Skip to main content
Erschienen in: International Journal of Clinical Oncology 5/2016

21.03.2016 | Original Article

Prognostic value of glucosylceramide synthase and P-glycoprotein expression in oral cavity cancer

verfasst von: Ji Won Kim, Yangsoon Park, Jong-Lyel Roh, Kyung-Ja Cho, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim

Erschienen in: International Journal of Clinical Oncology | Ausgabe 5/2016

Einloggen, um Zugang zu erhalten

Abstract

Background

Glucosylceramide synthase (GCS) and P-glycoprotein (P-gp) overexpression are associated with multidrug resistance in several human cancers. This study investigated the prognostic value of GCS and P-gp in oral cavity squamous cell carcinoma (OSCC).

Methods

The association between GCS and P-gp overexpression and clinical outcomes was assessed in 186 human clinical specimens of primary tumors obtained from curative surgery. Immunohistochemistry staining results were scored as high or low for GCS, and positive or negative for P-gp. Univariate and multivariate analyses using the Cox proportional hazards model were conducted to assess the significance of differences in recurrence or survival outcomes between variables.

Results

GCS overexpression was observed in 128 (68.8 %) patients and P-gp overexpression in 43 (23.1 %) patients. High GCS expression was significantly correlated with P-gp immunopositivity (P = 0.005). GCS and P-gp overexpression was significantly correlated with cervical nodal metastasis (P < 0.05). Univariate analyses showed that tumor lymphovascular invasion, positive neck lymph nodes, advanced overall TNM stage, high GCS expression, and P-gp immunopositivity were associated with poor locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) (P < 0.05). Multivariate analyses showed that lymphovascular invasion, nodal positivity, and P-gp overexpression remained independent prognostic variables for LRC, DFS, and OS, and that GCS expression was an independent predictor of LRC and DFS (P < 0.05).

