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Oncogenomics Oncogene (2004) 23, 2401–2407 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines Manabu Wada1, Shujiro Yazumi1, Shigeo Takaishi1, Kazunori Hasegawa1, Mitsutaka Sawada1, Hidenori Tanaka1, Hiroshi Ida1,2, Chouhei Sakakura3, Kosei Ito2, Yoshiaki Ito2 and Tsutomu Chiba*,1 1Department of Gastroenterology and Hepatology, Graduate School of Internal Medicine, Kyoto University, Kyoto 606-8507, Japan; 2Institute of Molecular and Cell Biology and Oncology Research Institute, National University of Singapore, 30 Medical Drive, Singapore 117609, Singapore; 3Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan RUNX3, a Runt domain transcription factor involved in Introduction TGF-b signaling, is a candidate tumor-suppressor gene localized in 1p36, a region commonlydeleted in a wide Pancreatic and bile duct carcinomas, respectively, are varietyof human tumors, including those of the stomach, the fifth and the seventh leading causes of cancer deaths bile duct, and pancreas. Recently, frequent inactivation of in Japan. Their prognosis has not changed significantly RUNX3 has been demonstrated in human gastric in recent years, despite improvements in diagnosis and carcinomas. In this study, to examine the involvement of treatment. Traditional chemotherapy and radiotherapy RUNX3 abnormalities in tumorigenesis of bile duct as regimens have proved to be largely ineffective (Schnall well as pancreatic cancers, we investigated not onlythe and Macdonald, 1996). At present, surgical resection is expression but also methylation status of RUNX3 in 10 the best treatment option for early-stage tumors of the human bile duct and 12 pancreatic cancer cell lines. Seven bile duct and pancreas. Unfortunately, however, most (70%) of the bile duct and nine (75%) of the pancreatic bile duct and pancreatic tumors have usually invaded cancer cell lines exhibited no expression of RUNX3 by regional lymph nodes and have metastasized beyond both Northern blot analysis and the reverse transcriptase those nodes by the time they are diagnosed, making polymerase chain reaction. All of the 16 cell lines that did curative resection difficult. For this reason, further not express RUNX3 also showed methylation of the clarification of the mechanisms of the carcinogenesis of promoter CpG island of the gene, whereas the six cell lines bile duct and pancreatic tumors is required. that showed RUNX3 expression were not methylated or Multiple tumor-suppressor pathways are known to be onlypartiallymethylatedin the RUNX3 promoter region. abrogated in bile duct and pancreatic carcinomas. For Moreover, treatment with the methylation inhibitor 50- example, the Rb/p16 pathway is disrupted in more than aza-20-deoxycitidine activated RUNX3 mRNA expression 95% of pancreatic carcinomas, and p53 is frequently in all of 16 cancer cell lines that originallylacked RUNX3 inactivated in both bile duct and pancreatic carcinomas expression. Finally, hemizygous deletion of RUNX3,as (Goggins et al., 1999). In addition, Smad4 has also been detected byfluorescence in situ hybridization, was found in found to be inactivated in more than 50% of pancreatic 15 of the 16 cancer cell lines that lacked RUNX3 carcinomas (Yoshida et al., 1995; Schutte et al., 1997; expression. These data suggest that the inactivation of Goggins et al., 1999), and abnormalities of either Smad4 RUNX3 plays an important role in bile duct and or TGF-b receptor II (TbR-II) are often present in pancreatic carcinogenesis, and that methylation is a human bile duct cancer cell lines (Yazumi et al., 2000). common mechanism bywhich the gene is inactivated. Therefore, disregulation of the TGF-b/Smad signaling Oncogene (2004) 23, 2401–2407. doi:10.1038/sj.onc.1207395 pathway apparently plays an important role in the Published online 26 January 2004 pathogenesis of both pancreatic and bile duct carcino- mas. ONCOGENOMICS Keywords: RUNX3; bile duct cancer; pancreatic cancer; The human runt-related (RUNX) genes encode the a methylation subunit of the Runt domain transcription factor PEBP2/ CBF (Ito, 1999), and are homologues to the Drosophila genes runt (Kania et al., 1990) and lozenge (Daga et al., 1996). The mammalian and Drosophila genes share an evolutionarily conserved region of 128 amino acids, termed the Runt domain, that is required for DNA binding and heterodimerization with the b subunit PEBP2b/CBFb (Ito, 1999). RUNX3 belongs to the *Correspondence: T Chiba; E-mail: [email protected] Runt domain family, which includes RUNX1 and Received 4 August 2003; revised 16 November 2003; accepted 20 RUNX2. All the three genes are master regulators of November 2003 gene expression in major developmental pathways. Loss of RUNX3 in bile duct and pancreatic cancer M Wada et al 2402 Interestingly, in primary cultures of RUNX3-null gastric Table 1 mRNA expression, methylation, and hemizygous deletion of epithelial cells, the cells were