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Published in: World Journal of Surgical Oncology 1/2006

Open Access 01-12-2006 | Research

Relationship of hypoxia-inducible factor 1α and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer

Authors: Ken Mizokami, Yoshihiro Kakeji, Shinya Oda, Yoshihiko Maehara

Published in: World Journal of Surgical Oncology | Issue 1/2006

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Abstract

Background

Hypoxia-inducible factor-1α (HIF-1α) plays an essential role in oxygen homeostasis. The expression of HIF-1α-inducible genes is associated with tumor progression. p21 mediates cell cycle arrest and is one of the downstream genes targeted by HIF-1.

Patients and methods

We examined the relationship between HIF-1α and p21 expression, apoptosis and tumor progression using tissue specimens obtained surgically from 126 patients with gastric cancer.

Results

Immunohistochemical analysis indicated that loss of p21 expression correlated positively with patient age and tumor size. Lymph node metastasis was significantly more frequent in tumors with loss of p21 expression (P = 0.022). HIF-1α-positive/p21-negative tumors had a lower apoptotic index than any other tumor samples, and patients with HIF-1α-positive/p21-negative tumors also had a significantly poorer prognosis than the other patient populations.

Conclusion

These results suggest that loss of HIF-1α-dependent p21 expression results in decreased apoptosis, increased cell survival and more aggressive tumors.
Appendix
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Literature
1.
go back to reference Semenza GL: Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999, 15: 551-578. 10.1146/annurev.cellbio.15.1.551.CrossRefPubMed Semenza GL: Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999, 15: 551-578. 10.1146/annurev.cellbio.15.1.551.CrossRefPubMed
2.
go back to reference Semenza GL: HIF-1 and human disease: one highly involved factor. Genes Dev. 2000, 14: 1983-1991.PubMed Semenza GL: HIF-1 and human disease: one highly involved factor. Genes Dev. 2000, 14: 1983-1991.PubMed
3.
go back to reference Griffiths EA, Pritchard SA, Welch IM, Price PM, West CM: Is the hypoxia-inducible factor pathway important in gastric cancer?. Eur J Cancer. 2005, 41: 2792-2805. 10.1016/j.ejca.2005.09.008.CrossRefPubMed Griffiths EA, Pritchard SA, Welch IM, Price PM, West CM: Is the hypoxia-inducible factor pathway important in gastric cancer?. Eur J Cancer. 2005, 41: 2792-2805. 10.1016/j.ejca.2005.09.008.CrossRefPubMed
4.
go back to reference Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996, 379: 88-91. 10.1038/379088a0.CrossRefPubMed Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996, 379: 88-91. 10.1038/379088a0.CrossRefPubMed
5.
go back to reference el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B: WAF1, a potential mediator of p53 tumor suppression. Cell. 1993, 75: 817-825. 10.1016/0092-8674(93)90500-P.CrossRefPubMed el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B: WAF1, a potential mediator of p53 tumor suppression. Cell. 1993, 75: 817-825. 10.1016/0092-8674(93)90500-P.CrossRefPubMed
6.
go back to reference Salnikow K, Costa M, Figg WD, Blagosklonny MV: Hyperinducibility of Hypoxia-responsive Genes without p53/p21-dependent Checkpoint in Aggressive Prostate Cancer. Cancer Res. 2000, 60: 5630-7113.PubMed Salnikow K, Costa M, Figg WD, Blagosklonny MV: Hyperinducibility of Hypoxia-responsive Genes without p53/p21-dependent Checkpoint in Aggressive Prostate Cancer. Cancer Res. 2000, 60: 5630-7113.PubMed
7.
go back to reference Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E: Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998, 394: 485-490. 10.1038/28867.CrossRefPubMed Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E: Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998, 394: 485-490. 10.1038/28867.CrossRefPubMed
8.
go back to reference Japanese Research Society for Gastric Cancer. Japanese classification of gastric carcinoma. Tokyo: Kanehara and Co, Ltd. 1995, 12: 1995. Japanese Research Society for Gastric Cancer. Japanese classification of gastric carcinoma. Tokyo: Kanehara and Co, Ltd. 1995, 12: 1995.
9.
go back to reference Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Overexpression of Hypoxia-inducible Factor 1{{alpha}} in Common Human Cancers and Their Metastases. Cancer Res. 1999, 59: 5830-7113.PubMed Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Overexpression of Hypoxia-inducible Factor 1{{alpha}} in Common Human Cancers and Their Metastases. Cancer Res. 1999, 59: 5830-7113.PubMed
10.
