Loss of GDF10/BMP3b as a prognostic marker collaborates with TGFBR3 to enhance chemotherapy resistance and epithelial-mesenchymal transition in oral squamous cell carcinoma.
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.
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
Chieh-Wen
CW
Cheng
Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Jenn-Ren
JR
Hsiao
Department of Physiology, Mackay Memorial Hospital, Taipei, Taiwan.|Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu, Taiwan.
Chi-Chen
CC
Fan
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
Yu-Kang
YK
Lo
Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan.
Chi-Yuan
CY
Tzen
Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Li-Wha
LW
Wu
Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wei-Yu
WY
Fang
Department of Medical Biotechnology, Chang Gung University, Taoyuan, Taiwan.
Ann-Joy
AJ
Cheng
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
Chung-Hsing
CH
Chen
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
I-Shou
IS
Chang
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
Shih Sheng
SS
Jiang
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.|Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
Jang-Yang
JY
Chang
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.|Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Alan Yueh-Luen
AY
Lee
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D055413:Growth Differentiation Factor 10 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis
C525785:GDF10 protein, human; D055413:Growth Differentiation Factor 10; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan
EMT; GDF10/BMP3b; TGFBR3; chemotherapy resistance; oral cancer; prognostic marker