3 In relation
to their implication selleck products in carcinogenesis, less is known for PLK2, PLK3, and PKL4. A recent paper indicated that PLK2 is down-regulated by promoter hypermethylation in primary lymphomas and its overexpression in B cells lymphomas leads to apoptosis, suggesting that PLK2 act as a bona fide tumor suppressor gene.17 PLK3 expression has been also reported to diminish in some human tumors and it could contribute to generation of genetic instability, due to its role in the DNA damage response machinery.4 The antineoplastic function of PLK3 has been further substantiated by the observation that PLK3-deficient mice spontaneously develop tumors in various organs, including the liver.18 Recent evidence suggests a role for PLK4 as a tumor suppressor in hepatocarcinogenesis, becuase mice heterozygous for PLK4 (PLK4+/−) spontaneously develop liver and lung tumors.19 However, no comprehensive analysis Nutlin-3 ic50 on PLK proteins has been performed in human HCC to date. In this study, we investigated the status and the role of PLK proteins in
a collection of human HCC as well as the molecular mechanisms responsible for modification of PLK levels in liver cancer. Our results indicate a deregulation of the four PLKs in human HCC, suggesting an oncogenic role for PLK1 and a tumor-suppressive function of PLK2,
PLK3, and 4 in human hepatocarcinogenesis. Org 27569 FOXM1, forkhead box M1; HCC, hepatocellular carcinoma; HCCB, hepatocellular carcinoma with better outcome; HCCP, hepatocellular carcinoma with poorer survival; LOH, loss of heterozygosity; mRNA, messenger RNA; PLK, polo-like kinase; siRNA, small interfering RNA; SL, surrounding nontumorous liver. Six normal livers, 75 HCCs, and corresponding surrounding nontumorous liver tissues (SL) were used. Normal (disease-free) livers were from autopsy cases of healthy Caucasian individuals. Tumors were divided in HCC with shorter/poor survival (HCCP; n = 40) and longer/better survival (HCCB; n = 35), characterized by <3 and >3 years’ survival following partial liver resection, respectively.20 Patient features are reported in Supporting Table 1. Liver tissues were kindly provided by Snorri S. Thorgeirsson (National Cancer Institute, Bethesda, MD). Institutional Review Board approval was obtained from participating hospitals and the National Institutes of Health. Human HCC cell lines (HepG2, HuH7, PLC, Hep3B, SNU-387, SNU-423, HLE, HuH6, SK-Hep1, and THLE-2), purchased from either the American Type Culture Collection or the Riken Cell Bank, were subjected to either small interfering RNA (siRNA) or demethylating treatments as reported in the Supporting Information.