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.

Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer

“…The clinicopathological characteristics in 154 patients are shown in Table S4 . The multivariate Cox analysis showed that cigarette smoking, differentiation, and lymph node metastasis are independent risk factors to predict poor outcome of OSCC patients (Table S5 ), which is similar to our recent study on OSCC 41 . Subsequently, our results indicated that the expression of Cdc7 is significantly positively correlated with HCLK2 ( P = 0.001) and ATR ( P = 0.037); it has the same trend with the expression of HSP90 (Fig.…”

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

“…We conducted RNA-Seq analysis to identify differentially expressed genes (DEGs) between clinical TNBC specimens and tumor-matched controls and found significant downregulation of growth differentiation factor-10 (GDF10), a member of the transforming growth factor-β (TGF-β) superfamily [12]. GDF10 plays an important role in cell proliferation and differentiation and is also known as BMP-3B due to its close relationship with bone morphogenetic protein-3 (BMP3), another member of the TGF-β superfamily [12]. TGF-β signals through three cell surface receptors, namely TGFBR1/2/3 [13,14].…”

Distinct lymphocyte antigens 6 (Ly6) family members Ly6D, Ly6E, Ly6K and Ly6H drive tumorigenesis and clinical outcome

“…We have previously shown that increased levels of Ly6A/E (Sca-1) promote breast tumorigenesis via disruption of TGF-β signaling and suppression of GDF10 expression in mouse models [ 2 ]. GDF10 has been shown to regulate epithelial to mesenchymal transition, growth and invasion in oral squamous cell carcinoma [ 16 ]. These finding suggest that Ly6 genes family members have important role multiple cancer but a comprehensive analysis of multiple members of Ly6 gene family and its relation to cancer patient survival is lacking.…”