CXCL1

Gene Summary

Gene:CXCL1; C-X-C motif chemokine ligand 1
Aliases: FSP, GRO1, GROa, MGSA, NAP-3, SCYB1, MGSA-a
Location:4q13.3
Summary:This antimicrobial gene encodes a member of the CXC subfamily of chemokines. The encoded protein is a secreted growth factor that signals through the G-protein coupled receptor, CXC receptor 2. This protein plays a role in inflammation and as a chemoattractant for neutrophils. Aberrant expression of this protein is associated with the growth and progression of certain tumors. A naturally occurring processed form of this protein has increased chemotactic activity. Alternate splicing results in coding and non-coding variants of this gene. A pseudogene of this gene is found on chromosome 4. [provided by RefSeq, Sep 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:growth-regulated alpha protein
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CXCL1 (cancer-related)

Matte I, Garde-Granger P, Bessette P, Piché A
Ascites from ovarian cancer patients stimulates MUC16 mucin expression and secretion in human peritoneal mesothelial cells through an Akt-dependent pathway.
BMC Cancer. 2019; 19(1):406 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: CA125 is a well-established ovarian cancer (OC) serum biomarker. The CA125 heavily glycosylated epitope is carried by the MUC16 mucin, a high molecular weight transmembrane mucin. Upon proteolytic cleavage, the extracellular domain of MUC16 is released from the cell surface into malignant ascites and blood vessels. Previous studies have shown that both tumor and surrounding mesothelial cells may express MUC16. Although little is known about the regulation of MUC16 expression in these cells, recent evidence suggest that inflammatory cytokines may stimulate MUC16 expression. Because malignant ascites is a pro-inflammatory environment, we investigated whether OC ascites stimulate the expression and release of MUC16 by human peritoneal mesothelial cells (HPMCs).
METHODS: HPMCs were isolated from peritoneal lavages of women operated for conditions other than cancer. MUC16 protein expression was determined by immunoblot, immunofluorescence or immunohistochemistry depending on the experiments. The release of MUC16 from the cell surface was measured using EIA and MUC16 mRNA expression by ddPCR.
RESULTS: We show that high-grade serous ascites from patients with OC (n = 5) enhance MUC16 expression in HPMCs. Malignant ascites, but not benign peritoneal fluids, stimulate the release of MUC16 in HPMCs in a dose-dependent manner, which is abrogated by heat inactivation. Moreover, we establish that ascites-induced MUC16 expression occurs at the post-transcriptional level and demonstrate that ascites-induced MUC16 expression is mediated, at least partially, through an Akt-dependent pathway. A cytokine array identified upregulation of several cytokines and chemokines in ascites that mediate MUC16 upregulation versus those that do not, including CCL7, CCL8, CCL16, CCL20, CXCL1, IL-6, IL-10, HGF and IL-1 R4. However, when individually tested, none of these factors affected MUC16 expression or secretion. Concentrations of CA125 in the serum of a given patient did not correlate with the ability of its corresponding ascites to stimulate MUC16 release in HPMCs.
CONCLUSIONS: Collectively, these data indicate that mesothelial cells are an important source of MUC16 in the context of ovarian cancer and malignant ascites is a strong modulator of MUC16 expression in HPMCs and uncover the Akt pathway as a driving factor for upregulation of MUC16. Factors in ascites associated with enhanced MUC16 expression and release remains to be identified.

Münch NS, Fang HY, Ingermann J, et al.
High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome.
Gastroenterology. 2019; 157(2):492-506.e2 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND & AIMS: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.
METHODS: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.
RESULTS: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.
CONCLUSIONS: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.

Tiwari A, Mukherjee B, Hassan MK, et al.
Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion.
BMC Cancer. 2019; 19(1):346 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.
METHODS: Immunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot.
RESULTS: In prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines.
CONCLUSION: FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.

