CXCL1 as an Unfavorable Prognosis Factor Negatively Regulated by DACH1 in Non-small Cell Lung Cancer.
Journal: Frontiers in oncology
Januar/30/2020
Background: Interaction between cancer cells with microenvironment is essential for cancer progression, therapeutic resistance and prognosis. Chemokine CXCL1 shows variable roles in the development of cancers. DACH1 has been considered as a tumor suppressor and represses the expressions of several chemokines. The relationship between CXCL1 and DACH1 in non-small cell lung cancer (SCLC) deserves further investigation. Methods: Immunohistochemistry staining was performed on tumor tissue microarrays from lung cancer patients to detect CXCL1 protein. The CXCL1 concentration in the serum of adenocarcinoma patients was measured by ELISA. The CXCL1 protein secreted by cancer cell lines was detected by SearchLight proteome array and human cytokine antibody array. The meta-analysis of CXCL1 expression form public databases was performed and correlation between CXCL1 and DACH1 was analyzed. Moreover, the association between clinicopathological features and prognosis with CXCL1 and DACH1 was analyzed by tissue array and KM-plotter from public database. Results: The protein abundance of CXCL1 in lung cancer tissues was significantly higher than that in adjacent normal tissues. CXCL1 was closely related to TNM stage, tumor size, and lymph node metastasis and predicted worse overall survival in adenocarcinoma. The level of CXCL1 in the peripheral blood of adenocarcinoma patients also significantly elevated and positively related with clinical stage. The meta-analysis demonstrated that CXCL1 mRNA level was increased in lung cancer tissues and high level of CXCL1 indicated tumor progression in lung adenocarcinoma.
In addition, public database analyses showed that CXCL1 negatively correlated with DACH1. Stable overexpressing DACH1 in cultured lung cancer cells remarkably decreased CXCL1 protein. Moreover, ectopic expression of DACH1 significantly inhibited the expression of CXCL1, Ki67, and cyclin D1 in tumor tissues compared with A549 cells with empty vector. Survival analysis showed that high CXCL1 and low DACH1 indicated poor overall survival and progression-free survival. Conclusion: CXCL1 is closely associated with tumor progression and poor survival. DACH1 significantly inhibits the expression of CXCL1 and indicates good prognosis. Therefore, combined detection of CXCL1 and DACH1 could more precisely predict prognosis of lung adenocarcinoma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966305/bin/fonc-09-01515-g0003.jpg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966305/bin/fonc-09-01515-g0004.jpg
Shengnan Yu; Ming Yi; Linping Xu; Shuang Qin; Anping Li; Kongming Wu
Pancreatic stellate cells activated by mutant KRAS-mediated PAI-1 upregulation foster pancreatic cancer progression via IL-8.
Journal: Theranostics
November/7/2019
Background: The dense fibrotic stroma enveloping pancreatic tumors is a major cause of drug resistance. Pancreatic stellate cells (PSCs) in the stroma can be activated to induce intra-tumor fibrosis and worsen patient survival; however, the molecular basics for the regulation of PSC activation remains unclear. Methods: The in vitro coculture system was used to study cancer cell-PSC interactions. Atomic force microscopy was used to measure the stiffness of tumor tissues and coculture gels. Cytokine arrays, qPCR, and Western blotting were performed to identify the potential factors involved in PSC activation and to elucidate underlying pathways. Results: PSC activation characterized by α-SMA expression was associated with increased pancreatic tumor stiffness and poor prognosis. Coculture with cancer cells induced PSC activation, which increased organotypic coculture gel stiffness and cancer cell invasion. Cancer cells-derived PAI-1 identified from coculture medium could activate PSCs, consistent with pancreatic cancer tissue microarray analysis showing a strong positive correlation between PAI-1 and α-SMA expression. Suppression by knocking down PAI-1 in cancer cells demonstrated the requirement of PAI-1 for coculture-induced PSC activation and gel stiffness. PAI-1 could be upregulated by KRAS in pancreatic cancer cells through ERK. In PSCs, inhibition of LRP-1, ERK, and c-JUN neutralized the effect of PAI-1, suggesting the contribution of LRP-1/ERK/c-JUN signaling. Furthermore, activated PSCs might exacerbate malignant behavior of cancer cells via IL-8 because suppression of IL-8 signaling reduced pancreatic tumor growth and fibrosis in vivo. Conclusions: KRAS-mutant pancreatic cancer cells can activate PSCs through PAI-1/LRP-1 signaling to promote fibrosis and cancer progression.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831292/bin/thnov09p7168g001.jpg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831292/bin/thnov09p7168g002.jpg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831292/bin/thnov09p7168g003.jpg
Hao-Chen Wang; Yung-Lun Lin; Ching-Cheng Hsu; Ying-Jui Chao; Ya-Chin Hou; Tai-Jan Chiu+4 authors
Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection.
