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XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis.

ABSTRACT: Lung cancer is the most frequently diagnosed cancer and the main cause of cancer death in the world. X-box binding protein 1 (XBP1), which is an important transcription factor involved in regulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, might act as a potent oncogenic protein in the processes of tumorigenesis, tumor proliferation and metastasis in various cancers. However, the clinical significance and pathological role of XBP1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the expression of XBP1s protein in the 104 NSCLC tumor tissues and matched adjacent normal lung tissues (ANLT) by Immunohistochemical (IHC), and we found overexpressed XBP1s protein was associated with NSCLC TNM stages, lymph node metastasis and poor prognosis. The further gain-and loss-of-function experiments indicated overexpression of XBP1s protein promoted cell invasion, migration and metastasis both in vitro and in vivo. Further study showed XBP1s protein could upregulate insulin-like growth factor binding protein-3 (IGFBP3) expression, and regulated NSCLC cells invasion and metastasis by regulating IGFBP3. Taken together, XBP1s protein is markedly overexpressed in NSCLC and serves as an oncogene that play a critical role in NSCLC tumorigenesis and development. Importantly, XBP1s protein might not only be a potential biomarker for metastasis and prognosis but also a potential therapeutic target in NSCLC.

SUBMITTER: Luo Q

PROVIDER: S-EPMC8169999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeuro-oncological ventral antigen 1 (NOVA1) is a neuron-specific RNA-binding protein which regulates alternative splicing in the developing nervous system. Recent research has found that NOVA1 plays a significant role in carcinogenesis. In this paper, we examine the role of NOVA1 in non-small cell lung cancer (NSCLC) and its underlying molecular mechanisms.MethodsThe expression of NOVA1 in NSCLC was detected by immunohistochemistry and correlations between NOVA1 expression and clinicopathological factors were analyzed by chi-square tests. Kaplan-Meier survival analysis and the Cox regression model were used to evaluate the predictive effect of prognostic factors. Western blotting, Cell Counting Kit-8, colony formation, apoptosis, migration and invasion assays were used to detect the effects of silencing (si)NOVA1 RNA on Wnt/β-catenin signaling and biological behavior in NSCLC cell lines.ResultsOur study showed that expression of NOVA1 was up-regulated and significantly correlated with poor differentiation (p = 0.020), advanced TNM stage (P = 0.001), T stage (P = 0.001) and lymph node metastasis (P = 0.000) as well as the expression of β-catenin (P = 0.012) in NSCLC. The down-regulation of NSCLC by siRNA significantly inhibited proliferation, migration and invasion and promoted apoptosis in NSCLC cells. Expression of Wnt signaling molecules, including β-catenin, activated β-catenin, cyclin D1, matrix metalloproteinase (MMP)-2 and MMP-7, was also significantly reduced by siNOVA1. The inhibition of Wnt/β-catenin signaling in A549 and H1299 cells by siNOVA1 was reversed after treatment with a β-catenin expression plasmid.ConclusionThe present study suggests that NOVA1 may serve as a potential prognosis biomarker in NSCLC. High NOVA1 expression was associated with poor survival rate. Finally, in vitro experiments verified that NOVA1 promotes NSCLC cell proliferation and invasion by regulating Wnt/β-catenin signaling.

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XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis.

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