Bardi GT, Al-Rayan N, Richie JL, et al.
Detection of Inflammation-Related Melanoma Small Extracellular Vesicle (sEV) mRNA Content Using Primary Melanocyte sEVs as a Reference.
Int J Mol Sci. 2019; 20(5) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Melanoma-derived small extracellular vesicles (sEVs) participate in tumor pathogenesis. Tumor pathogenesis is highly dependent on inflammatory processes. Given the potential for melanoma sEVs to carry tumor biomarkers, we explored the hypothesis that they may contain inflammation-related mRNA content. Biophysical characterization showed that human primary melanocyte-derived sEVs trended toward being smaller and having less negative (more neutral) zeta potential than human melanoma sEVs (A-375, SKMEL-28, and C-32). Using primary melanocyte sEVs as the control population, RT-qPCR array results demonstrated similarities and differences in gene expression between melanoma sEV types. Upregulation of pro-angiogenic chemokine ligand CXCL1, CXCL2, and CXCL8 mRNAs in A-375 and SKMEL-28 melanoma sEVs was the most consistent finding. This paralleled increased production of CXCL1, CXCL2, and CXCL8 proteins by A-375 and SKMEL-28 sEV source cells. Overall, the use of primary melanocyte sEVs as a control sEV reference population facilitated the detection of inflammation-related melanoma sEV mRNA content.

Yahata T, Mizoguchi M, Kimura A, et al.
Programmed cell death ligand 1 disruption by clustered regularly interspaced short palindromic repeats/Cas9-genome editing promotes antitumor immunity and suppresses ovarian cancer progression.
Cancer Sci. 2019; 110(4):1279-1292 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Programmed cell death ligand 1 (PD-L1) on tumor cells suppresses anti-tumor immunity and has an unfavorable prognostic impact in ovarian cancer patients. We herein report the pathophysiological and therapeutic impacts of PD-L1 disruption in ovarian cancer. PD-L1 was genetically disrupted in the murine ovarian cancer cell line ID8 using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome editing. PD-L1 knockout (KO) and control ovarian cancer cells were intraperitoneally inoculated into syngeneic mice, and survival and tumor dissemination were evaluated. Survival times were significantly longer in the PD-L1-KO ID8-inoculated groups than in their control groups, and its therapeutic benefit was enhanced in combination with the cisplatin treatment. Tumor weights and ascites volumes were significantly lower in the PD-L1-KO ID8 groups than in their control groups. Immunohistochemical and immunofluorescence analyses showed that intratumoral CD4

Chen L, Lu D, Sun K, et al.
Identification of biomarkers associated with diagnosis and prognosis of colorectal cancer patients based on integrated bioinformatics analysis.
Gene. 2019; 692:119-125 [PubMed] Related Publications
BACKGROUND: The current study aimed to identify potential diagnostic and prognostic gene biomarkers for colorectal cancer (CRC) based on the Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) dataset.
METHODS: Microarray data of gene expression profiles of CRC from GEO and RNA-sequencing dataset of CRC from TCGA were downloaded. After screening overlapping differentially expressed genes (DEGs) by R software, functional enrichment analyses of the DEGs were performed using the DAVID database. Then, the STRING database and Cytoscape were used to construct a protein-protein interaction (PPI) network and identify hub genes. The receiver operating characteristic (ROC) curves were conducted to assess the diagnostic values of the hub genes. Cox proportional hazards regression was performed to screen the potential prognostic genes. Kaplan-Meier curve and the time-dependent ROC curve were used to assess the prognostic values of the potential prognostic genes for CRC patients.
RESULTS: Integrated analysis of GEO and TCGA databases revealed 207 common DEGs in CRC. A PPI network consisted of 70 nodes and 170 edges were constructed and top 10 hub genes were identified. The area under curve (AUC) of the ROC curves of the hub genes were 0.900, 0.927, 0.869, 0.863, 0.980, 0.682, 0.903, 0.790, 0.995, and 0.989 for CCL19, CXCL1, CXCL5, CXCL11, CXCL12, GNG4, INSL5, NMU, PYY, and SST, respectively. A prognostic gene signature consisted of 9 genes including SLC4A4, NFE2L3, GLDN, PCOLCE2, TIMP1, CCL28, SCGB2A1, AXIN2, and MMP1 was constructed with a good performance in predicting overall survivals of CRC patients. The AUC of the time-dependent ROC curve was 0.741 for 5-year survival.
CONCLUSION: The results in this study might provide some directive significance for further exploring the potential biomarkers for diagnosis and prognosis prediction of CRC patients.

