Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma

Chieh Wen Cheng, Jenn Ren Hsiao, Chi Chen Fan, Yu Kang Lo, Chi Yuan Tzen, Li Wha Wu, Wei Yu Fang, Ann Joy Cheng, Chung Hsing Chen, I. Shou Chang, Shih Sheng Jiang, Jang Yang Chang, Alan Yueh Luen Lee

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-β (TGF-β) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-β signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-β receptor (TGFBR3) through TGF-β-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.

Original languageEnglish
Pages (from-to)499-513
Number of pages15
JournalMolecular Carcinogenesis
Volume55
Issue number5
DOIs
Publication statusPublished - 2016 May 1

Fingerprint

Growth Differentiation Factor 10
Epithelial-Mesenchymal Transition
Squamous Cell Carcinoma
Drug Therapy
Transforming Growth Factors
Mouth Neoplasms
betaglycan
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

Cheng, Chieh Wen ; Hsiao, Jenn Ren ; Fan, Chi Chen ; Lo, Yu Kang ; Tzen, Chi Yuan ; Wu, Li Wha ; Fang, Wei Yu ; Cheng, Ann Joy ; Chen, Chung Hsing ; Chang, I. Shou ; Jiang, Shih Sheng ; Chang, Jang Yang ; Lee, Alan Yueh Luen. / Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma. In: Molecular Carcinogenesis. 2016 ; Vol. 55, No. 5. pp. 499-513.
@article{9a348ad752f24cd6b10c2eff9391f569,
title = "Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma",
abstract = "Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-β (TGF-β) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-β signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-β receptor (TGFBR3) through TGF-β-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.",
author = "Cheng, {Chieh Wen} and Hsiao, {Jenn Ren} and Fan, {Chi Chen} and Lo, {Yu Kang} and Tzen, {Chi Yuan} and Wu, {Li Wha} and Fang, {Wei Yu} and Cheng, {Ann Joy} and Chen, {Chung Hsing} and Chang, {I. Shou} and Jiang, {Shih Sheng} and Chang, {Jang Yang} and Lee, {Alan Yueh Luen}",
year = "2016",
month = "5",
day = "1",
doi = "10.1002/mc.22297",
language = "English",
volume = "55",
pages = "499--513",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",
number = "5",

}

Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma. / Cheng, Chieh Wen; Hsiao, Jenn Ren; Fan, Chi Chen; Lo, Yu Kang; Tzen, Chi Yuan; Wu, Li Wha; Fang, Wei Yu; Cheng, Ann Joy; Chen, Chung Hsing; Chang, I. Shou; Jiang, Shih Sheng; Chang, Jang Yang; Lee, Alan Yueh Luen.

In: Molecular Carcinogenesis, Vol. 55, No. 5, 01.05.2016, p. 499-513.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma

AU - Cheng, Chieh Wen

AU - Hsiao, Jenn Ren

AU - Fan, Chi Chen

AU - Lo, Yu Kang

AU - Tzen, Chi Yuan

AU - Wu, Li Wha

AU - Fang, Wei Yu

AU - Cheng, Ann Joy

AU - Chen, Chung Hsing

AU - Chang, I. Shou

AU - Jiang, Shih Sheng

AU - Chang, Jang Yang

AU - Lee, Alan Yueh Luen

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-β (TGF-β) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-β signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-β receptor (TGFBR3) through TGF-β-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.

AB - Growth differentiation factor-10 (GDF10), commonly referred as BMP3b, is a member of the transforming growth factor-β (TGF-β) superfamily. GDF10/BMP3b has been considered as a tumor suppressor, however, little is known about the molecular mechanism of its roles in tumor suppression in oral cancer. Clinical significance of GDF10 downregulation in oral squamous cell carcinoma (OSCC) was evaluated using three independent cohorts of OSCC patients. The molecular mechanisms of GDF10 in the suppression of cell survival, cell migration/invasion and epithelial-mesenchymal transition (EMT) were investigated by using oral cancer cell lines. The present study shows that GDF10 is downregulated during oral carcinogenesis, and GDF10 expression is also an independent risk factor for overall survival of OSCC patients. Overexpression of GDF10 attenuates cell proliferation, transformation, migration/invasion, and EMT. GDF10-inhibited EMT is mediated by ERK signaling but not by typical TGF-β signaling. In addition, overexpression of GDF10 promotes DNA damage-induced apoptosis and sensitizes the response to all-trans retinoic acid (ATRA) and camptothecin (CPT). Intriguingly, the expression of GDF10 is induced by type III TGF-β receptor (TGFBR3) through TGF-β-SMAD2/3 signaling. Our findings suggest that TGFBR3 is an upstream activator of GDF10 expression and they share the same signaling to inhibit EMT and migration/invasion. These results support that GDF10 acts as a hinge to collaborate with TGFBR3 in the transition of EMT-MET program. Taken together, we illustrated the clinical significance and the molecular mechanisms of tumor-suppressive GDF10 in OSCC.

UR - http://www.scopus.com/inward/record.url?scp=84923675792&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923675792&partnerID=8YFLogxK

U2 - 10.1002/mc.22297

DO - 10.1002/mc.22297

M3 - Article

C2 - 25728212

AN - SCOPUS:84923675792

VL - 55

SP - 499

EP - 513

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

IS - 5

ER -