Functional analysis of a lung cancer risk haplotype in the IL1B gene regulatory region

Landvik, Nina E.; Hart, Kent; Haugen, Aage; Zienolddiny, Shanbeh

doi:10.1038/jhg.2012.106

Cited by 11 publications

(8 citation statements)

References 13 publications

(47 reference statements)

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“…In agreement, immunoblotting recorded a significant IL1B increase in PTK7, sPTK7 and Chz cells. An inflammatory IL1B cytokine is involved in cancer onset and progression [27,28]. …”

Section: Resultsmentioning

confidence: 99%

Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Golubkov

Strongin

2014

Cell Communication and Signaling

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BackgroundThe full-length membrane protein tyrosine kinase 7 (PTK7) pseudokinase, an important component of the planar cell polarity and the Wnt canonical and non-canonical pathways, is a subject of step-wise proteolysis in cells and tissues. The proteolysis of PTK7 involves membrane type-matrix metalloproteinase (MT1-MMP), members of the Disintegrin Domain and Metalloproteinase (ADAM) family, and γ-secretase. This multi-step proteolysis results in the generation of the digest fragments of PTK7. These fragments may be either liberated into the extracellular milieu or retained on the plasma membrane or released into the cytoplasm and then transported into the nucleus.ResultsWe employed the genome-wide transcriptional and kinome array analyses to determine the role of the full-length membrane PTK7 and its proteolytic fragments in the downstream regulatory mechanisms, with an emphasis on the cell migration-related genes and proteins. Using fibrosarcoma HT1080 cells stably expressing PTK7 and its mutant and truncated species, the structure of which corresponded to the major PTK7 digest fragments, we demonstrated that the full-length membrane 1–1070 PTK7, the N-terminal 1–694 soluble ectodomain fragment, and the C-terminal 622–1070 and 726–1070 fragments differentially regulate multiple genes and signaling pathways in our highly invasive cancer cell model. Immunoblotting of the selected proteins were used to validate the results of our high throughput assays.ConclusionsOur results suggest that PTK7 levels need to be tightly controlled to enable migration and that the anti-migratory effect of the full-length membrane PTK7 is linked to the down-regulation of multiple migration-related genes and to the activation of the Akt and c-Jun pathway. In turn, the C-terminal fragments of PTK7 act predominantly via the RAS-ERK and CREB/ATF1 pathway and through the up-regulation of cadherin-11. In general, our data correlate well with the distinct functionality of the full-length receptor tyrosine kinases and their respective intracellular domain (ICD) proteolytic fragments.

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“…In agreement, immunoblotting recorded a significant IL1B increase in PTK7, sPTK7 and Chz cells. An inflammatory IL1B cytokine is involved in cancer onset and progression [27,28]. …”

Section: Resultsmentioning

confidence: 99%

Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Golubkov

Strongin

2014

Cell Communication and Signaling

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“…High expression of some interleukins, such as IL-1α and IL-1β, has been associated with a more aggressive tumor type and poor prognosis [55-57]. ADSCs-SCCs-co-culture - both, with A431-SCCs and primary SCCs, led to a strong increase in IL-1α and β gene expression in ADSCs.…”

Section: Discussionmentioning

confidence: 99%

Alterations of gene expression and protein synthesis in co-cultured adipose tissue-derived stem cells and squamous cell-carcinoma cells: consequences for clinical applications

et al. 2014

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IntroductionThis is the first study evaluating the interactions of human adipose tissue derived stem cells (ADSCs) and human squamous cell carcinoma cells (SCCs), with regard to a prospective cell-based skin regenerative therapy and a thereby unintended co-localization of ADSCs and SCCs.MethodsADSCs were co-cultured with A431-SCCs and primary SCCs (pSCCs) in a transwell system, and cell-cell interactions were analyzed by assessing doubling time, migration and invasion, angiogenesis, quantitative real time PCR of 229 tumor associated genes, and multiplex protein assays of 20 chemokines and growth factors and eight matrix metalloproteinases (MMPS). Results of co-culture were compared to those of the respective mono-culture.ResultsADSCs’ proliferation on the plate was significantly increased when co-cultured with A431-SCCs (P = 0.038). PSCCs and ADSCs significantly decreased their proliferation in co-culture if cultured on the plate (P <0.001 and P = 0.03). The migration of pSCC was significantly increased in co-culture (P = 0.009), as well as that of ADSCs in A431-SCC-co-culture (P = 0.012). The invasive behavior of pSCCs and A431-SCCs was significantly increased in co-culture by a mean of 33% and 35%, respectively (P = 0.038 and P <0.001). Furthermore, conditioned media from co-cultured ADSC-A431-SCCs and co-cultured ADSCs-pSCCs induced tube formation in an angiogenesis assay in vitro.In A431-SCC-co-culture 36 genes were up- and 6 were down-regulated in ADSCs, in A431-SCCs 14 genes were up- and 8 genes were down-regulated. In pSCCs-co-culture 36 genes were up-regulated in ADSCs, two were down-regulated, one gene was up-regulated in pSCC, and three genes were down-regulated. Protein expression analysis revealed that three proteins were exclusively produced in co-culture (CXCL9, IL-1b, and MMP-7). In A431-SCC-co-culture the concentration of 17 proteins was significantly increased compared to the ADSCs mono-culture (2.8- to 357-fold), and 15 proteins were expressed more highly (2.8- to 1,527-fold) compared to the A431-SCCs mono-culture. In pSCC-co-culture the concentration of 10 proteins was increased compared to ADSCs-mono-culture (2.5- to 77-fold) and that of 15 proteins was increased compared to pSCC mono-culture (2.6- to 480-fold).ConclusionsThis is the first study evaluating the possible interactions of primary human ADSCs with human SCCs, pointing towards a doubtlessly increased oncological risk, which should not be neglected when considering a clinical use of isolated human ADSCs in skin regenerative therapies.

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“…Subsequently, they provided evidence that 1L1B rs12621220 (-3893) GA and rs1143623 (-1464) GC in the enhancer region may also affect this risk and the four SNPs (G-3893A, G-1464C, T-511C, C-31T) formed a specific risk haplotype GGCT associated with increased IL1B gene expression [17]. They also showed that this haplotype have high transcriptional activity in the human lung epithelial A549 cell line in vitro [18]. A study in a Danish population showed that the carriers of the C allele of IL1B-31 were at higher risk of lung cancer than TT genotype [19].…”

Section: Introductionmentioning

confidence: 93%

IL1B gene polymorphisms, age and the risk of non-small cell lung cancer in a Chinese population

Li¹,

Zhao²,

Zhao³

et al. 2015

Lung Cancer

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Functional analysis of a lung cancer risk haplotype in the IL1B gene regulatory region

Cited by 11 publications

References 13 publications

Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Downstream signaling and genome-wide regulatory effects of PTK7 pseudokinase and its proteolytic fragments in cancer cells

Alterations of gene expression and protein synthesis in co-cultured adipose tissue-derived stem cells and squamous cell-carcinoma cells: consequences for clinical applications

IL1B gene polymorphisms, age and the risk of non-small cell lung cancer in a Chinese population

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