Haralambiev L, Wien L, Gelbrich N, et al.
Effects of Cold Atmospheric Plasma on the Expression of Chemokines, Growth Factors, TNF Superfamily Members, Interleukins, and Cytokines in Human Osteosarcoma Cells.
Anticancer Res. 2019; 39(1):151-157 [PubMed] Related Publications
BACKGROUND/AIM: Therapeutic options for osteosarcoma (OS) are still limited. Cold atmospheric plasma (CAP) leads to inhibition of tumor growth and metastasis, but underlying mechanisms are not fully understood. The aim of this study was to investigate CAP-induced changes in cytokine expression in OS cells.
MATERIALS AND METHODS: OS cell lines (U2-OS, MNNG/HOS) were treated with CAP and administered to an RT2 Profiler PCR Array (Qiagen, Hilden, Germany) detecting 84 chemokines, growth factors, TNF superfamily members, interleukins, and cytokines.
RESULTS: The analyses showed that 15 factors (C5, CCL5, CNTF, CSF1, CSF3, CXCL1, IL-1A, IL-1B, IL-18, IL-22, IL23A, MSTN, NODAL, TGFβ2, THPO) were induced, but only one factor (VEGFA) was suppressed after CAP treatment.
CONCLUSION: No extensive systemic cell response with presumably far-reaching consequences for neighboring cells was detectable after CAP treatment. Since the antitumoral effect of CAP on OS cells has already been demonstrated, intraoperative treatment with CAP represents a promising and systemic safe option for the therapy of OS.

Cabrero-de Las Heras S, Martínez-Balibrea E
CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer.
World J Gastroenterol. 2018; 24(42):4738-4749 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women, worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates. In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines (CXCL1 to 17) are small (8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors (CXCR) 1 to 8. Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively. In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore, the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer. These pathways have been studied in tumor tissues (using immunohistochemistry or measuring mRNA levels) or serum [using enzyme-linked immuno sorbent assay (ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes the most recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.

Allegra M, De Cicco P, Ercolano G, et al.
Indicaxanthin from Opuntia Ficus Indica (L. Mill) impairs melanoma cell proliferation, invasiveness, and tumor progression.
Phytomedicine. 2018; 50:19-24 [PubMed] Related Publications
BACKGROUND: A strong, reciprocal crosstalk between inflammation and melanoma has rigorously been demonstrated in recent years, showing how crucial is a pro-inflammatory microenvironment to drive therapy resistance and metastasis.
PURPOSE: We investigated on the effects of Indicaxanthin, a novel, anti-inflammatory and bioavailable phytochemical from Opuntia Ficus Indica fruits, against human melanoma both in vitro and in vivo.
STUDY DESIGN AND METHODS: The effects of indicaxanthin were evaluated against the proliferation of A375 human melanoma cell line and in a mice model of cutaneous melanoma. Cell proliferation was assessed by MTT assay, apoptosis by Annexin V-Fluorescein Isothiocyanate/Propidium Iodide staining, protein expression by western blotting, melanoma lesions were subcutaneously injected in mice with B16/F10 cells, chemokine release was quantified by ELISA.
RESULTS: Data herein presented demonstrate that indicaxanthin effectively inhibits the proliferation of the highly metastatic and invasive A375 cells as shown by growth inhibition, apoptosis induction and cell invasiveness reduction. More interestingly, in vitro data were paralleled by those in vivo showing that indicaxanthin significantly reduced tumor development when orally administered to mice. The results of our study also clarify the molecular mechanisms underlying the antiproliferative effect of indicaxanthin, individuating the inhibition of NF-κB pathway as predominant.
CONCLUSION: In conclusion, we demonstrated that indicaxanthin represents a novel phytochemical able to significantly inhibit human melanoma cell proliferation in vitro and to impair tumor progression in vivo. When considering the resistance of melanoma to the current therapeutical approach and the very limited number of phytochemicals able to partially counteract it, our findings may be of interest to explore indicaxanthin potential in further and more complex melanoma studies in combo therapy, i.e. where different check points of melanoma development are targeted.

