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Published in: Cancer Cell International 1/2017

Open Access 01-12-2017 | Primary Research

Repression of GPRC5A is associated with activated STAT3, which contributes to tumor progression of head and neck squamous cell carcinoma

Authors: Shuli Liu, Dongxia Ye, Tong Wang, Wenzheng Guo, Hongyong Song, Yueling Liao, Dongliang Xu, Hanguang Zhu, Zhiyuan Zhang, Jiong Deng

Published in: Cancer Cell International | Issue 1/2017

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Abstract

Background

G protein–coupled receptor family C group 5 member A (GPRC5A), a retinoic acid-inducible gene, is a lung tumor suppressor. Previously, we showed that repression of GPRC5A expression was associated with pathologic differentiation grade of oral squamous cell carcinomas (OSCC) and overexpression of GPRC5A gene inhibited the malignant phenotype in OSCC cells, suggesting that GPRC5A also functions as a tumor suppressor in oral cancer. However, the molecular mechanisms underlying GPRC5A deficiency in head and neck squamous cell carcinoma (HNSCC) are still unclear.

Methods

In this study, we used Western blot analysis and immunohistochemical (IHC) staining to investigate the expression of GPRC5A in both HNSCC cell lines and clinical samples. GPRC5A stable transfectants and their parental HNSCC cells were characterized for their biological activities in anchorage-independent growth.

Results

IHC analysis showed that, GPRC5A expression was high in normal tissue, but gradually decreased in oral leukoplakia, a precancerous stage, and greatly suppressed in primary cancer. Repression of GPRC5A was correlated with activated STAT3, which associates with aggressive clinicopathological features in HNSCC patients. Moreover, overexpression of GPRC5A suppressed IL-6-induced-STAT3 activation and inhibited anchorage-independent growth in HNSCC cells.

