 infectious plaque forming unit to vector particle (N ¼ 10) and distal histologically normal surrounding ratio. tissues (ST) of HCC patients (N ¼ 27) were included in the analyses. Immediately after surgical resection, tissues were Cell culture and virus transduction snap-frozen and stored in liquid nitrogen. Frozen sections Human HCC cell lines Hep3B and PLC/PRF/5 were of all tumor samples studied were evaluated
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