TSSC3 promotes autophagy via inactivating the Src-mediated PI3K/Akt/mTOR pathway to suppress tumorigenesis and metastasis in osteosarcoma, and predicts a favorable prognosis

Abstract

BackgroundOver the last two or three decades, the pace of development of treatments for osteosarcoma tends has been slow. Novel effective therapies for osteosarcoma are still lacking. Previously, we reported that tumor-suppressing STF cDNA 3 (TSSC3) functions as an imprinted tumor suppressor gene in osteosarcoma; however, the underlying mechanism by which TSSC3 suppresses the tumorigenesis and metastasis remain unclear.MethodsWe investigated the dynamic expression patterns of TSSC3 and autophagy-related proteins (autophagy related 5 (ATG5) and P62) in 33 human benign bone tumors and 58 osteosarcoma tissues using immunohistochemistry. We further investigated the correlations between TSSC3 and autophagy in osteosarcoma using western blotting and transmission electronic microscopy. CCK-8, Edu, and clone formation assays; wound healing and Transwell assays; PCR; immunohistochemistry; immunofluorescence; and western blotting were used to investigated the responses in TSSC3-overexpressing osteosarcoma cell lines, and in xenografts and metastasis in vivo models, with or without autophagy deficiency caused by chloroquine or ATG5 silencing.ResultsWe found that ATG5 expression correlated positively with TSSC3 expression in human osteosarcoma tissues. We demonstrated that TSSC3 was an independent prognostic marker for overall survival in osteosarcoma, and positive ATG5 expression associated with positive TSSC3 expression suggested a favorable prognosis for patients. Then, we showed that TSSC3 overexpression enhanced autophagy via inactivating the Src-mediated PI3K/Akt/mTOR pathway in osteosarcoma. Further results suggested autophagy contributed to TSSC3-induced suppression of tumorigenesis and metastasis in osteosarcoma in vitro and in vivo models.ConclusionsOur findings highlighted, for the first time, the importance of autophagy as an underlying mechanism in TSSC3-induced antitumor effects in osteosarcoma. We also revealed that TSSC3-associated positive ATG5 expression might be a potential predictor of favorable prognosis in patients with osteosarcoma.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0856-6) contains supplementary material, which is available to authorized users.

miR-210-5p promotes epithelial–mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells

“…In contrast, Gugnoni et al 30 reported that preventing autophagy could lead to EMT and cancer metastasis. Another study also confirmed that autophagy inhibited EMT and may lead to reversion of the EMT phenotype in cancer cells 63 . In order to examine the underlying relationship between OS cells and EMT, we silenced ATG5, which is recognized to have an essential role in autophagosome formation.…”

Aurora-B Knockdown Inhibits Osteosarcoma Metastasis by Inducing Autophagy via the mTOR/ULK1 Pathway

“…Autophagy is known to be involved in tumor progression (26,27). In order to elucidate the effect of Aurora-B inhibition induced autophagy on the metastasis of OS cells, wound healing, transwell migration and invasion assays were performed to detect migration and invasion ability of OS cells.…”

“…These ndings indicate that autophagy plays an essential role in the process of Aurora-B affecting the ability of motility and invasive in OS cells. Autophagy is reported to inhibit cell migration by accelerating the degradation of MMP family proteins (26,27), therefore, we sought to determine the MMP2 protein levels in Aurora-Bknockdown OS cells with or without CQ treatment. Results showed that the suppression of MMP2 expression due to Aurora-B knockdown could be restored by CQ treatment (Fig.…”

Second-generation Src/Abl inhibitor bosutinib effectively induces apoptosis in human esophageal squamous cell carcinoma (ESCC) cells via inhibiting Src/Abl signaling

“…The non-receptor tyrosine kinase Src has been involved in multiple cancer-related process including proliferation and survival through Src-mediated PI3K/AKT/mTOR, MAPK/ ERK and JAK/STAT3 signaling [27][28][29], therefore it has been recently indicated as a promising therapeutic target in the treatment of solid tumors including ESCC [30]. In addition, it has been reported that Src is not only involved in tumor progression but also associated with the resistance to anticancer drugs in traditional and targeted therapies [31].…”