Conclusions

Repressed GPRC5A associates with increased tumor grade and activated STAT3, which may be used as a prognostic marker for tumor progression of HNSCC.
Literature
2.
go back to reference Tsantoulis PK, Kastrinakis NG, Tourvas AD, Laskaris G, Gorgoulis VG. Advances in the biology of oral cancer. Oral Oncol. 2007;43(6):523–34.CrossRefPubMed Tsantoulis PK, Kastrinakis NG, Tourvas AD, Laskaris G, Gorgoulis VG. Advances in the biology of oral cancer. Oral Oncol. 2007;43(6):523–34.CrossRefPubMed
3.
go back to reference Chidzonga MM, Mahomva L. Squamous cell carcinoma of the oral cavity, maxillary antrum and lip in a Zimbabwean population: a descriptive epidemiological study. Oral Oncol. 2006;42(2):184–9.CrossRefPubMed Chidzonga MM, Mahomva L. Squamous cell carcinoma of the oral cavity, maxillary antrum and lip in a Zimbabwean population: a descriptive epidemiological study. Oral Oncol. 2006;42(2):184–9.CrossRefPubMed
4.
go back to reference Scully C. Oral precancer: preventive and medical approaches to management. Eur J Cancer B Oral Oncol. 1995;31(1):16–26.CrossRef Scully C. Oral precancer: preventive and medical approaches to management. Eur J Cancer B Oral Oncol. 1995;31(1):16–26.CrossRef
5.
go back to reference Schepman K, der Meij E, Smeele L, der Waal I. Concomitant leukoplakia in patients with oral squamous cell carcinoma. Oral Dis. 1999;5(3):206–9.CrossRefPubMed Schepman K, der Meij E, Smeele L, der Waal I. Concomitant leukoplakia in patients with oral squamous cell carcinoma. Oral Dis. 1999;5(3):206–9.CrossRefPubMed
6.
go back to reference Tao Q, Fujimoto J, Men T, Ye X, Deng J, Lacroix L, Clifford JL, Mao L, Van Pelt CS, Lee JJ, et al. Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene. J Natl Cancer Inst. 2007;99(22):1668–82.CrossRefPubMed Tao Q, Fujimoto J, Men T, Ye X, Deng J, Lacroix L, Clifford JL, Mao L, Van Pelt CS, Lee JJ, et al. Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene. J Natl Cancer Inst. 2007;99(22):1668–82.CrossRefPubMed
7.
go back to reference Cheng Y, Lotan R. Molecular cloning and characterization of a novel retinoic acid-inducible gene that encodes a putative G protein-coupled receptor. J Biol Chem. 1998;273(52):35008–15.CrossRefPubMed Cheng Y, Lotan R. Molecular cloning and characterization of a novel retinoic acid-inducible gene that encodes a putative G protein-coupled receptor. J Biol Chem. 1998;273(52):35008–15.CrossRefPubMed
8.
go back to reference Liu SL, Zhong SS, Ye DX, Chen WT, Zhang ZY, Deng J. Repression of G protein–coupled receptor family C group 5 member A is associated with pathologic differentiation grade of oral squamous cell carcinoma. J Oral Pathol Med. 2013;42(10):761–8.CrossRefPubMed Liu SL, Zhong SS, Ye DX, Chen WT, Zhang ZY, Deng J. Repression of G protein–coupled receptor family C group 5 member A is associated with pathologic differentiation grade of oral squamous cell carcinoma. J Oral Pathol Med. 2013;42(10):761–8.CrossRefPubMed
9.
go back to reference Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.CrossRefPubMed Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.CrossRefPubMed
10.
13.
go back to reference Chen Y, Deng J, Fujimoto J, Kadara H, Men T, Lotan D, Lotan R. Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor. Cancer Res. 2010;70(21):8917–26.CrossRefPubMedPubMedCentral Chen Y, Deng J, Fujimoto J, Kadara H, Men T, Lotan D, Lotan R. Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor. Cancer Res. 2010;70(21):8917–26.CrossRefPubMedPubMedCentral
14.
go back to reference Rickman DS, Millon R, De Reynies A, Thomas E, Wasylyk C, Muller D, Abecassis J, Wasylyk B. Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays. Oncogene. 2008;27(51):6607–22.CrossRefPubMed Rickman DS, Millon R, De Reynies A, Thomas E, Wasylyk C, Muller D, Abecassis J, Wasylyk B. Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays. Oncogene. 2008;27(51):6607–22.CrossRefPubMed
15.
go back to reference Sudbo J, Kildal W, Risberg B, Koppang HS, Danielsen HE, Reith A. DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med. 2001;344(17):1270–8.CrossRefPubMed Sudbo J, Kildal W, Risberg B, Koppang HS, Danielsen HE, Reith A. DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med. 2001;344(17):1270–8.CrossRefPubMed
16.