Conclusion

GCS and P-gp expression is associated with poor prognosis, suggesting suitability as novel biomarkers in OSCC.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Sigel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29CrossRef Sigel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29CrossRef
2.
Zurück zum Zitat Sano D, Myers JN (2007) Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev 26:645–662CrossRefPubMed Sano D, Myers JN (2007) Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev 26:645–662CrossRefPubMed
3.
Zurück zum Zitat Murthy V, Agarwal JP, Laskar SG et al (2010) Analysis of prognostic factors in 1180 patients with oral cavity primary cancer treated with definitive or adjuvant radiotherapy. J Cancer Res Ther 6:282–289CrossRefPubMed Murthy V, Agarwal JP, Laskar SG et al (2010) Analysis of prognostic factors in 1180 patients with oral cavity primary cancer treated with definitive or adjuvant radiotherapy. J Cancer Res Ther 6:282–289CrossRefPubMed
4.
Zurück zum Zitat Kang H, Kiess A, Chung CH (2015) Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol 12:11–26CrossRefPubMed Kang H, Kiess A, Chung CH (2015) Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol 12:11–26CrossRefPubMed
5.
Zurück zum Zitat da Silva SD, Ferlito A, Takes RP et al (2011) Advances and applications of oral cancer basic research. Oral Oncol 47:783–791CrossRefPubMed da Silva SD, Ferlito A, Takes RP et al (2011) Advances and applications of oral cancer basic research. Oral Oncol 47:783–791CrossRefPubMed
6.
Zurück zum Zitat Oliveira LR, Ribeiro-Silva A (2011) Prognostic significance of immunohistochemical biomarkers in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 40:298–307CrossRefPubMed Oliveira LR, Ribeiro-Silva A (2011) Prognostic significance of immunohistochemical biomarkers in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 40:298–307CrossRefPubMed
7.
Zurück zum Zitat Mizutani T, Masuda M, Nakai E et al (2008) Genuine functions of P-glycoprotein (ABCB1). Curr Drug Metab 9:167–174CrossRefPubMed Mizutani T, Masuda M, Nakai E et al (2008) Genuine functions of P-glycoprotein (ABCB1). Curr Drug Metab 9:167–174CrossRefPubMed
8.
Zurück zum Zitat Sikic BI, Fisher GA, Lum BL et al (1997) Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. Cancer Chemother Pharmacol 40(Suppl):S13–S19CrossRefPubMed Sikic BI, Fisher GA, Lum BL et al (1997) Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. Cancer Chemother Pharmacol 40(Suppl):S13–S19CrossRefPubMed
9.
Zurück zum Zitat Sagol O, Yavuzsen T, Oztop I et al (2005) The effect of apoptotic activity, survivin, Ki-67, and P-glycoprotein expression on prognosis in pancreatic carcinoma. Pancreas 30:343–348CrossRefPubMed Sagol O, Yavuzsen T, Oztop I et al (2005) The effect of apoptotic activity, survivin, Ki-67, and P-glycoprotein expression on prognosis in pancreatic carcinoma. Pancreas 30:343–348CrossRefPubMed
10.
Zurück zum Zitat Wang B, Li XQ, Ma X et al (2008) Immunohistochemical expression and clinical significance of P-glycoprotein in previously untreated extranodal NK/T-cell lymphoma, nasal type. Am J Hematol 83:795–799CrossRefPubMed Wang B, Li XQ, Ma X et al (2008) Immunohistochemical expression and clinical significance of P-glycoprotein in previously untreated extranodal NK/T-cell lymphoma, nasal type. Am J Hematol 83:795–799CrossRefPubMed
11.
Zurück zum Zitat Rocco A, Compare D, Liguori E et al (2012) MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells. Lab Invest 92:1407–1418CrossRefPubMed Rocco A, Compare D, Liguori E et al (2012) MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells. Lab Invest 92:1407–1418CrossRefPubMed
12.
Zurück zum Zitat Ralhan R, Swain RK, Agarwal S et al (1999) P-glycoprotein is positively correlated with p53 in human oral pre-malignant and malignant lesions and is associated with poor prognosis. Int J Cancer 84:80–85CrossRefPubMed Ralhan R, Swain RK, Agarwal S et al (1999) P-glycoprotein is positively correlated with p53 in human oral pre-malignant and malignant lesions and is associated with poor prognosis. Int J Cancer 84:80–85CrossRefPubMed
13.