Braun SA, Baran J, Schrumpf H, et al.
Ingenol mebutate induces a tumor cell-directed inflammatory response and antimicrobial peptides thereby promoting rapid tumor destruction and wound healing.
Eur J Med Res. 2018; 23(1):45 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: Ingenol mebutat (IM)-gel is effective for the topical treatment of epithelial tumors, including actinic keratoses (AKs) or anogenital warts (AGW). AK patients treated with IM develop intensified inflammatory reactions on sights of prior clinical visible or palpable AKs as compared to the surrounding actinically damaged skin, suggesting the induction of a tumor cell-directed inflammation. AGW patients treated with IM develop even stronger inflammatory reactions with large erosions, suggesting a directed inflammatory response against HPV-infected keratinocytes. Of note, even widespread erosions heal very fast without any superinfections. Here, we set out to elucidate underlying molecular and cellular mechanisms of these clinical observations.
METHODS: The effects of IM (10
RESULTS: Ingenol mebutat significantly and dose-dependently induced the expression of proinflammatory chemokines (CXCL8, CCL2) and AMP (RNase7, HBD3) in HEK and epithelial cancer cell lines. A significantly stronger induction of CXCL8 and CCL2 was observed in our tested tumor cells as compared to HEK. We did not observe any significant effect of IM on HEK migration, respectively wound healing responses in vitro for any tested concentration (10
CONCLUSIONS: Our data suggest that tumor cells are more susceptible to IM as compared to differentiated HEK. This is evident by a stronger IM-mediated induction of proinflammatory chemokines in tumor cells, which may result in a tumor cell-directed inflammatory response and rapid tumor destruction. In addition, IM induces AMP in keratinocytes and seems not to severely interfere with keratinocyte migration, which contributes to a fast and uncomplicated wound healing. Surprising is a selective inhibition of keratinocyte migration by IM at the concentration of 10

Chen Y, Chen Q, Xie F, et al.
Traditional Chinese Medicine Extract from Huaier Increases the Expression of Duffy Antigen Receptor for Chemokines and Reduces the Expression of Its Ligands.
Anal Cell Pathol (Amst). 2018; 2018:6756092 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Aims: The aim of the present study is to investigate whether the aqueous extract from Huaier, a traditional Chinese medicine (TCM), can affect the expression of Duffy antigen receptor for chemokines (DARC) and its ligands. Moreover, we compare the status of DARC in primary and metastatic breast cancer tissues from the same patient.
Methods: Immunohistochemistry was used to detect the expression of DARC in primary and metastatic focuses in 30 patients with breast cancer. The effect of Huaier aqueous extract on the expression of DARC and its ligands was investigated by quantitative real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay.
Results: The expression score of DARC in primary focuses was significantly higher than that in metastatic focuses, while changes of ER, PR, and HER2 receptors were not significantly different between primary and metastatic focuses. Huaier aqueous extract promoted the expression of DARC and reduced the secretion of CC chemokine ligand 2 (CCL-2), CXC chemokine ligand 8 (CXCL-8, IL-8), matrix metalloproteinase 2 (MMP-2), and CXC chemokine ligand 1 (CXCL-1).
Conclusion: The present study demonstrates that difference in expression level of DARC between primary and metastatic focuses of breast cancer was significant, while differences in expression of ER, PR, and HER2 between primary and metastatic focuses were not significant. DARC may play a negative role in the metastasis of breast cancer. Traditional Chinese medicine extract from Huaier can increase DARC expression and reduce the expression of its ligands such as CCL-2, IL-8, MMP-2, and CXCL-1.

Hsu YL, Chen YJ, Chang WA, et al.
Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1.
Int J Mol Sci. 2018; 19(8) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Crosstalk of a tumor with its microenvironment is a critical factor contributing to cancer development. This study investigates the soluble factors released by tumor-associated dendritic cells (TADCs) responsible for increasing cancer stem cell (CSC) properties, cell mobility, and epithelial-to-mesenchymal transition (EMT). Dendritic cells (DCs) of colon cancer patients were collected for phenotype and CXCL1 expression by flow cytometry and Luminex assays. The transcriptome of CXCL1-treated cancer cells was established by next generation sequencing. Inflammatory chemokine CXCL1, present in large amounts in DCs isolated from colon cancer patients, and SW620-conditioned TADCs, enhance CSC characteristics in cancer, supported by enhanced anchorage-independent growth, CD133 expression and aldehyde dehydrogenase activity. Additionally, CXCL1 increases the metastatic ability of a cancer by enhancing cell migration, matrix metalloproteinase-7 expression and EMT. The enhanced CXCL1 expression in DCs is also noted in mice transplanted with colon cancer cells. Transcriptome analysis of CXCL1-treated SW620 cells indicates that CXCL1 increases potential oncogene expression in colon cancer, including

Logue SE, McGrath EP, Cleary P, et al.
Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy.
Nat Commun. 2018; 9(1):3267 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.

