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The MK2 Pathway Is Linked to G-CSF, Cytokine Production and Metastasis

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The MK2 Pathway Is Linked to G-CSF, Cytokine Production and Metastasis Qeadan et al. J Transl Med (2020) 18:137 https://doi.org/10.1186/s12967-020-02294-z Journal of Translational Medicine RESEARCH Open Access The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach Fares Qeadan1, Pranshu Bansal2, Joshua A. Hanson3 and Ellen J. Beswick4* Abstract Background: Gastric cancer is associated with chronic infammation, but there is still much to understand about the tumor microenvironment and the underlying tumor-promoting mechanisms. The Map kinase-activated protein kinase 2 (MK2) pathway is a regulator of infammatory cytokine production that we have been studying in gastrointes- tinal cancers. Here, we set out to determine the signifcance of this gene in gastric cancer along with its downstream mediators and if there were diferences in the primary tumors with and without metastasis. Methods: Human gastric cancer tissues with and without metastasis were examined for MK2 expression and cytokine profle in organ culture supernatants. Advanced statistical methods including a lower triangular correlation matrix, novel rooted correlation network, linear and logistic regression modeling along with Kruskal–Wallis testing with Sidak correction for multiple testing were applied to gain understanding of cytokines/chemokines linked to metastasis. Results: The MK2 pathway is strongly linked with metastasis and a panel of cytokines. Gene expression was able to classify gastric cancer metastasis 85.7% of the time. A signifcant association with a panel of cytokines was found, including G-CSF, GM-CSF, Mip-1β, IFN-α, MCP-1, IL-1β, IL-6, and TNF-α. Mip-1β was found to have the strongest asso- ciation with MK2 and metastasis after Sidak correction for multiple testing. Conclusions: MK2 gene expression and a novel associated cytokine panel are linked to gastric cancer metastasis. G-CSF is the strongest cytokine to diferentiate between metastasis and non-metastasis patients and had the lowest P value, while Mip-1β showed the strongest association with MK2 and metastasis after Sidak correction. MK2 and asso- ciated cytokines are potential biomarkers for gastric cancer metastasis. The novel intercorrelation analysis approach is a promising method for understanding the complex nature of cytokine/chemokine regulation and links to disease outcome. Keywords: Gastric cancer, Map kinase-activated protein kinase 2, Granulocyte colony-stimulating factor, Cytokines, Chemokines Background Gastric cancer is often diagnosed in later stages with high mortality rates associated with progression [1]. Tus, *Correspondence: [email protected] 4 Division of Gastroenterology, Department of Internal Medicine, treatment options for gastric cancer are also more lim- University of Utah, Salt Lake City, UT, USA ited than many other cancers making it a more difcult Full list of author information is available at the end of the article cancer to treat. Gastric cancer is often associated with © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Qeadan et al. J Transl Med (2020) 18:137 Page 2 of 13 chronic infammation and history of Helicobacter pylori VEGF, Mip-1α, and IL-8 were close to reaching signif- infection. Chronic infammation has long been accepted cance. MK2 and the associated cytokine network could as a risk factor for cancer development and progression, be a biomarker panel for gastric cancer and MK2 inhibi- yet new treatment options targeting infammation in can- tion a potential therapeutic target for gastric cancer. cer still remain limited. Tus, it is critical to understand the infammatory pathways linked with more severe dis- Methods ease and poor outcome in order to identify infammatory Human tissue samples biomarkers in order to develop more efective treatment approaches. Human tissue samples were collected under an IRB We have been studying the Map kinase-activated pro- approved human protocol at University of New Mexico tein kinase 2 (MK2) pathway as a potential target for Health Sciences Center with the assistance of the UNM infammation and tumor growth in gastrointestinal Cancer Center Human Tissue Repository. Fresh samples cancers in mouse models [2, 3], and here we examine were collected as matched tumor and normal tissues as the relevance of this pathway to human gastric cancer. determined by surgical pathology and transferred to the MK2 is downstream of p38 MAP-kinase