Zurück zum Zitat Li DW, Gao S, Shen B et al (2011) Effect of apoptotic and proliferative indices, P-glycoprotein and survivin expression on prognosis in laryngeal squamous cell carcinoma. Med Oncol 28(Suppl 1):S333–S340CrossRefPubMed Li DW, Gao S, Shen B et al (2011) Effect of apoptotic and proliferative indices, P-glycoprotein and survivin expression on prognosis in laryngeal squamous cell carcinoma. Med Oncol 28(Suppl 1):S333–S340CrossRefPubMed
14.
Zurück zum Zitat Shabbits JA, Mayer LD (2002) P-glycoprotein modulates ceramide-mediated sensitivity of human breast cancer cells to tubulin-binding anticancer drugs. Mol Cancer Ther 1:205–213PubMed Shabbits JA, Mayer LD (2002) P-glycoprotein modulates ceramide-mediated sensitivity of human breast cancer cells to tubulin-binding anticancer drugs. Mol Cancer Ther 1:205–213PubMed
15.
Zurück zum Zitat Ichikawa S, Sakiyama H, Suzuki G et al (1996) Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc Natl Acad Sci USA 93:4638–4643CrossRefPubMedPubMedCentral Ichikawa S, Sakiyama H, Suzuki G et al (1996) Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc Natl Acad Sci USA 93:4638–4643CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Morad SA, Cabot MC (2013) Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 13:51–65CrossRefPubMed Morad SA, Cabot MC (2013) Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 13:51–65CrossRefPubMed
17.
Zurück zum Zitat Liu YY, Han TY, Giuliano AE et al (2001) Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15:719–730CrossRefPubMed Liu YY, Han TY, Giuliano AE et al (2001) Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15:719–730CrossRefPubMed
18.
Zurück zum Zitat Juul N, Szallasi Z, Eklund AC et al (2010) Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials. Lancet Oncol 11:358–365CrossRefPubMed Juul N, Szallasi Z, Eklund AC et al (2010) Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials. Lancet Oncol 11:358–365CrossRefPubMed
19.
Zurück zum Zitat Zhang X, Wu X, Su P et al (2012) Doxorubicin influences the expression of glucosylceramide synthase in invasive ductal breast cancer. PLoS One 7:e48492CrossRefPubMedPubMedCentral Zhang X, Wu X, Su P et al (2012) Doxorubicin influences the expression of glucosylceramide synthase in invasive ductal breast cancer. PLoS One 7:e48492CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Sun CC, Zhang Z, Zhang SY et al (2012) Up-regulation of glucosylceramide synthase in urinary bladder neoplasms. Urol Oncol 30:444–449CrossRefPubMed Sun CC, Zhang Z, Zhang SY et al (2012) Up-regulation of glucosylceramide synthase in urinary bladder neoplasms. Urol Oncol 30:444–449CrossRefPubMed
21.
Zurück zum Zitat Liu YY, Patwardhan GA, Xie P et al (2011) Glucosylceramide synthase, a factor in modulating drug resistance, is overexpressed in metastatic breast carcinoma. Int J Oncol 39:425–431PubMedPubMedCentral Liu YY, Patwardhan GA, Xie P et al (2011) Glucosylceramide synthase, a factor in modulating drug resistance, is overexpressed in metastatic breast carcinoma. Int J Oncol 39:425–431PubMedPubMedCentral
22.
Zurück zum Zitat Gouazé V, Liu YY, Prickett CS et al (2005) Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res 65(9):3861–3867CrossRefPubMed Gouazé V, Liu YY, Prickett CS et al (2005) Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res 65(9):3861–3867CrossRefPubMed
23.
Zurück zum Zitat Edge SB, Byrd DR, Compton CC et al (2010) AJCC Cancer Staging Manual, 7th edn. Springer-Verlag, New York, pp 29–40 Edge SB, Byrd DR, Compton CC et al (2010) AJCC Cancer Staging Manual, 7th edn. Springer-Verlag, New York, pp 29–40
24.
Zurück zum Zitat Rabkin D, Chhieng DC, Miller MB et al (1995) P-glycoprotein expression in the squamous cell carcinoma of the tongue base. Laryngoscope 105:1294–1299CrossRefPubMed Rabkin D, Chhieng DC, Miller MB et al (1995) P-glycoprotein expression in the squamous cell carcinoma of the tongue base. Laryngoscope 105:1294–1299CrossRefPubMed
25.
Zurück zum Zitat Warnakulasuriya S, Jia C, Johnson N et al (2000) p53 and P-glycoprotein expression are significant prognostic markers in advanced head and neck cancer treated with chemo/radiotherapy. J Pathol 191:33–38CrossRefPubMed Warnakulasuriya S, Jia C, Johnson N et al (2000) p53 and P-glycoprotein expression are significant prognostic markers in advanced head and neck cancer treated with chemo/radiotherapy. J Pathol 191:33–38CrossRefPubMed
26.