go back to reference Noda H, Maehara Y, Irie K, Kakeji Y, Yonemura T, Sugimachi K: Growth pattern and expressions of cell cycle regulator proteins p53 and p21WAF1/CIP1 in early gastric carcinoma. Cancer. 2001, 92: 1828-1835. 10.1002/1097-0142(20011001)92:7<1828::AID-CNCR1699>3.0.CO;2-Q.CrossRefPubMed Noda H, Maehara Y, Irie K, Kakeji Y, Yonemura T, Sugimachi K: Growth pattern and expressions of cell cycle regulator proteins p53 and p21WAF1/CIP1 in early gastric carcinoma. Cancer. 2001, 92: 1828-1835. 10.1002/1097-0142(20011001)92:7<1828::AID-CNCR1699>3.0.CO;2-Q.CrossRefPubMed
11.
go back to reference Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G: Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res. 2001, 7: 1661-1668.PubMed Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G: Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res. 2001, 7: 1661-1668.PubMed
12.
go back to reference Kerr JF, Winterford CM, Harmon BV: Apoptosis. Its significance in cancer and cancer therapy. Cancer. 1994, 73: 2013-2026. 10.1002/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO;2-J.CrossRefPubMed Kerr JF, Winterford CM, Harmon BV: Apoptosis. Its significance in cancer and cancer therapy. Cancer. 1994, 73: 2013-2026. 10.1002/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO;2-J.CrossRefPubMed
13.
go back to reference Dixon WJ : BMDP statistical software. Berkeley, CA: University of California Press. 1988 Dixon WJ : BMDP statistical software. Berkeley, CA: University of California Press. 1988
14.
go back to reference Ogawa M, Maeda K, Onoda N, Chung YS, Sowa M: Loss of p21WAF1/CIP1 expression correlates with disease progression in gastric carcinoma. Br J Cancer. 1997, 75: 1617-1620.PubMedCentralCrossRefPubMed Ogawa M, Maeda K, Onoda N, Chung YS, Sowa M: Loss of p21WAF1/CIP1 expression correlates with disease progression in gastric carcinoma. Br J Cancer. 1997, 75: 1617-1620.PubMedCentralCrossRefPubMed
15.
go back to reference Noda H, Maehara Y, Irie K, Kakeji Y, Yonemura T, Sugimachi K: Increased proliferative activity caused by loss of p21(WAF1/CIP1) expression and its clinical significance in patients with early-stage gastric carcinoma. Cancer. 2002, 94: 2107-2112. 10.1002/cncr.10417.CrossRefPubMed Noda H, Maehara Y, Irie K, Kakeji Y, Yonemura T, Sugimachi K: Increased proliferative activity caused by loss of p21(WAF1/CIP1) expression and its clinical significance in patients with early-stage gastric carcinoma. Cancer. 2002, 94: 2107-2112. 10.1002/cncr.10417.CrossRefPubMed
16.
go back to reference Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G: Overexpression of Hypoxia-inducible Factor 1{{alpha}} Is a Marker for an Unfavorable Prognosis in Early-Stage Invasive Cervical Cancer. Cancer Res. 2000, 60: 4693-7113.PubMed Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G: Overexpression of Hypoxia-inducible Factor 1{{alpha}} Is a Marker for an Unfavorable Prognosis in Early-Stage Invasive Cervical Cancer. Cancer Res. 2000, 60: 4693-7113.PubMed
17.
go back to reference Birner P, Gatterbauer B, Oberhuber G, Schindl M, Rossler K, Prodinger A, Budka H, Hainfellner JA: Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer. 2001, 92: 165-171. 10.1002/1097-0142(20010701)92:1<165::AID-CNCR1305>3.0.CO;2-F.CrossRefPubMed Birner P, Gatterbauer B, Oberhuber G, Schindl M, Rossler K, Prodinger A, Budka H, Hainfellner JA: Expression of hypoxia-inducible factor-1 alpha in oligodendrogliomas: its impact on prognosis and on neoangiogenesis. Cancer. 2001, 92: 165-171. 10.1002/1097-0142(20010701)92:1<165::AID-CNCR1305>3.0.CO;2-F.CrossRefPubMed
18.
go back to reference Beasley NJ, Leek R, Alam M, Turley H, Cox GJ, Gatter K, Millard P, Fuggle S, Harris AL: Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res. 2002, 62: 2493-2497.PubMed Beasley NJ, Leek R, Alam M, Turley H, Cox GJ, Gatter K, Millard P, Fuggle S, Harris AL: Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res. 2002, 62: 2493-2497.PubMed
19.
go back to reference Yu JL, Rak JW, Carmeliet P, Nagy A, Kerbel RS, Coomber BL: Heterogeneous vascular dependence of tumor cell populations. Am J Pathol. 2001, 158: 1325-1334.PubMedCentralCrossRefPubMed Yu JL, Rak JW, Carmeliet P, Nagy A, Kerbel RS, Coomber BL: Heterogeneous vascular dependence of tumor cell populations. Am J Pathol. 2001, 158: 1325-1334.PubMedCentralCrossRefPubMed
20.
go back to reference Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL: HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 2001, 61: 6669-6673.PubMed Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL: HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 2001, 61: 6669-6673.PubMed
21.
