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Journal of Cancer Research and Clinical Oncology

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01.10.2010 | Original Paper

Decreased nuclear expression and increased cytoplasmic expression of ING5 may be linked to tumorigenesis and progression in human head and neck squamous cell carcinoma

verfasst von: Xiaohan Li, Takeshi Nishida, Akira Noguchi, Yang Zheng, Hiroyuki Takahashi, Xianghong Yang, Shinji Masuda, Yasuo Takano

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 10/2010

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Abstract

Purpose

This study aimed to assess the protein level of inhibitor of growth gene 5 (ING5) in head and neck squamous cell carcinoma (HNSCC) and to explore its roles in tumorigenesis and cancer progression.

Methods

ING5 expression was assessed in 172 cases of HNSCC by immunohistochemistry using tissue microarray, and in 3 oral SCC cell lines by immunohistochemistry and Western blot. Expression of ING5 was compared with clinicopathological variables, TUNEL assay staining, and the expression of several tumorigenic markers. In addition, double immunofluorescence labeling was performed in order to analyze the colocalization of ING5 with p300 and p21.

Results

ING5 expression was primarily observed in the nuclei, but was also occasionally found in the cytoplasm of both SCC cell lines and tissue samples of HNSCC. Nuclear expression of ING5 in HNSCC was significantly lower than that of non-cancerous epithelium, and was positively correlated with a well-differentiated status. In contrast, cytoplasmic expression of ING5 was significantly increased in HNSCC, and was inversely correlated with a well-differentiated status and nuclear ING5 expression. In addition, nuclear expression of ING5 was positively correlated with p21 and p300 expression, and with the apoptotic index. In contrast, cytoplasmic expression of ING5 was negatively correlated with the expression of p300, p21, and PCNA. Although no statistical association was found between the expression of nuclear ING5 and mutant p53 in HNSCC, patients with high expression of nuclear ING5 tended to have converse prognoses when grouped according to mutant p53 expression.

Conclusions

Our results suggest that a decrease in nuclear ING5 localization and cytoplasmic translocation are involved in tumorigenesis and tumor differentiation in HNSCC. Nuclear ING5 may modulate the transactivation of target genes, and may promote apoptosis and cell cycle arrest by interacting with the p300 and p21 proteins. ING5 may function as a tumor suppressor gene or oncogene tightly linked with p53 status, and may play an important role in the prognosis of HNSCC patients. Therefore, we propose that ING5 represents a novel potential molecular therapeutic target for HNSCC.

Abbas T, Dutta A (2009) p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9:400–414CrossRefPubMed

Barnes L, Eveson JW, Reichart P, Sidransky D (2005) World Health Organization classification of tumours: pathology and genetics of head and neck tumours, 3rd edn. IARC Press, Lyon, pp 109–110

Borkosky SS, Gunduz M, Nagatsuka H, Beder LB, Gunduz E, Ali MA, Rodriguez AP, Cilek MZ, Tominaga S, Yamanaka N, Shimizu K, Nagai N (2009) Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 135:703–713CrossRefPubMed

Cengiz B, Gunduz M, Nagatsuka H, Beder L, Gunduz E, Tamamura R, Mahmut N, Fukushima K, Ali MA, Naomoto Y, Shimizu K, Nagai N (2007) Fine deletion mapping of chromosome 2q21–37 shows three preferentially deleted regions in oral cancer. Oral Oncol 43:241–247CrossRefPubMed

Champagne KS, Saksouk N, Peña PV, Johnson K, Ullah M, Yang XJ, Côté J, Kutateladze TG (2008) The crystal structure of the ING5 PHD finger in complex with an H3K4me3 histone peptide. Proteins 72:1371–1376CrossRefPubMed

Doyon Y, Cayrou C, Ullah M, Landry AJ, Côté V, Selleck W, Lane WS, Tan S, Yang XJ, Côté J (2006) ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell 21:51–64CrossRefPubMed

Fabbro M, Henderson BR (2003) Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp Cell Res 282:59–69CrossRefPubMed

Gong W, Suzuki K, Russell M, Riabowol K (2005) Function of the ING family of PHD proteins in cancer. Int J Biochem Cell Biol 37:1054–1065CrossRefPubMed

Gunduz M, Ouchida M, Fukushima K, Hanafusa H, Etani T, Nishioka S, Nishizaki K, Shimizu K (2000) Genomic structure of the human ING1 gene and tumor-specific mutations detected in head and neck squamous cell carcinomas. Cancer Res 60:3143–3146PubMed

