Downregulation of MTSS1 expression is an independent prognosticator in squamous cell carcinoma of the lung

Kayser, Gian; Csanádi, Ágnes; Kakanou, S; Prasse, Antje; Kassem, Ahmad; Stickeler, Elmar; Passlick, Bernward; Hausen, Axel zur

doi:10.1038/bjc.2015.2

Cited by 24 publications

(17 citation statements)

References 40 publications

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“…Tumor-associated genes, MTSS1 , NKX6-2 , and BTG2 had CpGs that were highly significant in heavy smokers but showed little or no significance in light smokers (S4 Table). Metastasis Suppressor 1 ( MTSS1 ), is inactivated in metastatic cancer [39] and has prognostic value for breast cancer [40] and lung cancer [41]. NKX6-2 and BTG2 (B-Cell Translocation Gene 2) are candidate tumor suppressor genes [42,43].…”

Section: Discussionmentioning

confidence: 99%

Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes

Su¹,

Wang²,

Campbell³

et al. 2016

PLoS ONE

108

124

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Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking–associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology.

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Section: Discussionmentioning

confidence: 99%

Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes

Su¹,

Wang²,

Campbell³

et al. 2016

PLoS ONE

108

124

View full text Add to dashboard Cite

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“…To the best of our knowledge the present study was the first to outline the differential role of MTSS1 in invasion and proliferation in three subtypes of NSCLC. NSCLC consists of LAC, LCC and SCC (3). In the present study, H920 (LAC), H1581 (LCC) and SW900 (SCC) cell lines were used as representative cell models of the subtypes of NSCLC.…”

Section: Discussionmentioning

confidence: 99%

“…Non-small cell lung cancer (NSCLC), which is the predominant form of the disease, accounts for >80% of all cases of lung cancer (2). There are three types of NSCLC: Lung adenocarcinoma (LAC), large-cell carcinoma (LCC) and squamous cell carcinoma (SCC) (3). Despite great advances in surgery, chemotherapy and radiotherapy, the long-term survival of patients with NSCLC remains poor due to rapid growth and high rate of recurrence and metastasis (4,5).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of MTSS1 on invasion and proliferation in subtypes of non-small cell lung cancer cells

Ling

Chen

Liao

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Non-small cell lung cancer (NSCLC) accounts for >80% of all cases of lung cancer and can be divided into lung adenocarcinoma (LAC), large-cell carcinoma (LCC), and squamous cell carcinoma (SCC). Accumulating evidence suggests that MTSS1, which is a newly discovered protein associated with tumor progression and metastasis, may have differential roles in cancer malignancy. As it has been demonstrated that MTSS1 is overexpressed in NSCLC and may be an independent prognostic factor in patients with SCC, the present study explored the differential roles of MTSS1 in the invasion and proliferation of different subtypes of NSCLC. Stable overexpression and knockdown of MTSS1 was performed in human NSCLC H920 (LAC), H1581 (LCC) and SW900 cell lines (SCC), and western blot, cell invasion, proliferation and FAK activity analyses were used to investigate the effects. Overexpression of MTSS1 enhanced the invasion and proliferation abilities of H920 and H1581 cells, and these effects were abolished by treatment with selective FAK inhibitor 14, which did not affect the expression of MTSS1. Notably, overexpression of MTSS1 inhibited invasion and proliferation in SW900 cells, and this effect was enhanced by the selective FAK inhibitor. Knockdown of MTSS1 decreased the invasion and proliferation abilities of H920 and H1581 cells, whereas knockdown increased invasion and proliferation in SW900 cells. Furthermore, while overexpression of MTSS1 induced FAK phosphorylation and activity in H920 and H1581 cells, MTSS1 overexpression inhibited FAK phosphorylation/activity in SW900 cells. Knockdown of MTSS1 decreased FAK phosphorylation/activity in H920 and H1581 cells, whereas knockdown increased these processes in SW900 cells. To the best of our knowledge, the present study was the first to demonstrate that MTSS1 has differential roles in various subtypes of NSCLC, acting via a FAK-dependent mechanism. The results indicated that MTSS1 may enhance invasion and proliferation in LAC and LCC cells, whereas MTS11 inhibits these processes in SCC cells. These findings provide novel insight into the functional role of MTSS1 in cancer and may help elucidate therapeutic strategies for the treatment of various types of cancer. IntroductionLung cancer remains the leading cause of death from cancer worldwide, with ~1.4 million deaths each year (1). Non-small cell lung cancer (NSCLC), which is the predominant form of the disease, accounts for >80% of all cases of lung cancer (2). There are three types of NSCLC: Lung adenocarcinoma (LAC), large-cell carcinoma (LCC) and squamous cell carcinoma (SCC) (3). Despite great advances in surgery, chemotherapy and radiotherapy, the long-term survival of patients with NSCLC remains poor due to rapid growth and high rate of recurrence and metastasis (4,5). Therefore, it is imperative that the precise molecular mechanisms underlying the invasion and metastasis of NSCLC are investigated.Metastasis suppressor 1 (MTSS1), which is also known as MIM (missing-in-metastasis), was first identified as a potential...

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“…This suggests that ARID2 might regulate directly MTSS1 expression, although further work is necessary to finally confirm this. MTSS1 is a well described migration and invasion inhibitor, associated with worse prognosis in several tumor types 28,29,41 and its deficiency might well explain the higher migration and invasion capabilities of ARID2-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, among those genes whose expression rely on ARID2, we found MTSS1, a well described metastasis inhibitor 28,28,29 . The observed significant reduction of MTSS1 expression likely explain the higher invasion capabilities of ARID2-deficient cells.…”

Section: Arid2 Is Essential To Maintain the Expression Of The Metastamentioning

confidence: 92%

ARID2deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer

Moreno

González-Silva

Monterde

et al. 2020

Preprint

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Red de Enfermedades Raras byimpairing DNA repair. Importantly, our results indicate that ARID2-deficiency could be(CIBERER).Tenerife, Spain. RUNNING TITLEARID2-deficiency directs sensitivity to PARP inhibition. KEY WORDSARID2/Lung Cancer/Next-generation sequencing technologies/SWI-SNF FINANCIAL SUPPORTI. ABSTRACTThe survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. Last decade's research has evidenced a clear role of chromatin structure in cancer development and several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown.In this study, we have performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure, as well as functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development.We have identified ARID2 production loss in 20% of lung cancer patients. Additionally, we have shown that ARID2-deficiency provokes profound chromatin structural changes, alters the transcriptional programme and impairs DNA repair which bolster the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we have demonstrated that ARID2 deficiency significantly affects the sensitivity of the cells to PARP inhibition.All these results support that ARID2 is a bona-fide tumor suppressor gene in lung cancer that might be exploited therapeutically.

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Downregulation of MTSS1 expression is an independent prognosticator in squamous cell carcinoma of the lung

Cited by 24 publications

References 40 publications

Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes

Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes

Differential effects of MTSS1 on invasion and proliferation in subtypes of non-small cell lung cancer cells

ARID2deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer

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