go back to reference Bruick RK: Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proceedings of the National Academy of Sciences of the United States of America. 2000, 97: 9082-9087. 10.1073/pnas.97.16.9082.PubMedCentralCrossRefPubMed Bruick RK: Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proceedings of the National Academy of Sciences of the United States of America. 2000, 97: 9082-9087. 10.1073/pnas.97.16.9082.PubMedCentralCrossRefPubMed
22.
go back to reference Iida T, Mine S, Fujimoto H, Suzuki K, Minami Y, Tanaka Y: Hypoxia-inducible factor-1alpha induces cell cycle arrest of endothelial cells. Genes Cells. 2002, 7: 143-149. 10.1046/j.1356-9597.2001.00512.x.CrossRefPubMed Iida T, Mine S, Fujimoto H, Suzuki K, Minami Y, Tanaka Y: Hypoxia-inducible factor-1alpha induces cell cycle arrest of endothelial cells. Genes Cells. 2002, 7: 143-149. 10.1046/j.1356-9597.2001.00512.x.CrossRefPubMed
23.
go back to reference Shimizu S, Eguchi Y, Kamiike W, Itoh Y, Hasegawa J, Yamabe K, Otsuki Y, Matsuda H, Tsujimoto Y: Induction of apoptosis as well as necrosis by hypoxia and predominant prevention of apoptosis by Bcl-2 and Bcl-XL. Cancer Res. 1996, 56: 2161-2166.PubMed Shimizu S, Eguchi Y, Kamiike W, Itoh Y, Hasegawa J, Yamabe K, Otsuki Y, Matsuda H, Tsujimoto Y: Induction of apoptosis as well as necrosis by hypoxia and predominant prevention of apoptosis by Bcl-2 and Bcl-XL. Cancer Res. 1996, 56: 2161-2166.PubMed
24.
go back to reference Schmaltz C, Hardenbergh PH, Wells A, Fisher DE: Regulation of proliferation-survival decisions during tumor cell hypoxia. Mol Cell Biol. 1998, 18: 2845-2854.PubMedCentralCrossRefPubMed Schmaltz C, Hardenbergh PH, Wells A, Fisher DE: Regulation of proliferation-survival decisions during tumor cell hypoxia. Mol Cell Biol. 1998, 18: 2845-2854.PubMedCentralCrossRefPubMed
25.
go back to reference Kinzler KW, Vogelstein B: Life (and death) in a malignant tumour. Nature. 1996, 379: 19-20. 10.1038/379019a0.CrossRefPubMed Kinzler KW, Vogelstein B: Life (and death) in a malignant tumour. Nature. 1996, 379: 19-20. 10.1038/379019a0.CrossRefPubMed
26.
go back to reference Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ, Giaccia AJ: Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol. 1994, 14: 6264-6277.PubMedCentralCrossRefPubMed Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ, Giaccia AJ: Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol. 1994, 14: 6264-6277.PubMedCentralCrossRefPubMed
27.
go back to reference Suzuki H, Tomida A, Tsuruo T: Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene. 2001, 20: 5779-5788. 10.1038/sj.onc.1204742.CrossRefPubMed Suzuki H, Tomida A, Tsuruo T: Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene. 2001, 20: 5779-5788. 10.1038/sj.onc.1204742.CrossRefPubMed
28.
go back to reference Sumiyoshi Y, Kakeji Y, Egashira A, Mizokami K, Orita H, Maehara Y: Overexpression of hypoxia-inducible factor 1alpha and p53 is a marker for an unfavorable prognosis in gastric cancer. Clin Cancer Res. 2006, 12: 5112-5117. 10.1158/1078-0432.CCR-05-2382.CrossRefPubMed Sumiyoshi Y, Kakeji Y, Egashira A, Mizokami K, Orita H, Maehara Y: Overexpression of hypoxia-inducible factor 1alpha and p53 is a marker for an unfavorable prognosis in gastric cancer. Clin Cancer Res. 2006, 12: 5112-5117. 10.1158/1078-0432.CCR-05-2382.CrossRefPubMed
29.
go back to reference Ratcliffe PJ, Pugh CW, Maxwell PH: Targeting tumors through the HIF system. Nat Med. 2000, 6: 1315-1316. 10.1038/82113.CrossRefPubMed Ratcliffe PJ, Pugh CW, Maxwell PH: Targeting tumors through the HIF system. Nat Med. 2000, 6: 1315-1316. 10.1038/82113.CrossRefPubMed
30.
go back to reference Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KM, Stratford IJ, Harris AL: Targeting gene expression to hypoxic tumor cells. Nat Med. 1997, 3: 515-520. 10.1038/nm0597-515.CrossRefPubMed Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KM, Stratford IJ, Harris AL: Targeting gene expression to hypoxic tumor cells. Nat Med. 1997, 3: 515-520. 10.1038/nm0597-515.CrossRefPubMed
31.
go back to reference Harris AL: Hypoxia--a key regulatory factor in tumour growth. Nature Rev Cancer. 2002, 2: 38-47. 10.1038/nrc704.CrossRef Harris AL: Hypoxia--a key regulatory factor in tumour growth. Nature Rev Cancer. 2002, 2: 38-47. 10.1038/nrc704.CrossRef
Metadata
Title
Relationship of hypoxia-inducible factor 1α and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer
Authors
Ken Mizokami
Yoshihiro Kakeji
Shinya Oda
Yoshihiko Maehara
Publication date
01-12-2006
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2006
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/1477-7819-4-94

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