Abstract
Increasing evidence demonstrates that dysregulation of XBP1 function contributes to tumorigenesis in some cancers. However, little is known about the role of XBP1 in the progression of osteosarcoma (OS). The expression of XBP1 in OS samples was measured by quantitative RT-PCR and Western blotting assays. Cell cycle analysis and cell counting kit 8 (CCK8) assays were performed to determine the effects of XBP1 expression on cells growth capacity. Cell apoptosis coassay was applied to determine cell survival. The expression of genes affected by XBP1 was examined by quantitative RT-RCR and validated by Western blotting assays. XBP1 was overexpressed in OS clinical samples compared with corresponding non-cancerous tissues. Overexpression of XBP1 was significantly associated with advanced clinical stages, high degree of malignancy and low tumor necrosis rate. Furthermore, hypoxia activated XBP1, and silencing XBP1 significantly enhanced OS cell apoptosis. Knock-down of XBP1 resulted in inhibition of OS growth. Most importantly, knockdown of XBP1 led to down-regulation of PIK3R3 and mTOR. Taken together, XBP1 is up-regulated and has a pro-tumor effect in OS with activation of PI3K/mTOR signaling. Thus, targeting XBP1 may provide a new potential therapeutic method for OS.
Highlights
Osteosarcoma (OS) is the most frequent primary bone malignant neoplasm in children and young adults, which is of high propensity of local invasion and distant metastases [1,2]
We found that PI3K/mTOR signaling was involved in the process of XBP1-regulated OS progression, which suggests a novel mechanism of XBP1’s role in OS
We considered PI3K/mTOR signaling pathways, which played an important role in cell growth and survival [43,44]
Summary
Osteosarcoma (OS) is the most frequent primary bone malignant neoplasm in children and young adults, which is of high propensity of local invasion and distant metastases [1,2]. Tumor cells can induce a series of adaptive response signaling pathways to survival in the condition of deprivation of oxygen, ATP, or other essential nutrients [6] One such adaptive pathway is the endoplasmic reticulum (ER) stress response. Recent researches in human endothelial cells suggest a new mechanism that XBP1 is involved. Zeng et al indicated that VEGF-induced XBP1s regulated endothelial cell growth in a PI3K/Akt/GSK3β/β-catenin/E2F2–dependent manner [22]. Though these findings were not reported in tumor cells, it provided us new perspectives to investigate cancers. We found that PI3K/mTOR signaling was involved in the process of XBP1-regulated OS progression, which suggests a novel mechanism of XBP1’s role in OS. XBP1 may be a novel target for OS treatment
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