Gunduz M, Ouchida M, Fukushima K, Ito S, Jitsumori Y, Nakashima T, Nagai N, Nishizaki K, Shimizu K (2002) Allelic loss and reduced expression of the ING3, a candidate tumor suppressor gene at 7q31, in human head and neck cancers. Oncogene 21:4462–4470CrossRefPubMed

Gunduz M, Nagatsuka H, Demircan K, Gunduz E, Cengiz B, Ouchida M, Tsujigiwa H, Yamachika E, Fukushima K, Beder L, Hirohata S, Ninomiya Y, Nishizaki K, Shimizu K, Nagai N (2005) Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas. Gene 356:109–117CrossRefPubMed

Hara Y, Zheng Z, Evans SC, Malatjalian D, Riddell DC, Guernsey DL, Wang LD, Riabowol K, Casson AG (2003) ING1 and p53 tumor suppressor gene alterations in adenocarcinomas of the esophagogastric junction. Cancer Lett 192:109–116CrossRefPubMed

Harris SL, Levine AJ (2005) The p53 pathway: positive and negative feedback loops. Oncogene 24:2899–2908CrossRefPubMed

He GH, Helbing CC, Wagner MJ, Sensen CW, Riabowol K (2005) Phylogenetic analysis of the ING family of PHD finger proteins. Mol Biol Evol 22:104–116CrossRefPubMed

Iyer NG, Ozdag H, Caldas C (2004) p300/CBP and cancer. Oncogene 23:4225–4231CrossRefPubMed

Kameyama K, Huang CL, Liu D, Masuya D, Nakashima T, Sumitomo S, Takami Y, Kinoshita M, Yokomise H (2003) Reduced ING1b gene expression plays an important role in carcinogenesis of non-small cell lung cancer patients. Clin Cancer Res 9:4926–4934PubMed

Kumada T, Tsuneyama K, Hatta H, Ishizawa S, Takano Y (2004) Improved 1-h rapid immunostaining method using intermittent microwave irradiation: practicability based on 5 years application in Toyama Medical and Pharmaceutical University Hospital. Mod Pathol 17:1141–1149CrossRefPubMed

Nouman GS, Anderson JJ, Crosier S, Shrimankar J, Lunec J, Angus B (2003) Downregulation of nuclear expression of the p33(ING1b) inhibitor of growth protein in invasive carcinoma of the breast. J Clin Pathol 56:507–511CrossRefPubMed

PPeña PV, Davrazou F, Shi X, Walter KL, Verkhusha VV, Gozani O, Zhao R, Kutateladze TG (2006) Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442:31–32CrossRef

Russell M, Berardi P, Gong W, Riabowol K (2006) Grow-ING, Age-ING and Die-ING: ING proteins link cancer, senescence and apoptosis. Exp Cell Res 312:951–961CrossRefPubMed

Shiseki M, Nagashima M, Pedeux RM, Kitahama-Shiseki M, Miura K, Okamura S, Onogi H, Higashimoto Y, Appella E, Yokota J, Harris CC (2003) p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res 63:2373–2378PubMed

Soussi T, Lozano G (2005) p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun 331:834–842CrossRefPubMed

Soussi T, Wiman KG (2007) Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 12:303–312CrossRefPubMed

Toyama T, Iwase H, Watson P, Muzik H, Saettler E, Magliocco A, DiFrancesco L, Forsyth P, Garkavtsev I, Kobayashi S, Riabowol K (1999) Suppression of ING1 expression in sporadic breast cancer. Oncogene 18:5187–5193CrossRefPubMed

Unoki M, Kumamoto K, Takenoshita S, Harris CC (2009) Reviewing the current classification of inhibitor of growth family proteins. Cancer Sci 100:1173–1179CrossRefPubMed

Weisz L, Oren M, Rotter V (2007) Transcription regulation by mutant p53. Oncogene 26:2202–2211CrossRefPubMed

Ythier D, Larrieu D, Brambilla C, Brambilla E, Pedeux R (2008) The new tumor suppressor genes ING: genomic structure and status in cancer. Int J Cancer 123:1483–1490CrossRefPubMed

Titel: Decreased nuclear expression and increased cytoplasmic expression of ING5 may be linked to tumorigenesis and progression in human head and neck squamous cell carcinoma
verfasst von: Xiaohan Li
Takeshi Nishida
Akira Noguchi
Yang Zheng
Hiroyuki Takahashi
Xianghong Yang
Shinji Masuda
Yasuo Takano
Publikationsdatum: 01.10.2010
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 10/2010
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-010-0815-x

Springer Medizin

Decreased nuclear expression and increased cytoplasmic expression of ING5 may be linked to tumorigenesis and progression in human head and neck squamous cell carcinoma