go back to reference Liu S, Ye D, Xu D, Liao Y, Zhang L, Liu L, Yu W, Wang Y, He Y, Hu J, et al. Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma. Oncotarget. 2016;7(18):25251–63.PubMedPubMedCentral Liu S, Ye D, Xu D, Liao Y, Zhang L, Liu L, Yu W, Wang Y, He Y, Hu J, et al. Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma. Oncotarget. 2016;7(18):25251–63.PubMedPubMedCentral
17.
go back to reference Zhong S, Yin H, Liao Y, Yao F, Li Q, Zhang J, Jiao H, Zhao Y, Xu D, Liu S, et al. Lung tumor suppressor GPRC5A binds EGFR and restrains its effector signaling. Cancer Res. 2015;75(9):1801–14.CrossRefPubMed Zhong S, Yin H, Liao Y, Yao F, Li Q, Zhang J, Jiao H, Zhao Y, Xu D, Liu S, et al. Lung tumor suppressor GPRC5A binds EGFR and restrains its effector signaling. Cancer Res. 2015;75(9):1801–14.CrossRefPubMed
18.
go back to reference Papadimitrakopoulou VA, Hong WK, Lee JS, Martin JW, Lee JJ, Batsakis JG, Lippman SM. Low-dose isotretinoin versus beta-carotene to prevent oral carcinogenesis: long-term follow-up. J Natl Cancer Inst. 1997;89(3):257–8.CrossRefPubMed Papadimitrakopoulou VA, Hong WK, Lee JS, Martin JW, Lee JJ, Batsakis JG, Lippman SM. Low-dose isotretinoin versus beta-carotene to prevent oral carcinogenesis: long-term follow-up. J Natl Cancer Inst. 1997;89(3):257–8.CrossRefPubMed
19.
go back to reference Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36(10):575–80.CrossRefPubMed Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med. 2007;36(10):575–80.CrossRefPubMed
20.
go back to reference Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. 1984;53(3):563–8.CrossRefPubMed Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. 1984;53(3):563–8.CrossRefPubMed
21.
go back to reference Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, Benner SE, Xu XC, Lee JS, Papadimitrakopoulou VM, et al. Predicting cancer development in oral leukoplakia: 10 years of translational research. Clin Cancer Res. 2000;6(5):1702–10.PubMed Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, Benner SE, Xu XC, Lee JS, Papadimitrakopoulou VM, et al. Predicting cancer development in oral leukoplakia: 10 years of translational research. Clin Cancer Res. 2000;6(5):1702–10.PubMed
22.
go back to reference Shi P, Liu W, Zhou ZT, He QB, Jiang WW. Podoplanin and ABCG2: malignant transformation risk markers for oral lichen planus. Cancer Epidemiol Biomark Prev. 2010;19(3):844–9.CrossRef Shi P, Liu W, Zhou ZT, He QB, Jiang WW. Podoplanin and ABCG2: malignant transformation risk markers for oral lichen planus. Cancer Epidemiol Biomark Prev. 2010;19(3):844–9.CrossRef
23.
go back to reference Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42(5):461–74.CrossRefPubMed Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of oral premalignant lesions. Oral Oncol. 2006;42(5):461–74.CrossRefPubMed
24.
go back to reference Pitiyage G, Tilakaratne WM, Tavassoli M, Warnakulasuriya S. Molecular markers in oral epithelial dysplasia: review. J Oral Pathol Med. 2009;38(10):737–52.CrossRefPubMed Pitiyage G, Tilakaratne WM, Tavassoli M, Warnakulasuriya S. Molecular markers in oral epithelial dysplasia: review. J Oral Pathol Med. 2009;38(10):737–52.CrossRefPubMed
25.
go back to reference Mithani SK, Mydlarz WK, Grumbine FL, Smith IM, Califano JA. Molecular genetics of premalignant oral lesions. Oral Dis. 2007;13(2):126–33.CrossRefPubMed Mithani SK, Mydlarz WK, Grumbine FL, Smith IM, Califano JA. Molecular genetics of premalignant oral lesions. Oral Dis. 2007;13(2):126–33.CrossRefPubMed
26.
go back to reference Pontes HA, de Aquino Xavier FC, da Silva TS, Fonseca FP, Paiva HB, Pontes FS, dos Santos Pinto D, Jr. Metallothionein and p-Akt proteins in oral dysplasia and in oral squamous cell carcinoma: an immunohistochemical study. J Oral Pathol Med. 2009;38(8):644–50.CrossRefPubMed Pontes HA, de Aquino Xavier FC, da Silva TS, Fonseca FP, Paiva HB, Pontes FS, dos Santos Pinto D, Jr. Metallothionein and p-Akt proteins in oral dysplasia and in oral squamous cell carcinoma: an immunohistochemical study. J Oral Pathol Med. 2009;38(8):644–50.CrossRefPubMed
29.
30.
go back to reference Kawaguchi J, Mee PJ, Smith AG. Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors. Bone. 2005;36(5):758–69.CrossRefPubMed Kawaguchi J, Mee PJ, Smith AG. Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors. Bone. 2005;36(5):758–69.CrossRefPubMed
31.