Journal: Immunity, inflammation and diseaseNovember/6/2019
Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multifactorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that focal ischemic stroke induction results in functional defects of lymphocytes in the spleen, thymus, and peripheral blood, leading to spontaneous bacterial infection in the lungs without inoculation. However, how ischemic stroke alters immune cell niche and the expression of cytokines and chemokines in the lungs has not been fully characterized.Ischemic stroke was induced in mice by tMCAO. Immune cell profiles in the brain and the lungs at 24- and 72-hour time points were compared by flow cytometric analysis. Cytokine and chemokine expression in the lungs were determined by multiplex bead arrays. Tissue damage and bacterial burden in the lungs following tMCAO were evaluated.
RESULTS
Ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b+ dendritic cells, but reduces the percentage of CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and eosinophils in the lungs. The alteration of immune cell niche in the lungs coincides with a significant reduction in the levels of multiple chemokines in the lungs, including CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. Spontaneous bacterial infection and tissue damage following tMCAO, however, were not observed.
This is the first report to demonstrate a significant reduction of lymphocytes and multiple proinflammatory chemokines in the lungs following ischemic stroke in mice. These findings suggest that ischemic stroke directly impacts pulmonary immunity.
Breanne Farris; Kelly Monaghan; Wen Zheng; Courtney Amend; Heng Hu; Amanda Ammer+3 authors
Change of cytokines after intravitreal ranibizumab in patients with recurrent branch retinal vein occlusion and macular edema.
Journal: European journal of ophthalmology
November/6/2019
To investigate the relations of vascular endothelial growth factor, growth factors, soluble vascular endothelial growth factor receptors, and inflammatory factors to recurrence of macular edema after anti-vascular endothelial growth factor therapy in patients with branch retinal vein occlusion.This study retrospectively investigated 17 patients with branch retinal vein occlusion who received intravitreal ranibizumab injection three times within 6 months for recurrent macular edema. Aqueous humor samples were obtained from these patients at every recurrence. Levels of soluble vascular endothelial growth factor receptor-1, soluble vascular endothelial growth factor receptor-2, vascular endothelial growth factor, placental growth factor, platelet-derived growth factor-AA, soluble intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin-6, interleukin-8, interleukin-12(p70), and interleukin-13 were measured by the suspension array method. Aqueous flare values were measured with a laser flare meter and central macular thickness was determined by optical coherence tomography.Mean best-corrected visual acuity and central macular thickness improved significantly over time after intravitreal ranibizumab injection, but the aqueous flare value at recurrence after intravitreal ranibizumab injection showed no significant change compared with baseline. Aqueous humor levels of soluble vascular endothelial growth factor receptor-1, soluble vascular endothelial growth factor receptor-2, vascular endothelial growth factor, platelet-derived growth factor-AA, monocyte chemoattractant protein-1, and interleukin-8 decreased significantly over time after intravitreal ranibizumab injection. However, there were no significant changes of the other five factors/cytokines (placental growth factor, soluble intercellular adhesion molecule-1, interleukin-6, interleukin-12, and interleukin-13) at recurrence after intravitreal ranibizumab injection compared with baseline.These findings suggest that persistent inflammation may influence the recurrence of macular edema in branch retinal vein occlusion patients, and that adding steroid therapy might be an effective strategy for preventing recurrence.
Hidetaka Noma; Kanako Yasuda; Masahiko Shimura