Sang L, Wang XM, Xu DY, Zhao WJ
Bioinformatics analysis of aberrantly methylated-differentially expressed genes and pathways in hepatocellular carcinoma.
World J Gastroenterol. 2018; 24(24):2605-2616 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
AIM: To discover methylated-differentially expressed genes (MDEGs) in hepatocellular carcinoma (HCC) and to explore relevant hub genes and potential pathways.
METHODS: The data of expression profiling GSE25097 and methylation profiling GSE57956 were gained from GEO Datasets. We analyzed the differentially methylated genes and differentially expressed genes online using GEO2R. Functional and enrichment analyses of MDEGs were conducted using the DAVID database. A protein-protein interaction (PPI) network was performed by STRING and then visualized in Cytoscape. Hub genes were ranked by cytoHubba, and a module analysis of the PPI network was conducted by MCODE in Cytoscape software.
RESULTS: In total, we categorized 266 genes as hypermethylated, lowly expressed genes (Hyper-LGs) referring to endogenous and hormone stimulus, cell surface receptor linked signal transduction and behavior. In addition, 161 genes were labelled as hypomethylated, highly expressed genes (Hypo-HGs) referring to DNA replication and metabolic process, cell cycle and division. Pathway analysis illustrated that Hyper-LGs were enriched in cancer, Wnt, and chemokine signalling pathways, while Hypo-HGs were related to cell cycle and steroid hormone biosynthesis pathways. Based on PPI networks,
CONCLUSION: In the study, we disclose numerous novel genetic and epigenetic regulations and offer a vital molecular groundwork to understand the pathogenesis of HCC. Hub genes, including

Li J, Byrne KT, Yan F, et al.
Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy.
Immunity. 2018; 49(1):178-193.e7 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8

Donzelli S, Milano E, Pruszko M, et al.
Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages.
Breast Cancer Res. 2018; 20(1):59 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: As crucial regulators of the immune response against pathogens, macrophages have been extensively shown also to be important players in several diseases, including cancer. Specifically, breast cancer macrophages tightly control the angiogenic switch and progression to malignancy. ID4, a member of the ID (inhibitors of differentiation) family of proteins, is associated with a stem-like phenotype and poor prognosis in basal-like breast cancer. Moreover, ID4 favours angiogenesis by enhancing the expression of pro-angiogenic cytokines interleukin-8, CXCL1 and vascular endothelial growth factor. In the present study, we investigated whether ID4 protein exerts its pro-angiogenic function while also modulating the activity of tumour-associated macrophages in breast cancer.
METHODS: We performed IHC analysis of ID4 protein and macrophage marker CD68 in a triple-negative breast cancer series. Next, we used cell migration assays to evaluate the effect of ID4 expression modulation in breast cancer cells on the motility of co-cultured macrophages. The analysis of breast cancer gene expression data repositories allowed us to evaluate the ability of ID4 to predict survival in subsets of tumours showing high or low macrophage infiltration. By culturing macrophages in conditioned media obtained from breast cancer cells in which ID4 expression was modulated by overexpression or depletion, we identified changes in the expression of ID4-dependent angiogenesis-related transcripts and microRNAs (miRNAs, miRs) in macrophages by RT-qPCR.
RESULTS: We determined that ID4 and macrophage marker CD68 protein expression were significantly associated in a series of triple-negative breast tumours. Interestingly, ID4 messenger RNA (mRNA) levels robustly predicted survival, specifically in the subset of tumours showing high macrophage infiltration. In vitro and in vivo migration assays demonstrated that expression of ID4 in breast cancer cells stimulates macrophage motility. At the molecular level, ID4 protein expression in breast cancer cells controls, through paracrine signalling, the activation of an angiogenic programme in macrophages. This programme includes both the increase of angiogenesis-related mRNAs and the decrease of members of the anti-angiogenic miR-15b/107 group. Intriguingly, these miRNAs control the expression of the cytokine granulin, whose enhanced expression in macrophages confers increased angiogenic potential.
CONCLUSIONS: These results uncover a key role for ID4 in dictating the behaviour of tumour-associated macrophages in breast cancer.

