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Shrna-Targeted MAP4K4 Inhibits Hepatocellular Carcinoma Growth

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Shrna-Targeted MAP4K4 Inhibits Hepatocellular Carcinoma Growth Published OnlineFirst December 30, 2010; DOI: 10.1158/1078-0432.CCR-10-0331 Clinical Cancer Human Cancer Biology Research ShRNA-Targeted MAP4K4 Inhibits Hepatocellular Carcinoma Growth An-Wen Liu1,2, Jing Cai2, Xiang-Li Zhao1, Ting-Hui Jiang1, Tian-Feng He1, Hua-Qun Fu2, Ming-Hua Zhu3, and Shu-Hui Zhang1 Abstract Purpose: Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is overexpressed in many types of cancer. Herein, we aimed to investigate its expression pattern, clinical significance, and biological function in hepatocellular carcinoma (HCC). Experimental Design: MAP4K4 expression was examined in 20 fresh HCCs and corresponding nontumor liver tissues. Immunohistochemistry for MAP4K4 was performed on additional 400 HCCs, of which 305 (76%) were positive for hepatitis B surface antigens. The clinical significance of MAP4K4 expression was analyzed. MAP4K4 downregulation was performed in HCC cell lines HepG2 and Hep3B with high abundance of MAP4K4, and the effects of MAP4K4 silencing on cell proliferation in vitro and tumor growth in vivo were evaluated. Quantitative real-time PCR arrays were employed to identify the MAP4K4-regulated signaling pathways. Results: MAP4K4 was aberrantly overexpressed in HCCs relative to adjacent nontumor liver tissues. This overexpression was significantly associated with larger tumor size, increased histologic grade, advanced tumor stage, and intrahepatic metastasis, as well as worse overall survival and higher early recurrence rate. Knockdown of the MAP4K4 expression reduced cell proliferation, blocked cell cycle at S phase, and increased apoptosis. The antitumor effects of MAP4K4 silencing were also observed in vivo, manifested as retarded tumor xenograft growth. Furthermore, multiple tumor progression–related signaling pathways including JNK, NFkB, and toll-like receptors were repressed by MAP4K4 downregulation. Conclusions: MAP4K4 overexpression is an independent predictor of poor prognosis of HCC patients, and inhibition of its expression might be of therapeutic significance. Clin Cancer Res; 17(4); 710–20. Ó2010 AACR. Introduction diagnosed at the advanced stage in developing countries where regular tumor surveillance has not been implemen- Hepatocellular carcinoma (HCC) is the third leading ted and therefore precluded from the curative treatments. cause of cancer mortality worldwide, with more than For patients with advanced HCC, the multikinase inhibitor 600,000 new cases diagnosed annually (1). The most sorafenib is available as a systemic therapy, offering a frequent risk factors for HCC include chronic viral hepa- significant survival advantage (7, 8). Despite significant titis, alcohol abuse, and dietary exposure to aflatoxins progress, advanced HCC still remains incurable. The iden- (2–5). Early HCC is potentially curable by resection, liver tification of molecular markers and pathways that contri- transplantation, or percutaneous treatment, and 5-year bute to the aggressive phenotype of HCC is obviously survival rates of up to 60% to 70% can be achieved in essential for development of more effective, targeted well-selected patients (6). Unfortunately, most patients are therapies. Mitogen-activated protein kinases (MAPK) are a family of conserved serine/threonine protein kinases 1 Authors' Affiliations: Department of Pathology, Yueyang Hospital, that function to transmit extracellular signals into the Shanghai University of Traditional Chinese Medicine, Shanghai, China; 2Department of Oncology, Second Affiliated Hospital, Nanchang Univer- cytoplasm. The different MAPKs can be divided into 3 sity, Nanchang, China; and 3Department of Pathology, Changhai Hospital main subgroups, that is, the extracellular signal-regu- and Institute of Liver Diseases, Second Military Medical University, Shang- lated protein kinase (ERK), c-Jun N-terminal kinase/ hai, China stress-activated protein kinases (JNK/SAPK), and p38 Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). (9). MAPKs are commonly activated through phosphor- ylation cascades, and subsequently phosphorylate a A.W. Liu and J. Cai have contributed equally to this work. number of effectors that contribute to the regulation Corresponding Author: Shu-Hui Zhang, Department of Pathology, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, of diverse cellular events, including differentiation (10, No. 110 of Ganhe Road, Shanghai 200437, China. Phone: 86-021- 11), proliferation (12, 13), survival (14), migration 65161782; Fax: 86-021-65161782. E-mail: [email protected] (15), and invasion (16). MAPK kinase kinase kinase doi: 