title: Preclinical trials for prevention of tumor progression of hepatocellular carcinoma by LZ-8 targeting c-Met dependent and independent pathways.
abstract: Hepatocellular carcinoma (HCC) is among the most lethal cancers. Mounting studies highlighted the essential role of the HGF/c-MET axis in driving HCC tumor progression. Therefore, c-Met is a potential therapeutic target for HCC. However, several concerns remain unresolved in c-Met targeting. First, the status of active c-Met in HCC must be screened to determine patients suitable for therapy. Second, resistance and side effects have been observed frequently when using conventional c-Met inhibitors. Thus, a preclinical system for screening the status of c-Met signaling and identifying efficient and safe anti-HCC agents is urgently required. In this study, immunohistochemical staining of phosphorylated c-Met (Tyr1234) on tissue sections indicated that HCCs with positive c-Met signaling accounted for approximately 46% in 26 cases. Second, many patient-derived HCC cell lines were established and characterized according to motility and c-Met signaling status. Moreover, LZ8, a medicinal peptide purified from the herb Lingzhi, featuring immunomodulatory and anticancer properties, was capable of suppressing cell migration and slightly reducing the survival rate of both c-Met positive and negative HCCs, HCC372, and HCC329, respectively. LZ8 also suppressed the intrahepatic metastasis of HCC329 in SCID mice. On the molecular level, LZ8 suppressed the expression of c-Met and phosphorylation of c-Met, ERK and AKT in HCC372, and suppressed the phosphorylation of JNK, ERK, and AKT in HCC329. According to receptor array screening, the major receptor tyrosine kinase activated in HCC329 was found to be the epidermal growth factor receptor (EGFR). Moreover, tyrosine-phosphorylated EGFR (the active EGFR) was greatly suppressed in HCC329 by LZ8 treatment. In addition, LZ8 blocked HGF-induced cell migration and c-Met-dependent signaling in HepG2. In summary, we designed a preclinical trial using LZ8 to prevent the tumor progression of patient-derived HCCs with c-Met-positive or -negative signaling.
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualein, Taiwan.
authors.forename: Jia-Ru
authors.initials: JR
authors.lastname: Wu
authors.affiliation: Research Centre for Hepatology, Buddhist Tzu Chi General Hospital and Department of Internal Medicine Tzu Chi University, Hualien, Taiwan.
authors.forename: Chi-Tan
authors.initials: CT
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualein, Taiwan.
authors.forename: Ren-In
authors.initials: RI
authors.lastname: You
authors.affiliation: Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualein, Taiwan.
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Ma
authors.affiliation: Research Centre for Hepatology, Buddhist Tzu Chi General Hospital and Department of Internal Medicine Tzu Chi University, Hualien, Taiwan.
authors.forename: Siou-Mei
authors.initials: SM
authors.lastname: Pan
authors.affiliation: Department of Surgery, Buddhist Tzu Chi General Hospital, School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ming-Che
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Institute of Medical Sciences, Tzu Chi University, Hualein, Taiwan; Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualein, Taiwan.
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Wu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005656:Fungal Proteins / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D005656:Fungal Proteins; C061148:LZ-8 protein, Ganoderma lucidum; D019859:Proto-Oncogene Proteins c-met