Hariharan N, Ashcraft KA, Svatek RS, et al.
Adipose Tissue-Secreted Factors Alter Bladder Cancer Cell Migration.
J Obes. 2018; 2018:9247864 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Background: Obesity is associated with an increased risk of bladder cancer recurrence. This study investigated the role of adipose tissue in bladder cancer progression.
Methods: Gene expression profiling was performed on adipose tissues collected from normal weight (
Results: Expression profiling demonstrated depot-specific or body mass index-specific differences. Increased T24 cell migration was observed using CM harvested from all ASCs. ASC CM from an obese patient significantly increased T24 cell migration and invasion compared to ASC CM collected from normal weight and overweight patients. We identified abundant expression of CXCL1, PAI1, IL6, CX3CL1, and CCL2 in all CM. Exogenous treatment of T24 cells with PAI1, IL6, and CXCL1 enhanced migration. Depletion of CXCL1, PAI1, and IL6 in an obese patient ASC CM abrogated T24 migration.
Conclusion: Factors secreted by adipose tissue influence the migration of bladder tumor cells and could play an active role in tumor progression.

Jin Z, Yao J, Xie N, et al.
Melittin Constrains the Expression of Identified Key Genes Associated with Bladder Cancer.
J Immunol Res. 2018; 2018:5038172 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
This work is aimed at investigating the effect of melittin on identified key genes in bladder cancer (BC) and further providing a theoretical basis for BC treatment. GSE35014 downloaded from the Gene Expression Omnibus (GEO) database was used to screen differentially expressed genes (DEGs) in BC cells and control. Results showed that a total of 389 upregulated and 169 downregulated genes were identified. Subsequently, GO analysis, KEGG pathway enrichment analysis, and PPI network analysis were employed to disclose the crucial genes and signaling pathways involved in BC. Fifteen module-related DEGs and their associated signaling pathways were obtained according to the PPI network and modular analyses. Based on the analysis of articles retrieved in the PubMed database, we found that melittin could induce apoptosis and constrain the progression of tumor cells as a result of regulating critical cancer-related signaling pathways, such as PI3K-Akt and TNF signaling pathways. Furthermore, PI3K-Akt and TNF signaling pathways were also found to be associated with module-related DEGs according to biological analyses. At last, qRT-PCR analysis demonstrated that melittin could constrain the expression of module-related DEGs (LPAR1, COL5A1, COL6A2, CXCL1, CXCL2, and CXCL3) associated with PI3K-Akt and TNF signaling pathways in BC cells. Functional assays revealed that melittin could constrain the proliferative and migrated abilities of BC cells. Conjointly, these findings provide a theoretical basis for these six genes as drug-sensitive markers of melittin in BC treatment.

Karapetsas A, Tokamani M, Evangelou C, Sandaltzopoulos R
The homeodomain transcription factor MEIS1 triggers chemokine expression and is involved in CD8+ T-lymphocyte infiltration in early stage ovarian cancer.
Mol Carcinog. 2018; 57(9):1251-1263 [PubMed] Related Publications
CD8+ T-lymphocytes infiltration is a favorable prognostic marker in ovarian cancer. Recently we identified MEIS1 as a gene overexpressed in early stage ovarian tumors enriched for CD8+ T-cells. Here, we report the molecular mechanism of the homeodomain transcription factor MEIS1 in lymphocyte recruitment. We validated that MEIS1 expression is a positive predictor of CD8+ T cells in early stage ovarian cancer. We showed that MEIS1 induces the expression of CCL18, CCL4, CXCL7, CCL5, CXCL1, and IL8 chemokines in cancer cells followed by their secretion in the culture medium ultimately triggering CD8+ T-lymphocyte recruitment in vitro. Knock down of MEIS1 expression by siRNA resulted in downregulation of these chemokines. We verified that MEIS1 binds to the promoters of chemokine genes, both in vitro and in vivo. We also showed that the expression levels of MEIS1 correlated tightly with the mRNA levels of chemokines CCL4 and CCL18 in early stage ovarian cancer patient samples and served as a positive prognostic marker, as shown by Kaplan-Meyer survival analysis. In conclusion, we propose that MEIS1 plays a pivotal role in the regulatory circuitry governing T-cell chemo-attraction during the early stages of ovarian cancer.

