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Published in: Journal of Cancer Research and Clinical Oncology 2/2003

01-02-2003 | Original Paper

The alteration of PTEN tumor suppressor expression and its association with the histopathological features of human primary hepatocellular carcinoma

Authors: X.-W. Wan, M. Jiang, H.-F. Cao, Y.-Q. He, S.-Q. Liu, X.-H. Qiu, M.-C. Wu, H.-Y. Wang

Published in: Journal of Cancer Research and Clinical Oncology | Issue 2/2003

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Abstract

Purpose

Although deletions or inactivating mutations of the tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) are involved in the development of a variety of tumors including glioblastoma, melanoma, prostate cancer, breast cancer, endometrial cancers etc., the role of PTEN expression in human primary hepatocellular carcinoma (HCC) has not yet been clarified. The aim of this study is to investigate the involvement of PTEN mRNA and protein expression in HCC.

Methods

The level of PTEN mRNA expression in HCC specimens was analyzed by Northern blot. PTEN poly-clonal antibody was raised by immunizing New Zealand white rabbit with (His)6-tagged PTEN fusion protein and characterized by Western blot. The level of PTEN protein expression was determined by immunohistochemistry. The significance of PTEN in HCC was analyzed by comparing its expression level with the clinicopathological parameters of HCC patients.

Results

Four transcripts of PTEN mRNA at 5.5 kb, 4.4 kb, 2.4 kb, and 1.8 kb were detected in most para-carcinoma liver tissues, and the expression level of PTEN mRNA in carcinoma liver tissues was found to decrease significantly. The poly-clonal antibody raised against histidine-tagged fusion PTEN protein showed specific immuno-reactivity to PTEN protein. Using the specific poly-clonal antibody prepared and characterized by ourselves, we found that PTEN protein was significantly down-regulated in HCC tissues compared with paired para-carcinoma tissues. The protein expression of PTEN is negatively associated with the pathological grading and presence of cancer thrombus of HCC.

