High expression of spliced X-Box Binding Protein 1 in lung tumors is associated with cancer aggressiveness and epithelial-to-mesenchymal transition

Tavernier, Quentin; Legras, Antoine; Didelot, Audrey; Normand, Claudine; Gibault, Laure; Badoual, Cécile; Pimpec‐Barthes, Françoise Le; Puig, Pierre Laurent; Pallet, Nicolas

doi:10.1038/s41598-020-67243-8

Cited by 14 publications

(13 citation statements)

References 39 publications

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“…Moreover, XBP1 is widely expressed in various cancers (15)(16)(17)(18). Previous study demonstrated that XBP1s mRNA levels are highly expressed in lung cancer (19), however, the biological role and molecular mechanisms of XBP1 in NSCLC remain unknown. In this study, we reveal that overexpression of XBP1 promotes NSCLC tumorigenesis, invasion and metastasis by regulating IGFBP3 expression.…”

Section: Introductionmentioning

confidence: 99%

XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis

et al. 2021

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“…ER stress participates in many physiological and pathological processes, including EMT, and most studies indicate that ER stress can promote EMT [ 10 , 11 , 12 , 13 , 14 ]. However, we found that HP-β-CD suppressed EMT by triggering ER stress.…”

Section: Discussionmentioning

confidence: 99%

“…ER stress is involved in most cancers, leading to unfolded protein response that promotes epithelial-mesenchymal transition (EMT), survival, and drug resistance [ 10 , 11 ]. For instance, enhanced ER stress was demonstrated to induce EMT and subsequently increase cell migration in human non-small cell lung cancer cells and lens epithelial cells [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

Zhao

Zhu

et al. 2021

Metabolites

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Cholesterol metabolism affects endoplasmic reticulum (ER) stress and modulates epithelial-mesenchymal transition (EMT). Our previous study demonstrated that 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) attenuated EMT by blocking the transforming growth factor (TGF)-β/Smad signaling pathway and activating ER stress in MDA-MB-231 cells. To further assess the detailed mechanisms between cholesterol metabolism, ER stress, and EMT, LXR-623 (an agonist of LXRα) and simvastatin were used to increase and decrease cholesterol efflux and synthesis, respectively. Here, we found that high HP-β-CD concentrations could locally increase cholesterol levels in the ER by decreasing LXRα expression and increasing Hydroxymethylglutaryl-Coenzyme A reductase (HMGCR) expression in MDA-MB-231 and BT-549 cells, which triggered ER stress and inhibited EMT. Meanwhile, tunicamycin-induced ER stress blocked the TGF-β/Smad signaling pathway. However, low HP-β-CD concentrations can decrease the level of membrane cholesterol, enhance the TGF-β receptor I levels in lipid rafts, which helped to activate TGF-β/Smad signaling pathway, inhibit ER stress and elevate EMT. Based on our findings, the use of high HP-β-CD concentration can lead to cholesterol accumulation in the ER, thereby inducing ER stress, which directly suppresses TGF-β pathway-induced EMT. However, HP-β-CD is proposed to deplete membrane cholesterol at low concentrations and concurrently inhibit ER stress and induce EMT by promoting the TGF-β signaling pathways.

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“…Epithelial–mesenchymal transition (EMT), characterized by the loss of epithelial characteristics and the acquisition of mesenchymal characteristics, is considered to be the first step in metastasis [ 41 ]. Previous studies reported that in breast cancer, lung cancer, oral squamous cell carcinoma, and hepatocellular carcinoma, XBP1-s promotes metastasis by directly upregulating the transcription of EMT-inducing factors, such as Snail and zinc finger E-box ( ZEB ), leading to poor prognosis and a low survival rate [ 42 , 111 , 112 , 125 , 126 ].…”

Section: The Role Of Xbp1 In Diseasesmentioning

confidence: 99%

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology

Luo

Alfason

Wei

et al. 2022

IJMS

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X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells. Its aberrant expression is closely related to inflammation, neurodegenerative disease, viral infection, and is crucial for promoting tumor progression and drug resistance. Meanwhile, recent studies reported that the function of XBP1-u has been underestimated, as it is not merely a precursor of XBP1-s. Instead, XBP-1u is a critical factor involved in various biological pathways including autophagy and tumorigenesis through post-translational regulation. Herein, we summarize recent research on the biological functions of both XBP1-u and XBP1-s, as well as their relation to diseases.

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High expression of spliced X-Box Binding Protein 1 in lung tumors is associated with cancer aggressiveness and epithelial-to-mesenchymal transition

Cited by 14 publications

References 39 publications

XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis

XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis

2-Hydroxypropyl-β-cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology

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