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  • Original Paper
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Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma

Abstract

Using microarrays, we have screened for genes reactivated by drugs that modify epigenetic mechanisms in pancreatic cancer cells. One of the genes identified was tissue factor pathway inhibitor 2 (TFPI-2), which encodes for a broad-spectrum serine proteinase inhibitor that negatively regulates the extracellular matrix degradation, an essential step in tumor invasion and metastasis. We therefore investigated the expression and methylation patterns of the TFPI-2 gene in pancreatic adenocarcinoma, and determined its role in tumor growth and invasion. In contrast to its abundant expression in normal pancreas, TFPI-2 mRNA was undetectable in a high fraction of pancreatic cancer cell lines and in primary pancreatic ductal neoplasms (IPMNs). Loss of TFPI-2 expression was associated with aberrant hypermethylation of its promoter CpG island. Treatment with the phorbol ester (PMA), known to stimulate the TFPI-2 promoter activity, augmented the TFPI-2 expression in cell lines with unmethylated or partially methylated TFPI-2, but failed to induce the expression in cell lines that harbored fully methylated TFPI-2. Aberrant methylation of TFPI-2 was also detected in 73% (102/140) of pancreatic cancer xenografts and primary pancreatic adenocarcinomas, was more likely in older patients with pancreatic cancer, and significantly correlated with progression of IPMNs (P=0.0002). Restored expression of the TFPI-2 gene in nonexpressing pancreatic cancer cells resulted in marked suppression in their proliferation, migration, and invasive potential in vitro. We thus conclude that epigenetic inactivation of TFPI-2 is a common mechanism that contributes to the aggressive phenotype of pancreatic ductal adenocarcinoma.

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Abbreviations

TFPI-2:

tissue factor pathway inhibitor 2

5Aza-dC:

5-aza-2′-deoxycytidine

TSA:

trichostatin A

RT–PCR:

reverse transcription–PCR

MSP:

methylation-specific PCR

IPMN:

intraductal papillary mucinous neoplasm

PMA:

phorbol 12-myristate-13-acetate

References

  • Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, Kinzler KW and Vogelstein B . (2003). Cancer Cell, 3, 89–95.

  • Brinckerhoff CE and Matrisian LM . (2002). Nat. Rev. Mol. Cell. Biol., 3, 207–214.

  • Chand HS, Du X, Ma D, Inzunza HD, Kamei S, Foster D, Brodie S and Kisiel W . (2004). Blood, 103, 1069–1077.

  • Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S and Pelicci PG . (2002). Science, 295, 1079–1082.

  • DiMagno EP, Reber HA and Tempero MA . (1999). Gastroenterology, 117, 1464–1484.

  • Ellenrieder V, Adler G and Gress TM . (1999). Ann. Oncol., 10, 46–50.

  • Evron E, Dooley WC, Umbricht CB, Rosenthal D, Sacchi N, Gabrielson E, Soito AB, Hung DT, Ljung B, Davidson NE and Sukumar S . (2001). Lancet, 357, 1335–1336.

  • Fukushima N, Walter KM, Uek T, Sato N, Matsubayashi H, Cameron JL, Hruban RH, Canto M, Yeo CJ and Goggins M . (2003). Cancer Biol. Ther., 2, 78–83.

  • Hahn SA, Seymour AB, Hoque AT, Schutte M, da Costa LT, Redston MS, Caldas C, Weinstein CL, Fischer A, Yeo CJ, Hruban RH and Kern SE . (1995). Cancer Res., 55, 4670–4675.

  • Harden SV, Sanderson H, Goodman SN, Partin AA, Walsh PC, Epstein JI and Sidransky D . (2003). J. Natl. Cancer Inst., 95, 1634–1637.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.

  • Hube F, Reverdiau P, Iochmann S, Rollin J, Cherpi-Antar C and Gruel Y . (2003). Biol. Chem., 384, 1029–1034.

  • Iacobuzio-Donahue CA, van der Heijden MS, Baumgartner MR, Troup WJ, Romm JM, Doheny K, Pugh E, Yeo CJ, Cameron JL, Goggins MG, Hruban RH and Kern SE . (2004). Cancer Res., 64, 871–875.

  • Izumi H, Takahashi C, Oh J and Noda M . (2000). FEBS Lett., 481, 31–36.

  • Jemal A, Murray T, Samuels A, Ghafoor A, Ward E and Thun MJ . (2003). CA Cancer J. Clin., 53, 5–26.

  • Jin M, Udagawa K, Miyagi E, Nakazawa T, Hirahara F, Yasumitsu H, Miyazaki K, Nagashima Y, Aoki I and Miyagi Y . (2001). Gynecol. Oncol., 83, 325–333.