Conclusions

Down-regulation of PTEN expression may play an important role in the development of HCC and the level of PTEN expression may be a potential adjuvant parameter in forecasting the progression and prognosis of HCC patients.
Literature
go back to reference Bonkhoff H, Fixemer T, Hunsicker I, Remberger K (2001) Progesterone receptor expression in human prostate cancer: correlation with tumor progression. Prostate 48:285–291CrossRefPubMed Bonkhoff H, Fixemer T, Hunsicker I, Remberger K (2001) Progesterone receptor expression in human prostate cancer: correlation with tumor progression. Prostate 48:285–291CrossRefPubMed
go back to reference Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245CrossRefPubMed Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245CrossRefPubMed
go back to reference Celebi JT, Shendrik I, Silvers DN, Peacocke M (2000) Identification of PTEN mutations in metastatic melanoma specimens. J Med Genet 37:653–657CrossRefPubMed Celebi JT, Shendrik I, Silvers DN, Peacocke M (2000) Identification of PTEN mutations in metastatic melanoma specimens. J Med Genet 37:653–657CrossRefPubMed
go back to reference Cheng A, Dube N, Gu F, Tremblay ML (2002) Coordinated action of protein tyrosine phosphatases in insulin signal transduction. Eur J Biochem 269:1050–1059CrossRefPubMed Cheng A, Dube N, Gu F, Tremblay ML (2002) Coordinated action of protein tyrosine phosphatases in insulin signal transduction. Eur J Biochem 269:1050–1059CrossRefPubMed
go back to reference Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159PubMed Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159PubMed
go back to reference De Vivo I, Gertig DM, Nagase S, Hankinson SE, O'Brien R, Speizer FE, Parsons R, Hunter DJ (2000) Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers. J Med Genet 37:336–341CrossRefPubMed De Vivo I, Gertig DM, Nagase S, Hankinson SE, O'Brien R, Speizer FE, Parsons R, Hunter DJ (2000) Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers. J Med Genet 37:336–341CrossRefPubMed
go back to reference Dunbar BS, Schwoebel ED (1990) Preparation of polyclonal antibodies. Methods Enzymol 182:663–670PubMed Dunbar BS, Schwoebel ED (1990) Preparation of polyclonal antibodies. Methods Enzymol 182:663–670PubMed
go back to reference Elo JP, Visakorpi T (2001) Molecular genetics of prostate cancer. Ann Med 33:130–141PubMed Elo JP, Visakorpi T (2001) Molecular genetics of prostate cancer. Ann Med 33:130–141PubMed
go back to reference Fujiwara Y, Hoon DS, Yamada T, Umeshita K, Gotoh M, Sakon M, Nishisho I, Monden M (2000) PTEN/MMAC1 mutation and frequent loss of heterozygosity identified in chromosome 10q in a subset of hepatocellular carcinomas. Jpn J Cancer Res 91:287–292PubMed Fujiwara Y, Hoon DS, Yamada T, Umeshita K, Gotoh M, Sakon M, Nishisho I, Monden M (2000) PTEN/MMAC1 mutation and frequent loss of heterozygosity identified in chromosome 10q in a subset of hepatocellular carcinomas. Jpn J Cancer Res 91:287–292PubMed
go back to reference Gu J, Tamura M, Yamada KM (1998) Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol 143:1375–1383CrossRefPubMed Gu J, Tamura M, Yamada KM (1998) Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol 143:1375–1383CrossRefPubMed
go back to reference Guo SP, Wang WL, Zhai YQ, Zhao YL (2001) Expression of nuclear factor-kappaB in hepatocellular carcinoma and its relation with the X protein of hepatitis B virus. World J Gastroenterol 7:340–344PubMed Guo SP, Wang WL, Zhai YQ, Zhao YL (2001) Expression of nuclear factor-kappaB in hepatocellular carcinoma and its relation with the X protein of hepatitis B virus. World J Gastroenterol 7:340–344PubMed
go back to reference Gray IC, Stewart LM, Phillips SM, Hamilton JA, Gray NE, Watson GJ, Spurr NK, Snary D (1998) Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br J Cancer 78:1296–1300PubMed Gray IC, Stewart LM, Phillips SM, Hamilton JA, Gray NE, Watson GJ, Spurr NK, Snary D (1998) Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br J Cancer 78:1296–1300PubMed
go back to reference Hsu SM, Raine P, Fanger H (1981) The use of antiavidin antibody and avidinbiotin-peroxidase complex in immunoperoxidase technics. Am J Clin Pathol 75:816–821PubMed Hsu SM, Raine P, Fanger H (1981) The use of antiavidin antibody and avidinbiotin-peroxidase complex in immunoperoxidase technics. Am J Clin Pathol 75:816–821PubMed
go back to reference Latta E, Chapman WB (2002) PTEN mutations and evolving concepts in endometrial neoplasia. Curr Opin Obstet Gynecol 14:59–65CrossRefPubMed Latta E, Chapman WB (2002) PTEN mutations and evolving concepts in endometrial neoplasia. Curr Opin Obstet Gynecol 14:59–65CrossRefPubMed
go back to reference Leslie NR, Downes CP (2002) PTEN: The down side of PI 3-kinase signalling. Cell Signal 14:285–295CrossRefPubMed Leslie NR, Downes CP (2002) PTEN: The down side of PI 3-kinase signalling. Cell Signal 14:285–295CrossRefPubMed
go back to reference Li DM, Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124–2129PubMed Li DM, Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124–2129PubMed
go back to reference Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMed Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMed
go back to reference Monto A, Wright TL (2001) The epidemiology and prevention of hepatocellular carcinoma. Semin Oncol 28:441–449CrossRefPubMed Monto A, Wright TL (2001) The epidemiology and prevention of hepatocellular carcinoma. Semin Oncol 28:441–449CrossRefPubMed
go back to reference Munger K (2002) Disruption of oncogene/tumor suppressor networks during human carcinogenesis. Cancer Invest 20:71–81CrossRefPubMed Munger K (2002) Disruption of oncogene/tumor suppressor networks during human carcinogenesis. Cancer Invest 20:71–81CrossRefPubMed
go back to reference Murillo H, Huang H, Schmidt LJ, Smith DI, Tindall DJ (2001) Role of PI3 K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology 142:4795–4805PubMed Murillo H, Huang H, Schmidt LJ, Smith DI, Tindall DJ (2001) Role of PI3 K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology 142:4795–4805PubMed
go back to reference Ostman A, Bohmer FD (2001) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol 11:258–266CrossRefPubMed Ostman A, Bohmer FD (2001) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol 11:258–266CrossRefPubMed