10.1158/1078-0432.CCR-10-0331 isoform 4 (MAP4K4), a germinal centre protein kinase Ó2010 American Association for Cancer Research. that belongs to the mammalian STE20/MAP4K family, is 710 Clin Cancer Res; 17(4) February 15, 2011 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst December 30, 2010; DOI: 10.1158/1078-0432.CCR-10-0331 MAP4K4 Silencing Inhibits HCC Growth Translational Relevance Quantitative reverse transcriptase polymerase chain reaction, Western blotting, and In this study, we showed that MAP4K4 is commonly immunohistochemistry upregulated in human hepatocellular carcinoma (HCC) Analysis of gene expression by quantitative reverse tran- specimens compared with adjacent nontumor liver scriptase polymerase chain reaction (qRT-PCR), Western tissues, and this upregulation is significantly associated blotting, and immunohistochemistry were conducted with tumor size, tumor grade, and intrahepatic metas- using standard procedures detailed in Supplementary tasis. Survival analyses have shown that high MAP4K4 Methods. expression serves as an independent predictor of poor prognosis in HCC patients. Downregulation of Patient cohorts MAP4K4 using RNA interference in HCC cell lines, The study protocol was approved by the Ethics Commit- HepG2 and Hep3B, significantly decreased cell prolif- tee of Second Military Medical University (Shanghai, eration and increased apoptosis. Moreover, MAP4K4 China), and written informed consent was obtained from silencing inhibited xenograft tumor growth in athymic each patient. Tumor samples from resection specimens nude mice. These findings suggest that MAP4K4 may were collected from 2 consecutive cohorts of patients with represent a potential therapeutic target for controlling HCC, who underwent surgical resection for the disease at HCC growth. Changhai Hospital and Institute of Liver Diseases (Shang- hai, China) between August 2007 and October 2008 for cohort A and between January 2001 and December 2002 for cohort B. The patients of both cohorts were selected on implicated in the activation of the JNK/SAPK pathway the basis of (a) distinctive pathologic diagnosis of HCC, (b) (17, 18). Recent studies (17, 19) have documented that receiving curative resection, defined as macroscopically MAP4K4 is overexpressed in many types of human complete removal of the neoplasm, and (c) availability cancer. The prognostic significance of MAP4K4 over- of detailed clinicopathologic data. Patients with preopera- expression has been shown in patients with stage II tive anticancer treatment or with evidence of other malig- pancreatic ductal adenocarcinoma (19). Silencing of nancies were excluded from the study. Cohort A consisted MAP4K4 using small interfering RNAs (siRNA) causes of 20 patients (14 men and 6 women; median age, 51 years; reduced tumor cell motility in ovarian carcinoma- range, 29–76 years), from whom fresh tumor samples derived cell line, SKOV-3 (17). These findings suggest coupled with adjacent nontumor liver tissues were an involvement of MAP4K4 in cancer progression. obtained for analysis of MAP4K4 gene expression. After However, little is known about its expression pattern, removal at surgery, all the fresh tissues were cut into small clinical relevance, and biological function in HCC. pieces, snap frozen in liquid nitrogen immediately, and Here, we showed that MAP4K4 is frequently overex- stored at À80C until RNA or protein extraction. Cohort B pressed in HCC tissues as well as several HCC cell lines comprised 400 patients (286 men and 114 women; med- including HepG2 and Hep3B, and that this upregulation ian age, 50 years; range, 27–78 years), whose paraffin- is significantly associated with worse prognosis of HCC embedded tumor specimens were available at the surgical patients. Short hairpin RNA (shRNA)-mediated silencing pathology archive of Changhai Hospital, allowing for of the MAP4K4 in HepG2 and Hep3B cells decreased cell immunohistochemical analysis. proliferation, blocked cell cycle progression at S phase, The clinicopathologic characteristics of both the study and increased spontaneous apoptosis. In vivo studies cohorts are summarized in Supplementary Table S1. In the further showed that MAP4K4 silencing dramatically following text, we focus on the description of the patients retarded xenograft tumor growth in nude mice. Using a of cohort B, who were selected for further elucidation of the quantitative real-time array, we found that the antitumor clinical significance of MAP4K4 expression. Of the 400 effects of MAP4K4 downregulation were likely associated studied patients, 305 (76%) and 245 (61%) patients were with the inactivation of multiple tumor progression– positive for hepatitis B surface antigens (HBsAg) and hepa- related signaling pathways, including JNK,
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