interleukin-8 and Gallbladder-Neoplasms

Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P = 0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P = 0.03 and P < 0.001). SDR analysis confirmed correlation between the biomarkers and ethnicity. We found higher IL-8 levels among Mapuche than non-Mapuche women. Novel inflammatory biomarkers were correlated with ethnicity and should be studied further for their role in gallbladder disease. These findings may elucidate underlying ethnic disparities in gallstones and carcinogenesis among Amerindians.

Topics: Aged; Carcinogenesis; Chemokine CCL20; Chemokine CXCL10; Chile; Ethnicity; Female; Gallbladder; Gallbladder Neoplasms; Gallstones; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indians, South American; Inflammation; Interleukin-6; Interleukin-8; Longitudinal Studies; Middle Aged; Ultrasonography

We previously demonstrated that cancer-associated fibroblasts (CAFs) promoted the proliferation of gallbladder cancer (GBC) cells, but the mechanism is not clear. Neuropilin-1 (NRP-1) plays an important role in various malignancies as transmembrane glycoprotein. Our goal was to reveal the relationship between CAFs and NRP-1 and their potential functions in GBC. In this study, we found NRP-1 was overexpressed in GBC tissue, associated with poor survival and was up-regulated by CAFs. The cytokine array cluster analysis revealed IL-8 secreted by CAFs facilitated the up-regulation of NRP-1 in tumour cells. NRP-1 knockdown suppressed tumour growth in vivo. Gene expression microarray analysis showed 581 differentially regulated genes under NRP-1 knockdown conditions. Ingenuity pathway analysis demonstrated that NRP-1 knockdown may inhibit tumour progression by affecting cell proliferation. We then confirmed that NRP-1 knockdown in NOZ and GBC-SD cells significantly inhibited cell proliferation. Additionally, the IL-8 mediated MDM2 and CCNA2 expression were affected by NRP-1 knockdown. Our findings suggested that NRP-1 was up-regulated by CAF-secreted IL-8, which subsequently promoted GBC cell proliferation, and these molecules may serve as useful prognostic biomarkers and therapeutic targets for GBC.

Topics: Animals; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Proliferation; Cholecystitis; Female; Gallbladder Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Male; Mice, Nude; Middle Aged; Multivariate Analysis; Neuropilin-1; Oligonucleotide Array Sequence Analysis; Prognosis; RNA, Small Interfering; Survival Analysis; Tumor Stem Cell Assay; Up-Regulation

Topics: Adult; Aged; Anesthesia, Epidural; Anesthesia, General; C-Reactive Protein; Cholecystectomy; Female; Gallbladder Neoplasms; Humans; Interleukin-2; Interleukin-8; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Random Allocation; Risk Assessment; Risk Factors; T-Lymphocyte Subsets; Time Factors; Treatment Outcome; Tumor Microenvironment; Tumor Necrosis Factor-alpha

In previous work, we found that prostate stem cell antigen (PSCA) gene, encoding a glycosylphosphatidylinositol-anchored protein, is a presumable tumor suppressor in gastric cancer and gallbladder cancer (GBC). The introduction of PSCA cDNA into GBC cell lines significantly suppressed tumorigenecity of cells in mice. The PSCA protein is thought to be involved in some form of intracellular signaling that remains to be elucidated.. Using microarrays, we conducted gene-expression profiling on tumors generated by a GBC cell line TGBC-1TKB, with and without expression of PSCA, which was implanted into mice. Genes whose expression was down-regulated by PSCA were selected, and their down-regulation was confirmed by real-time PCR.. We identified several immune-related genes down-regulated by PSCA, including interleukin 8 (IL8), IL1 receptor antagonist (IL1RN) and S100 calcium-binding proteins A8 (S100A8) and A9 (S100A9).. PSCA signaling may suppress tumor growth in vivo by modulating immunological characteristics of GBC cells.

Topics: Animals; Antigens, Neoplasm; Calgranulin A; Calgranulin B; Cell Line, Tumor; Gallbladder Neoplasms; Gene Expression Regulation, Neoplastic; Glycosylphosphatidylinositols; GPI-Linked Proteins; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-8; Mice; Neoplasm Proteins