PLK1/vimentin signaling facilitates immune escape by recruiting Smad2/3 to PD-L1 promoter in metastatic lung adenocarcinoma

Jang, Hay-Ran; Shin, Sol-Bi; Kim, Chang-Hyeon; Won, Jae-Yeon; Xu, Rong; Kim, Daeun; Yim, Hyungshin

doi:10.1038/s41418-021-00781-4

Cited by 55 publications

(46 citation statements)

References 61 publications

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“…44 In a recent study, it has been reported that PLK1mediated phosphorylation of vimentin can also activate TGFβ signaling pathway, leading to the metastasis and immune escape through the expression of PD-L1 which can serve as a shuttling protein in lung adenocarcinoma. 45 Therefore, the increase in vimentin- interest that miRNA-155 promotes cervical cancer cell proliferation through suppression of its target gene LKB1. 48 In addition, there are reports showing that expression of LKB1, an upstream kinase of AMPK, impeded TGFβ-induced Smad phosphorylation and their transcriptional activity in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Rahman

Ranjithkumar

Bansal

et al. 2022

American Journal of Transplantation

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Epithelial-mesenchymal transition (EMT) has been implicated to play a role in chronic lung allograft dysfunction (CLAD). Liver kinase B1 (LKB1), a tumor suppressor gene, can regulate EMT. However, its role in CLAD development following lung transplantation remains unknown. Using qRT-PCR, biopsies from lung transplant recipients with bronchiolitis obliterans syndrome (BOS) demonstrated significant downregulation of LKB1 (p = .0001), compared to stable biopsies. To determine the role of LKB1 in EMT development, we analyzed EMT in human bronchial epithelial cell line BEAS-2B.Knockdown of LKB1 by siRNA significantly dysregulated mesenchymal markers expression in BEAS-2B cells. Following incubation of human primary bronchial epithelial cell or BEAS-2B cells with exosomes isolated from BOS or stable lung transplant recipients, LKB1 expression was inhibited when incubated with BOS-exosome. Incubation with BOS-exosomes also decreased LKB1 expression and induced EMT markers in air-liquid interface culture method. Our results provide novel evidence that exosomes released from transplanted lungs undergoing chronic rejection are associated with inactivated tumor suppressor gene LKB1 and this loss induces EMT leading to the pathogenesis of CLAD following human lung transplantation. K E Y W O R D S basic (laboratory) research/science, biomarker, bronchiolitis obliterans (BOS), lung (allograft) function/dysfunction, molecular biology 1 | INTRODUC TI ON Lung transplantation (LTx) is a therapeutic option for patients with advanced lung diseases. Long-term survival after LTx is limited by chronic lung allograft dysfunction (CLAD). CLAD commonly manifests as bronchiolitis obliterans syndrome (BOS), defined by a sustained reduction in the forced expiratory volume in first second of expiration. 1 BOS occurs in 50% of recipients within 5 years post-LTx

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Section: Discussionmentioning

confidence: 99%

Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Rahman

Ranjithkumar

Bansal

et al. 2022

American Journal of Transplantation

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“…These results are in agreement with previous studies demonstrating that high expression of VIM or ITGB2 is related to cancer progression and metastasis [ 89 , 90 , 91 , 92 , 93 ]. In addition, hypoxia [ 94 , 95 , 96 ] and TGFβ [ 97 , 98 , 99 , 100 ] have been shown to induce VIM and ITGB2 expression. Although the effect of hypoxia on ITGB2 activity has not yet been described, hypoxia is known to be involved in the routing, recycling, and activation of various integrin β subunits [ 101 , 102 , 103 ], suggesting that it may also have an effect on ITGB2 activity.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion

Brochu-Gaudreau

Charbonneau

Harper

et al. 2022

Cancers

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Transforming growth factor β (TGFβ) plays a paradoxical role in cancer, first inhibiting then promoting its progression, a duality that poses a real challenge for the development of effective TGFβ-targeted therapies. The major TGFβ downstream effectors, SMAD2 and SMAD3, display both distinct and overlapping functions and accumulating evidence suggests that their activation ratio may contribute to the dual effect of TGFβ. However, the mechanisms responsible for their selective activation remain poorly understood. Here, we provide experimental evidence that hypoxia induces the pro-invasive arm of TGFβ signaling through a selective increase in SMAD3 interaction with SMAD-Anchor for Receptor Activation (SARA). This event relies on HDAC6-dependent SMAD3 bioavailability, as well as increased SARA recruitment to EEA1+ endosomes. A motility gene expression study indicated that SMAD3 selectively increased the expression of ITGB2 and VIM, two genes that were found to be implicated in hypoxia-induced cell invasion and associated with tumor progression and metastasis in cohorts of cancer patients. Furthermore, CAM xenograft assays show the significant benefit of selective inhibition of the SMAD3 signaling pathway as opposed to global TGFβ inhibition in preventing tumor progression. Overall, these results suggest that fine-tuning of the pro-invasive HDAC6-SARA-SMAD3 axis could be a better strategy towards effective cancer treatments.

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“…ANLN promotes LUAD progression via activating RHOA and involving the PI3K/AKT signaling ( Suzuki et al, 2005 ). PLK1/vimentin pathway promotes immune escape through recruitment of Smad2/3 to PD-L1 promoter in LUAD metastasis ( Jang et al, 2021 ). PLK1 induces migration of LUAD epithelial cells through STAT3 ( Yan et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Genomics and Prognosis Analysis of N6-Methyladenosine Regulators in Lung Adenocarcinoma

Zhang

2021

Front. Genet.

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Objective: N6-methyladenosine (m6A) modification is involved in modulating various biological processes in human cancers. But the implication of m6A modification in lung adenocarcinoma (LUAD) is still unclear. Hence, this study conducted a comprehensive analysis of the expression and clinical implication of m6A regulators in LUAD.Methods: Consensus clustering analysis of 502 LUAD samples in the TCGA dataset was presented based on the expression profiles of 20 m6A regulators using ConsensusClusterPlus package. Overall survival (OS), activation of signaling pathways and tumor immunity (immune/stromal score, tumor purity, expression of HLA and immune checkpoints, and immune cell infiltration) were compared between m6A modification patterns. The m6A-related genes between patterns were identified and prognostic m6A-related genes were imported into LASSO-cox regression analysis. The m6A risk score was developed and its prognostic implication was evaluated and externally verified in the GSE30219 and GSE72094 dataset. Furthermore, a nomogram that contained independent prognostic indicators was established, followed by external verification.Results: Two m6A modification patterns were clustered across LUAD based on the expression similarity of the m6A regulators via consensus clustering analysis, with distinct OS, activation of signaling pathways and tumor immunity. Totally, 213 m6A-related genes that were identified by comparing two patterns were significantly related to LUAD prognosis. By LASSO method, we constructed the m6A risk score that was a reliable and independent prognostic factor for LUAD. Patients with low m6A risk score displayed a prominent survival advantage. After incorporating independent clinical features, we developed the prognostic nomogram that exhibited high predictive accuracy and the best clinical net benefit for OS.Conclusion: Collectively, our study may provide a clinically useful tool for precise prognostic management and optimization of immunotherapeutic strategies for LUAD patients.

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PLK1/vimentin signaling facilitates immune escape by recruiting Smad2/3 to PD-L1 promoter in metastatic lung adenocarcinoma

Cited by 55 publications

References 61 publications

Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction

Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion

Genomics and Prognosis Analysis of N6-Methyladenosine Regulators in Lung Adenocarcinoma

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