Deregulation of CLTC interacts with TFG, facilitating osteosarcoma via the TGF-beta and AKT/mTOR signaling pathways.

Abstract

Although the treatment of osteosarcoma has improved, the overall survival rate of this common type of osseous malignancies has not changed for four decades. Thus, new targets for better therapeutic regimens are urgently needed. In this study, we found that high expression of clathrin heavy chain (CLTC) was an independent prognostic factor for tumor-free survival (HzR, 3.049; 95% CI, 1.476-6.301) and overall survival (HzR, 2.469; 95% CI, 1.005-6.067) of patients with osteosarcoma. Down-regulation of CLTC resulted in tumor-suppressive effects in vitro and in vivo. Moreover, we found that CLTC was transcriptionally regulated by a transcription factor-specificity protein 1 (SP1), which binds to the CLTC promoter at the -320 to -314-nt and +167 to +173-nt loci. Mechanistic investigations further revealed that CLTC elicited its pro-tumor effects by directly binding to and stabilizing trafficking from the endoplasmic reticulum to the Golgi regulator (TFG). Importantly, overexpression of TFG rescued both the tumor-suppressive effect and inhibition of the TGF-β and AKT/mTOR pathways caused by CLTC down-regulation, which indicated that the activity of CLTC was TFG-dependent. Immunohistochemistry analysis confirmed that CLTC expression was positively correlated with TFG expression. These findings collectively highlight CLTC as a new prognostic biomarker for patients with osteosarcoma, and the interruption of the SP1/CLTC/TFG axis may serve as a novel therapeutic strategy for osteosarcoma.

• Authors: Li Shijie, Pan Zhen, Qin Kang, Guo Hua, Yang Qingcheng, Cheng Dongdong
• Journal: Clinical and translational medicine (Clin Transl Med) Vol. 11 Issue 6 Pg. e377 (06 2021) ISSN: 2001-1326 [Electronic] United States
• PMID: 34185412 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Chemical References

• Biomarkers, Tumor
• CLTC protein, human
• Proteins
• TFG protein, human
• Transforming Growth Factor beta
• Clathrin Heavy Chains
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Adult
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Bone Neoplasms (genetics, metabolism, pathology)
• Cell Cycle
• Cell Movement
• Cell Proliferation
• Clathrin Heavy Chains (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Osteosarcoma (genetics, metabolism, pathology)
• Prognosis
• Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction
• Survival Rate
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Young Adult