and is associ- Beswick lab for processing. Tissue samples were divided ated with DNA damage and regulation of infammatory into pieces for RNA extraction and cytokine assays. cytokine production, specifcally, IL-1β, IL-6, and TNF-α [3–5]. Tese cytokines are known to have pro-tumori- Gene expression genic properties. IL-1β polymorphisms are linked with RNA was extracted from tissue pieces using a trizol increased gastric cancer risk in humans [6], and in mice, (TermoFisher Scientifc) method according to manufac- IL-1β overexpression induced gastric infammation and turer’s instructions. RNA concentrations were measured cancer [7]. IL-6 has been shown to induce gastric tumor using a Nanodrop instrument (TermoFisher Scientifc). cell invasion and is associated with metastasis [8, 9]. Real-time PCR was performed according to Applied Finally, TNF-α production induced by H. pylori infection Biosystems’ two-step protocol. Te RT reaction mixture may promote gastric cancer [10, 11] along with TNF-α includes random 2.5 μM hexamers, 500 μM dNTPs, 0.4 polymorphisms may also increase risk of developing gas- U/μL of the RNase inhibitors, 5.5 mM MgCl , Multi- tric cancer [12]. Tus, MK2-dowstream cytokines are 2 Scribe Reverse Transcriptase (3.125 U/μL) and its bufer, thought to be important players in chronic infammation and 1 μg of cellular RNA. Te RT step was performed that promotes gastric cancer. according to the following protocol: 10 min at 25 °C, Although IL-1β, IL-6, and TNF-α have been shown to 60 min at 37 °C, 5 min at 95 °C. Obtained cDNA sam- be regulated by MK2 signaling, cytokines often act in ples were stored at 80 °C and used for the PCR reac- autocrine or paracrine manners to regulate production − tion step. Te PCR reaction mix was prepared using the of other cytokines in the tumor microenvironment. We Assays-on-Demand™ gene expression assay mix (Applied also have recently shown that MK2 regulates chemokine Biosystems) for human 18S and MK2. cDNA (2 µl) was production in mouse models of gastrointestinal cancers added to a 20 mix of PCR primers and TaqMan® FAM [13], suggesting that MK2 may regulate expression of a × dye-labeled probe. Te reaction was carried out accord- wider network of cytokines and chemokines than previ- ing to the following protocol: 2 min at 50 °C, 10 min at ously thought. Te goal of this study is to examine the 95 °C (1 cycle), and 15 s at 95 °C and one min at 60 °C (45 importance of MK2 in gastric cancer and how MK2 is cycles) on Applied Biosystem’s StepOnePlus instrument. linked with a broader cytokine/chemokine network than Te endpoint used in real-time PCR quantifcation, CT, originally shown in the literature. Cytokines are often was defned as the PCR cycle number that crossed the shown to be associated with cancer risk and prognosis, signal threshold. Quantifcation of cytokine gene expres- but often viewed independently. Due to the complexity sion was performed using the comparative CT method of cytokine/chemokine regulation, here we have explored and reported as the fold diference relative to 18S mRNA. more in depth approaches to analyzing a larger panel and their association with the MK2 pathway. Rather than independent markers, we examined how cytokines and Cytokine arrays chemokines are associated with one another. We found Normal and tumor tissue pieces were divided into 8 mg MK2 expression to be linked to gastric cancer metasta- (± 0.5 mg) sections and incubated in RPMI complete sis and nine signifcant cytokine associations, including media for 16 h. Supernatants were analyzed by multiplex MK2-dowstream cytokines, IL-1β, IL-6, and TNFα along bead array for 26 cytokines/growth factors (Millipore, with other previously unrecognized cytokines linked to Billerica, MA) according to manufacturer’s instructions MK2; G-CSF, GM-CSF, Mip-1β, IFN-α, MCP-1, and IL-2. and analyzed on a Luminex 200 machine. Qeadan et al. J Transl Med (2020) 18:137 Page 3 of 13 Statistical analysis Results MK2 and cytokines were described numerically using MK2 gene expression is upregulated in gastric cancer the median and interquartile range, from the frst to and associated with metastasis the third quartile, for both being much less sensitive to Since we found in mouse models that MK2 activation is outliers and non-normality. Graphically, we used (i) raw increased by infammatory cytokine production [3], here data (with jitter) overlaid with Box-plots, and (ii) Histo- we examined gene expression in a panel of gastric cancer grams with density curves overlay.
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