go back to reference Poetsch M, Dittberner T, Woenckhaus C (2001) PTEN/MMAC1 in malignant melanoma and its importance for tumor progression. Cancer Genet Cytogenet 25:21–26CrossRef Poetsch M, Dittberner T, Woenckhaus C (2001) PTEN/MMAC1 in malignant melanoma and its importance for tumor progression. Cancer Genet Cytogenet 25:21–26CrossRef
go back to reference Rabe C, Pilz T, Klostermann C, Berna M, Schild HH, Sauerbruch T, Caselmann WH (2001) Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma. World J Gastroenterol 7:208–215PubMed Rabe C, Pilz T, Klostermann C, Berna M, Schild HH, Sauerbruch T, Caselmann WH (2001) Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma. World J Gastroenterol 7:208–215PubMed
go back to reference Reeves ME, DeMatteo RP (2000) Genes and viruses in hepatobiliary neoplasia. Semin Surg Oncol 19:84–93CrossRefPubMed Reeves ME, DeMatteo RP (2000) Genes and viruses in hepatobiliary neoplasia. Semin Surg Oncol 19:84–93CrossRefPubMed
go back to reference Sasaki H, Zlatescu MC, Betensky RA, Ino Y, Cairncross JG, Louis DN (2001) PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Am J Pathol 159:359–367PubMed Sasaki H, Zlatescu MC, Betensky RA, Ino Y, Cairncross JG, Louis DN (2001) PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Am J Pathol 159:359–367PubMed
go back to reference Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39PubMed Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39PubMed
go back to reference Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362 Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362
go back to reference Suzuki A, Hayashida M, Kawano H, Sugimoto K, Nakano T, Shiraki K (2000) Hepatocyte growth factor promotes cell survival from fas-mediated cell death in hepatocellular carcinoma cells via Akt activation and Fas-death-inducing signaling complex suppression. Hepatology 32:796–802PubMed Suzuki A, Hayashida M, Kawano H, Sugimoto K, Nakano T, Shiraki K (2000) Hepatocyte growth factor promotes cell survival from fas-mediated cell death in hepatocellular carcinoma cells via Akt activation and Fas-death-inducing signaling complex suppression. Hepatology 32:796–802PubMed
go back to reference Tamura M, Gu J, Takino T, Yamada KM (1999a) Tumor suppressor PTEN inhibition of cell invasion, migration and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res 59:442–449PubMed Tamura M, Gu J, Takino T, Yamada KM (1999a) Tumor suppressor PTEN inhibition of cell invasion, migration and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res 59:442–449PubMed
go back to reference Tamura M, Gu J, Tran H, Yamada KM (1999b) PTEN gene and integrin signaling in cancer. J Natl Cancer Inst 91:1820–1828PubMed Tamura M, Gu J, Tran H, Yamada KM (1999b) PTEN gene and integrin signaling in cancer. J Natl Cancer Inst 91:1820–1828PubMed
go back to reference Tang ZY (2000) Hepatocellular carcinoma. J Gastroenterol Hepatol 15 [Suppl]:G1–7 Tang ZY (2000) Hepatocellular carcinoma. J Gastroenterol Hepatol 15 [Suppl]:G1–7
go back to reference Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J (1998) Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 58:2720–2723PubMed Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J (1998) Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res 58:2720–2723PubMed
go back to reference Wang ZX, Wang HY, Wu MC (2001) Identification and characterization of a novel human hepatocellular carcinoma-associated gene. Br J Cancer 85:1162–1167CrossRefPubMed Wang ZX, Wang HY, Wu MC (2001) Identification and characterization of a novel human hepatocellular carcinoma-associated gene. Br J Cancer 85:1162–1167CrossRefPubMed
go back to reference Weng LP, Gimm O, Kum JB, Smith WM, Zhou XP, Wynford-Thomas D, Leone G, Eng C (2001) Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death. Hum Mol Genet 10:251–258CrossRefPubMed Weng LP, Gimm O, Kum JB, Smith WM, Zhou XP, Wynford-Thomas D, Leone G, Eng C (2001) Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death. Hum Mol Genet 10:251–258CrossRefPubMed
go back to reference Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, Said JW, Isaacs WB, Sawyers CL (1998) Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 95:5246–5250CrossRefPubMed Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, Said JW, Isaacs WB, Sawyers CL (1998) Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 95:5246–5250CrossRefPubMed
go back to reference Yamanaka T, Shiraki K, Nakazaawa S, Okano H, Ito T, Deguchi M, Takase K, Nakano T (2001) Impact of hepatitis B and C virus infection on the clinical prognosis of alcoholic liver cirrhosis. Anticancer Res 21:2937–2940PubMed Yamanaka T, Shiraki K, Nakazaawa S, Okano H, Ito T, Deguchi M, Takase K, Nakano T (2001) Impact of hepatitis B and C virus infection on the clinical prognosis of alcoholic liver cirrhosis. Anticancer Res 21:2937–2940PubMed
go back to reference Yao YJ, Ping XL, Zhang H, Chen FF, Lee PK, Ahsan H, Chen CJ, Lee PH, Peacocke M, Santella RM, Tsou HC (1999) PTEN/MMAC1 mutations in hepatocellular carcinomas. Oncogene 18:3181–3185PubMed Yao YJ, Ping XL, Zhang H, Chen FF, Lee PK, Ahsan H, Chen CJ, Lee PH, Peacocke M, Santella RM, Tsou HC (1999) PTEN/MMAC1 mutations in hepatocellular carcinomas. Oncogene 18:3181–3185PubMed
go back to reference Yeh KT, Chang JG, Chen YJ, Chen ST, Yu SY, Shih MC, Perng LI, Wang JC, Tsai M, Chang CP (2000) Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in hepatocellular carcinoma. Cancer Invest 18:123–129PubMed Yeh KT, Chang JG, Chen YJ, Chen ST, Yu SY, Shih MC, Perng LI, Wang JC, Tsai M, Chang CP (2000) Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in hepatocellular carcinoma. Cancer Invest 18:123–129PubMed
Metadata
Title
The alteration of PTEN tumor suppressor expression and its association with the histopathological features of human primary hepatocellular carcinoma
Authors
X.-W. Wan
M. Jiang
H.-F. Cao
Y.-Q. He
S.-Q. Liu
X.-H. Qiu
M.-C. Wu
H.-Y. Wang
Publication date
01-02-2003
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 2/2003
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-002-0410-x

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