less sensitive to TGF-b- RUNX3 in human bile duct and pancreatic cancer cell lines induced growth inhibition and apoptosis (Li et al., RUNX3 2002). Furthermore, RUNX3 protein has been found to bind the Smad2 and Smad3 proteins (Hanai et al., 1999). Cell lines Expression Methylation Reactivation Hemizygous These data suggest a possible role for RUNX3 in deletion transducing TGF-b signaling. Bile duct cancers Recently, Li et al. (2002) demonstrated that Runx3- Mz-ChA-1 + P NE À null mice develop hyperplasia of the gastric mucosa KMBC + U NE + through activation of cellular proliferation and suppres- TGBC24TKB + U NE + RBE À M+ + sion of apoptosis in epithelial cells. They also found that SK-ChA-1 À M+ + 47% of human gastric cancer cell lines lost expression of Mz-ChA-2 À M+ + RUNX3 through a combination of hemizygous deletion TGBC1TKB À M+ + of 1p36 and methylation of the RUNX3 promoter region TGBC2TKB À M+ + HuCCT1 À M+ + (Li et al., 2002). Interestingly, 1p36, where RUNX3 TFK-1 À M+ + maps to (Bae et al., 1995), is a region commonly deleted in a wide variety of human carcinomas, including those Pancreas cancers of the bile duct and pancreas (Weith et al., 1996; Kang AsPC1 + P NE À et al., 2000; Schleger et al., 2000). In the present study, T3M4 + P NE À KLM-1 + U NE + therefore, to elucidate the roles of RUNX3 in carcino- BxPC3 À M+ À genesis of the bile duct and pancreas, we examined not PK59 À M+ + only the expression but also the methylation status of PK1 À M+ + RUNX3 in human bile duct and pancreatic cancer cell PK8 À M+ + Kp4-1 À M+ + lines. PK-45H À M+ + PK-45P À M+ + MiaPaca2 À M+ + PK9 À M+ + Results 1C3D3 + U NE À Frequent loss of RUNX3 expression U, unmethylated; P, partially methylated; M, methylated; NE, not The expression of RUNX3 mRNA was examined in 10 examined; +, positive; À, negative bile duct and 12 pancreatic cancer cell lines by Northern blot analysis. Of the 22 cancer cell lines tested, seven (70%) bile duct and nine (75%) pancreatic cell lines did of the RUNX3 promotor CpG island, and three (Mz- not express RUNX3 mRNA (Table 1). Representative ChA-1, AsPC1, and T3M4) exhibited only partial results of Northern blot analysis are shown in Figure 1a. methylation of the RUNX3 promoter region. Sequence The results of the RT–PCR analysis were consistent analysis of each PCR product revealed that the cell lines with those of the Northern blot analysis (Figure 1b, that exhibited methylation of the RUNX3 promoter Table 1). On the other hand, both the human embryonic CpG islands possessed only a methylated allele, whereas pancreas-derived cell line 1C3D3 and all the four those that showed no methylation of the RUNX3 samples of normal biliary mucosa tested expressed promoter region had only an unmethylated allele. RUNX3 mRNA (Figure 1). Moreover, three cell lines (Mz-ChA-1, AsPC1, and T3M4) that exhibited partial methylation of the RUNX3 DNA methylation of the exon 1 region of RUNX3 promoter region had both methylated and unmethylated alleles (Figure 2). The human embryonic pancreas- The pattern of DNA methylation is often altered in derived cell line 1C3D3 had no methylation of RUNX3 cancer cells. Growing evidence suggests that aberrant promotor CpG island, and normal biliary mucosa DNA methylation of CpG islands around the promoter exhibited partial methylation of the RUNX3 promoter regions can have the same effect on the inactivation of region (Figure 2). tumor-suppressor genes as do mutations in the coding regions. The observation that the RUNX3 gene promo- Reactivation of RUNX3 expression ter consists of a CpG island suggests that DNA methylation may play a role in inhibiting RUNX3 Reactivation of RUNX3 was attempted in the 16 cancer expression. To study DNA methylation in the RUNX3 cell lines in which expression of the gene could not be gene promoter, genomic DNA was isolated, treated with detected with either Northern blot analysis or RT–PCR sodium bisulfite, and analysed by using MSP. As shown by incubating the cell lines with AZA alone, trichostatin in Figure 2 and Table 1, all 16 cancer cell lines that did A (TSA) alone, or AZA plus TSA. Representative not express RUNX3 had methylation of RUNX3 results of RT–PCR performed after incubation are promotor CpG island. In contrast, of the six cell lines shown in Figure 3. Incubation with TSA only reacti- that had RUNX3 gene expression, three (KMBC, vated the expression of RUNX3 in nine of the 16 cancer TGBC24TKB, and KLM-1) exhibited no methylation cell lines, whereas incubation with AZA alone or with Oncogene Loss of RUNX3 in bile duct and pancreatic cancer M Wada et al 2403 Figure 1 Expression of RUNX3 mRNA in bile duct and pancreatic cancer cell lines. (a) Northern blot analysis of mRNA (5 mg) from each cell line was performed by using the 32P-labeled Figure 2 MSP analysis of RUNX3 in bile duct and pancreatic RUNX3-specific probe and the GAPDH-specific probe.
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