Wu X, Tommasi di Vignano A, Zhou Q, et al.
The ARE-binding protein Tristetraprolin (TTP) is a novel target and mediator of calcineurin tumor suppressing function in the skin.
PLoS Genet. 2018; 14(5):e1007366 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-rasV12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFα, IL-8 and CXCL1. Furthermore, expression of the RNA-binding protein, tristetraprolin (TTP) was down-regulated in response to calcineurin inhibition, wherein TTP was shown to negatively regulate the production of pro-inflammatory cytokines in keratinocytes. The induction of TTP following TPA or UVB treatment was attenuated by calcineurin inhibition in keratinocytes, and correspondingly, disruption of calcineurin signaling down-regulated the amounts of TTP in both clinical and H-rasV12-transformed keratinocyte tumor models. Our results further demonstrated that calcineurin positively controls the stabilization of TTP in keratinocytes through a proteasome-dependent mechanism. Reducing the expression of TTP functionally promoted tumor growth of H-rasV12 expressing HKCs, while stabilizing TTP expression counteracted the tumor-promoting effects of calcineurin inhibition. Collectively these results suggest that calcineurin signaling, acting through TTP protein level stabilization, suppresses keratinocyte tumors by downregulating skin inflammation.

Taki M, Abiko K, Baba T, et al.
Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation.
Nat Commun. 2018; 9(1):1685 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8

Sasaki S, Baba T, Muranaka H, et al.
Involvement of Prokineticin 2-expressing Neutrophil Infiltration in 5-Fluorouracil-induced Aggravation of Breast Cancer Metastasis to Lung.
Mol Cancer Ther. 2018; 17(7):1515-1525 [PubMed] Related Publications
Adjuvant chemotherapy is used for human breast cancer patients, even after curative surgery of primary tumor, to prevent tumor recurrence primarily as a form of metastasis. However, anticancer drugs can accelerate metastasis in several mouse metastasis models. Hence, we examined the effects of postsurgical administration with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide, on lung metastasis process, which developed after the resection of the primary tumor arising from the orthotopic injection of a mouse triple-negative breast cancer cell line, 4T1. Only 5-FU markedly increased the numbers and sizes of lung metastasis foci, with enhanced tumor cell proliferation and angiogenesis as evidenced by increases in Ki67-positive cell numbers and CD31-positive areas, respectively. 5-FU-mediated augmented lung metastasis was associated with increases in intrapulmonary neutrophil numbers and expression of neutrophilic chemokines, Cxcl1 and Cxcl2 in tumor cells, with few effects on intrapulmonary T-cell or macrophage numbers. 5-FU enhanced Cxcl1 and Cxcl2 expression in 4T1 cells in a NFκB-dependent manner. Moreover, the administration of a neutrophil-depleting antibody or a Cxcr2 antagonist, SB225002, significantly attenuated 5-FU-mediated enhanced lung metastasis with depressed neutrophil infiltration. Furthermore, infiltrating neutrophils and 4T1 cells abundantly expressed prokineticin-2 (

Zhang MX, Hong SS, Cai QQ, et al.
Transcriptional control of the MUC16 promoter facilitates follicle-stimulating hormone peptide-conjugated shRNA nanoparticle-mediated inhibition of ovarian carcinoma in vivo.
Drug Deliv. 2018; 25(1):797-806 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Ovarian cancer is the leading cause of cancer death among gynecological malignancies. The high mortality rate has not been significantly reduced despite advances in surgery and chemotherapy. Gene therapy shows therapeutic potential, but several key issues must be resolved before clinical application. To minimize toxicity in noncancerous tissues, tumor-specific ligands are conjugated to vectors to increase the selectivity of drug delivery. The expression pattern of follicle-stimulating hormone (FSH) receptor in normal and cancer tissues provides an opportunity for highly selective drug delivery in ovarian cancer. Furthermore, tumor-specific promoters can conditionally regulate therapeutic gene expression in tumor or normal tissues. The mucin 16 (MUC16) promoter might be a potential tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas. Here, we screened the possible MUC16 promoter sequences and constructed MUC16 promoter-driven gro-α shRNA plasmid vectors. The vectors were specifically delivered into ovarian cancer cells via FSH peptide-conjugated nanoparticles. The predicted promoter sequence with TAAA repeats showed high transcriptional activity. The nanoparticle complex containing MUC16 promoter-driven gro-α shRNA and FSH peptides had the ability to decrease gro-α protein secretion in ovarian cancer cells and block tumor growth without obvious toxic effects in a nude mouse model bearing ovarian cancer. Our study provides a novel gene delivery system using a MUC16 promoter trigger and FSH peptide-mediated active targeting in ovarian cancer, and this system may be a promising strategy for specific genetic therapeutic delivery.

