Tetraspanin 7 promotes osteosarcoma cell invasion and metastasis by inducing EMT and activating the FAK-Src-Ras-ERK1/2 signaling pathway

Abstract

Background Tetraspanins are members of the 4-transmembrane protein superfamily (TM4SF) that function by recruiting many cell surface receptors and signaling proteins into tetraspanin-enriched microdomains (TEMs) that play vital roles in the regulation of key cellular processes including adhesion, motility, and proliferation. Tetraspanin7 (Tspan7) is a member of this superfamily that plays documented roles in hippocampal neurogenesis, synaptic transmission, and malignant transformation in certain tumor types. How Tspan7 influences the onset or progression of osteosarcoma (OS), however, remains to be defined. Herein, this study aimed to explore the relationship between Tspan7 and the malignant progression of OS, and its underlying mechanism of action. Methods In this study, the levels of Tspan7 expression in human OS cell lines were evaluated via qRT-PCR and western blotting. The effect of Tspan7 on proliferation was examined using CCK-8 and colony formation assays, while metastatic role of Tspan7 was assessed by functional assays both in vitro and in vivo. In addition, mass spectrometry and co-immunoprecipitation were performed to verify the interaction between Tspan7 and β1 integrin, and western blotting was used to explore the mechanisms of Tspan7 in OS progresses. Results We found that Tspan7 is highly expressed in primary OS tumors and OS cell lines. Downregulation of Tspan7 significantly suppressed OS growth, metastasis, and attenuated epithelial-mesenchymal transition (EMT), while its overexpression had the opposite effects in vitro. Furthermore, it exhibited reduced OS pulmonary metastases in Tspan7-deleted mice comparing control mice in vivo. Additionally, we proved that Tspan7 interacted with β1 integrin to facilitate OS metastasis through the activation of integrin-mediated downstream FAK-Src-Ras-ERK1/2 signaling pathway. Conclusion In summary, this study demonstrates for the first time that Tspan7 promotes OS metastasis via interacting with β1 integrin and activating the FAK-Src-Ras-ERK1/2 pathway, which could provide rationale for a new therapeutic strategy for OS.

Identification and validation of a novel prognostic model based on platinum resistance-related genes in bladder cancer

“…Although TSPAN7 is an anti-tumor factor in bladder cancer, it promoted lung cancer progression by inhibits the expression of E-cadherin and vimentin, which raises the level of N-cadherin ( 48 ). It also has an interaction with the activation of β1 integrin-mediated downstream FAK-Src-Ras-ERK1/2 signaling pathway in osteosarcoma ( 49 ), boosting the cell epithelial-mesenchymal transition (EMT) process, indicating that the mechanisms of this gene and its downstream products still need to be explored. In lung cancer, AKR1B1 is a STAT3 activator that promotes glutathione de novo synthesis, eliminates ROS, protects cell from death, and reduces EGFR TKI drug sensitivity by upregulating the cystine transporter SLC7A11, it would be a therapeutic target for dealing with EGFR TKI resistance ( 50 ).…”

Identification and Validation of a Novel Prognostic Model Based on Platinum Resistance-Related Genes in Bladder Cancer

“…TSPAN7 inhibits the expression of E-cadherin and vimentin, which raises the level of N-cadherin44. 44 It also has an interaction with the activation of β1 integrin-mediated downstream FAK-Src-Ras-ERK1/2 signaling pathway 45 , boosting the cell epithelial-mesenchymal transition (EMT) process. Interestingly, TSPAN7 also exerts an anti-tumor effects via the PTEN/PI3K/AKT pathway 46 , indicating that the mechanisms of this gene and its downstream products still need to be explored.…”

Overexpression of hsa_circ_0061817 Can Inhibit the Proliferation and Invasion of Lung Cancer Cells Based on Active Compounds

“…Studies have shown that tumor cells enhance the ability of tumor cell migration and movement by means of EMT and promote tumor invasion and metastasis [32]. More and more studies have shown that EMT is an important link in tumor invasion and metastasis [33,34] and promotes the invasion and migration ability of lung cells [35]. Its main characteristics are the increase of vimentin expression and the decrease of E-cadherin expression.…”