Zurück zum Zitat Uematsu T, Hasegawa T, Hiraoka BY et al (2001) Multidrug resistance gene 1 expression in salivary gland adenocarcinomas and oral squamous-cell carcinomas. Int J Cancer 92:187–194CrossRefPubMed Uematsu T, Hasegawa T, Hiraoka BY et al (2001) Multidrug resistance gene 1 expression in salivary gland adenocarcinomas and oral squamous-cell carcinomas. Int J Cancer 92:187–194CrossRefPubMed
27.
Zurück zum Zitat Soni S, Pande P, Shukla NK et al (2002) Coexpression of Ets-1 and p53 in oral carcinomas is associated with P-glycoprotein expression and poor prognosis. J Cancer Res Clin Oncol 128:336–342CrossRefPubMed Soni S, Pande P, Shukla NK et al (2002) Coexpression of Ets-1 and p53 in oral carcinomas is associated with P-glycoprotein expression and poor prognosis. J Cancer Res Clin Oncol 128:336–342CrossRefPubMed
28.
Zurück zum Zitat Friedrich RE, Punke C, Reymann A (2004) Expression of multi-drug resistance genes (mdr1, mrp1, bcrp) in primary oral squamous cell carcinoma. In Vivo 18:133–147PubMed Friedrich RE, Punke C, Reymann A (2004) Expression of multi-drug resistance genes (mdr1, mrp1, bcrp) in primary oral squamous cell carcinoma. In Vivo 18:133–147PubMed
29.
Zurück zum Zitat Larbcharoensub N, Leopairat J, Sirachainan E et al (2008) Association between multidrug resistance-associated protein 1 and poor prognosis in patients with nasopharyngeal carcinoma treated with radiotherapy and concurrent chemotherapy. Hum Pathol 39:837–845CrossRefPubMed Larbcharoensub N, Leopairat J, Sirachainan E et al (2008) Association between multidrug resistance-associated protein 1 and poor prognosis in patients with nasopharyngeal carcinoma treated with radiotherapy and concurrent chemotherapy. Hum Pathol 39:837–845CrossRefPubMed
30.
Zurück zum Zitat Furusaka T, Sasaki CT, Matsuda A et al (2013) Multidrug resistance in mucoepidermoid carcinoma of the parotid gland–immunohistochemical investigations of P-glycoprotein expression. Acta Otolaryngol 133:552–557CrossRefPubMed Furusaka T, Sasaki CT, Matsuda A et al (2013) Multidrug resistance in mucoepidermoid carcinoma of the parotid gland–immunohistochemical investigations of P-glycoprotein expression. Acta Otolaryngol 133:552–557CrossRefPubMed
31.
Zurück zum Zitat Warta R, Theile D, Mogler C et al (2014) Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma. PLoS One 9:e108908CrossRefPubMedPubMedCentral Warta R, Theile D, Mogler C et al (2014) Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma. PLoS One 9:e108908CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Liu YY, Gupta V, Patwardhan GA et al (2010) Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling. Mol Cancer 9:145CrossRefPubMedPubMedCentral Liu YY, Gupta V, Patwardhan GA et al (2010) Glucosylceramide synthase upregulates MDR1 expression in the regulation of cancer drug resistance through cSrc and beta-catenin signaling. Mol Cancer 9:145CrossRefPubMedPubMedCentral
33.
Zurück zum Zitat Fasanaro E, Staffieri C, Cappellesso R et al (2015) Prognostic significance of serine-phosphorylated STAT3 expression in pT1-T2 oral tongue carcinoma. Clin Exp Otorhinolaryngol 8:275–280CrossRefPubMedPubMedCentral Fasanaro E, Staffieri C, Cappellesso R et al (2015) Prognostic significance of serine-phosphorylated STAT3 expression in pT1-T2 oral tongue carcinoma. Clin Exp Otorhinolaryngol 8:275–280CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Lovato A, Lionello M, Staffieri A et al (2015) A higher angiogenin expression is associated with a nonnuclear Maspin location in laryngeal carcinoma. Clin Exp Otorhinolaryngol 8:268–274CrossRefPubMedPubMedCentral Lovato A, Lionello M, Staffieri A et al (2015) A higher angiogenin expression is associated with a nonnuclear Maspin location in laryngeal carcinoma. Clin Exp Otorhinolaryngol 8:268–274CrossRefPubMedPubMedCentral
Metadaten
Titel
Prognostic value of glucosylceramide synthase and P-glycoprotein expression in oral cavity cancer
verfasst von
Ji Won Kim
Yangsoon Park
Jong-Lyel Roh
Kyung-Ja Cho
Seung-Ho Choi
Soon Yuhl Nam
Sang Yoon Kim
Publikationsdatum
21.03.2016
Verlag
Springer Japan
Erschienen in
International Journal of Clinical Oncology / Ausgabe 5/2016
Print ISSN: 1341-9625
Elektronische ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-016-0973-1

Weitere Artikel der Ausgabe 5/2016

International Journal of Clinical Oncology 5/2016 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.