go back to reference Kennedy KA, Porter T, Mehta V, Ryan SD, Price F, Peshdary V, Karamboulas C, Savage J, Drysdale TA, Li SC, et al. Retinoic acid enhances skeletal muscle progenitor formation and bypasses inhibition by bone morphogenetic protein 4 but not dominant negative beta-catenin. BMC Biol. 2009;7:67.CrossRefPubMedPubMedCentral Kennedy KA, Porter T, Mehta V, Ryan SD, Price F, Peshdary V, Karamboulas C, Savage J, Drysdale TA, Li SC, et al. Retinoic acid enhances skeletal muscle progenitor formation and bypasses inhibition by bone morphogenetic protein 4 but not dominant negative beta-catenin. BMC Biol. 2009;7:67.CrossRefPubMedPubMedCentral
32.
go back to reference Krueger JG, Krane JF, Carter DM, Gottlieb AB. Role of growth factors, cytokines, and their receptors in the pathogenesis of psoriasis. J Invest Dermatol. 1990;94(6 Suppl):135s–40s.CrossRefPubMed Krueger JG, Krane JF, Carter DM, Gottlieb AB. Role of growth factors, cytokines, and their receptors in the pathogenesis of psoriasis. J Invest Dermatol. 1990;94(6 Suppl):135s–40s.CrossRefPubMed
33.
go back to reference Grossman RM, Krueger J, Yourish D, Granelli-Piperno A, Murphy DP, May LT, Kupper TS, Sehgal PB, Gottlieb AB. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA. 1989;86(16):6367–71.CrossRefPubMedPubMedCentral Grossman RM, Krueger J, Yourish D, Granelli-Piperno A, Murphy DP, May LT, Kupper TS, Sehgal PB, Gottlieb AB. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA. 1989;86(16):6367–71.CrossRefPubMedPubMedCentral
34.
go back to reference Yoshizaki K, Nishimoto N, Matsumoto K, Tagoh H, Taga T, Deguchi Y, Kuritani T, Hirano T, Hashimoto K, Okada N, et al. Interleukin 6 and expression of its receptor on epidermal keratinocytes. Cytokine. 1990;2(5):381–7.CrossRefPubMed Yoshizaki K, Nishimoto N, Matsumoto K, Tagoh H, Taga T, Deguchi Y, Kuritani T, Hirano T, Hashimoto K, Okada N, et al. Interleukin 6 and expression of its receptor on epidermal keratinocytes. Cytokine. 1990;2(5):381–7.CrossRefPubMed
35.
go back to reference Woods KV, El-Naggar A, Clayman GL, Grimm EA. Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens. Cancer Res. 1998;58(14):3132–41.PubMed Woods KV, El-Naggar A, Clayman GL, Grimm EA. Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens. Cancer Res. 1998;58(14):3132–41.PubMed
36.
go back to reference Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Smith CW, Enamorado I, Yeh NT, Kroog GS, Rudy S, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5(6):1369–79.PubMed Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Smith CW, Enamorado I, Yeh NT, Kroog GS, Rudy S, et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res. 1999;5(6):1369–79.PubMed
37.
go back to reference Arany I, Chen SH, Megyesi JK, Adler-Storthz K, Chen Z, Rajaraman S, Ember IA, Tyring SK, Brysk MM. Differentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck. Cancer Lett. 2003;199(1):83–9.CrossRefPubMed Arany I, Chen SH, Megyesi JK, Adler-Storthz K, Chen Z, Rajaraman S, Ember IA, Tyring SK, Brysk MM. Differentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck. Cancer Lett. 2003;199(1):83–9.CrossRefPubMed
38.
go back to reference Shimada K, Uzawa K, Kato M, Endo Y, Shiiba M, Bukawa H, Yokoe H, Seki N, Tanzawa H. Aberrant expression of RAB1A in human tongue cancer. Br J Cancer. 2005;92(10):1915–21.CrossRefPubMedPubMedCentral Shimada K, Uzawa K, Kato M, Endo Y, Shiiba M, Bukawa H, Yokoe H, Seki N, Tanzawa H. Aberrant expression of RAB1A in human tongue cancer. Br J Cancer. 2005;92(10):1915–21.CrossRefPubMedPubMedCentral
39.
go back to reference Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, Tomita K, Komiyama S, Weinstein IB. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 2002;62(12):3351–5.PubMed Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, Tomita K, Komiyama S, Weinstein IB. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 2002;62(12):3351–5.PubMed
Metadata
Title
Repression of GPRC5A is associated with activated STAT3, which contributes to tumor progression of head and neck squamous cell carcinoma
Authors
Shuli Liu
Dongxia Ye
Tong Wang
Wenzheng Guo
Hongyong Song
Yueling Liao
Dongliang Xu
Hanguang Zhu
Zhiyuan Zhang
Jiong Deng
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2017
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-017-0406-x

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