  • Kast C, Wang M and Whiteway M . (2003). J. Biol. Chem., 278, 6787–6794.

  • Kern SE . (2000). Med. Clin. N Am., 84, 691–695.

  • Konduri SD, Osman FA, Rao CN, Srinivas H, Yanamandra N, Tasiou A, Dinh DH, Olivero WC, Gujrati M, Foster DC, Kisiel W, Kouraklis G and Rao JS . (2002). Oncogene, 21, 921–928.

  • Konduri SD, Rao CN, Chandrasekar N, Tasiou A, Mohanam S, Kin Y, Lakka SS, Dinh D, Olivero WC, Gujrati M, Foster DC, Kisiel W and Rao JS . (2001). Oncogene, 20, 6938–6945.

  • Konduri SD, Srivenugopal KS, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Foster DC, Kisiel W, Ali-Osman F, Kondraganti S, Lakka SS and Rao JS . (2003). Oncogene, 22, 4509–4516.

  • Miyagi Y, Koshikawa N, Yasumitsu H, Miyagi E, Hirahara F, Aoki I, Misugi K, Umeda M and Miyazaki K . (1994). J. Biochem. (Tokyo), 116, 939–942.

  • Miyagi Y, Yasumitsu H, Eki T, Miyata S, Kkawa N, Hirahara F, Aoki I, Misugi K and Miyazaki K . (1996). Genomics, 35, 267–268.

  • Paciucci R, Tora M, Diaz VM and Real FX . (1998). Oncogene, 16, 625–633.

  • Petersen LC, Sprecher CA, Foster DC, Blumberg H, Hamamoto T and Kisiel W . (1996). Biochemistry, 35, 266–272.

  • Rao CN, Cook B, Liu Y, Chilukuri K, Stack MS, Foster DC, Kisiel W and Woodley DT . (1998). Int. J. Cancer, 76, 749–756.

  • Rao CN, Lakka SS, Kin Y, Konduri SD, Fuller GN, Mohanam S and Rao JS . (2001). Clin. Cancer Res., 7, 570–576.

  • Rao CN, Liu YY, Peavey CL and Woodley DT . (1995). Arch. Biochem. Biophys., 317, 311–314.

  • Rao CN, Segawa T, Navari JR, Xu L, Srivastava S, Moul JW and Phillips B . (2003). Int. J. Oncol., 22, 843–848.

  • Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, Cui H, Feinberg AP, Lengauer C, Kinzler KW, Baylin SB and Vogelstein B . (2002). Nature, 416, 552–556.

  • Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A and MacLeod AR . (2003). Nat. Genet., 33, 61–65.

  • Sato N, Fukushima N, Maitra A, Matsubayashi H, Yeo CJ, Cameron JL, Hruban RH and Goggins M . (2003a). Cancer Res., 63, 3735–3742.

  • Sato N, Maehara N, Su GH and Goggins M . (2003b). J. Natl. Cancer Inst., 95, 327–330.

  • Shinoda E, Yui Y, Hattori R, Tanaka M, Inoue R, Aoyama T, Takimoto Y, Mitsui Y, Miyahara K, Shizuta Y and Sasayama S . (1999). J. Biol. Chem., 274, 5379–5384.

  • Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman J, Hruban RH and Lillemoe KD . (2000). J. Gastrointest. Surg., 4, 567–579.

  • Sprecher CA, Kisiel W, Mathewes S and Foster DC . (1994). Proc. Natl. Acad. Sci. USA, 91, 3353–3357.

  • Takai D and Jones PA . (2002). Proc. Natl. Acad. Sci. USA, 99, 3740–3745.

  • Tanaka Y, Utsumi J, Matsui M, Sudo T, Nakamura N, Mutoh M, Kajita A, Sone S, Kigasawa K, Shibuya M, Reddy VN, Zhang Q and Iwata T . (2004). Invest. Ophthalmol. Vis. Sci., 45, 245–252.

  • Tasiou A, Konduri SD, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Obeyesekere M and Rao JS . (2001). Int. J. Oncol., 19, 591–597.

  • Westermarck J and Kahari VM . (1999). FASEB J., 13, 781–792.

  • Wojtukiewicz MZ, Sierko E, Zimnoch L, Kozlowski L and Kisiel W . (2003). Thromb. Haemost., 90, 140–146.

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Acknowledgements

This work was supported by the NCI grant (CA90709, CA62924) and the Michael Rolfe Foundation.

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Correspondence to Michael Goggins.

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Sato, N., Parker, A., Fukushima, N. et al. Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene 24, 850–858 (2005). https://doi.org/10.1038/sj.onc.1208050

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