Zhang W, Wu Q, Wang C, et al.
AKIP1 promotes angiogenesis and tumor growth by upregulating CXC-chemokines in cervical cancer cells.
Mol Cell Biochem. 2018; 448(1-2):311-320 [PubMed] Related Publications
Upregulation of A-kinase-interacting protein 1 (AKIP1) has been observed in breast and esophageal cancers, indicating that AKIP1 may be a potent oncogenic protein. However, the role of AKIP1 in cervical cancer still remains unknown. This study aimed to explore the role of AKIP1 in cervical cancer and to investigate the underlying mechanism of AKIP1 in tumor growth. Expression of AKIP1 in cervical cancer cells was determined by qRT-PCR and western blotting. Cell-Light EdU and colony formation assays were used to determine cell proliferation. CXCL1 and CXCL8 proteins were quantified by ELISA kits. Western blotting and qRT-PCR were used to examine the alterations in signaling-related proteins and mRNA, respectively. Endothelial cell tube formation assay was performed to evaluate the effect of AKIP1 on angiogenesis. A BALB/c nude mouse xenograft model was used to evaluate the role of AKIP1 in vivo. Cancer cell proliferation was inhibited and tumor growth and angiogenesis restrained in BALB/c nude mice by suppressing AKIP1 expression in cervical cancer cell lines. In addition, overexpression of AKIP1 in cervical cancer cells elevated the levels of CXCL1, CXCL2, and CXCL8. These three chemokines were not only involved in endothelial tube formation by binding to the endothelial receptor CXCR2, but also in cervical cancer cell proliferation and clone formation, which were induced by overexpression of AKIP1. Furthermore, we found that AKIP1-induced chemokine expression was decreased by an inhibitor of nuclear factor kappa-B kinase subunit β. These results show that AKIP1 is crucial in cervical cancer angiogenesis and growth by elevating the levels of the NF-κB-dependent chemokines CXCL1, CXCL2, and CXCL8.

Yung MM, Tang HW, Cai PC, et al.
GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade.
Theranostics. 2018; 8(5):1270-1285 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness.

Chen E, Qin X, Peng K, et al.
Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis.
Cell Physiol Biochem. 2018; 45(5):1731-1746 [PubMed] Related Publications
BACKGROUND/AIMS: Breast cancer is a common cause of cancer mortality throughout the world. The cross-talk between cancer cells and interstitial cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. CXC is one of four chemokine families involved in mediating survival, angiogenesis, and immunosensitization by chemoattracting leukocytes, and it incentivizes tumor cell growth, invasion and metastasis in the tumor microenvironment. However, the differential expression profiles and prognostic values of these chemokines remains to be elucidated.
METHODS: In this study, we compared transcriptional CXC chemokines and survival data of patients with breast carcinoma (BC) using the ONCOMINE dataset, Kaplan-Meier Plotter, TCGA and cBioPortal.
RESULTS: We discovered increased mRNA levels for CXCL8/10/11/16/17, whereas mRNA expression of CXCL1/2/3/4/5/6/7/12/14 was lower in BC patients compared to non-tumor tissues. Kaplan-Meier plots revealed that high mRNA levels of CXCL1/2/3/4/5/6/7/12/14 correlate with relapse-free survival (RFS) in all types of BC patients. Conversely, high CXCL8/10/11 predicted worse RFS in BC patients. Significantly, high transcription levels of CXCL9/12/13/14 conferred an overall survival (OS) advantage in BC patients, while high levels of CXCL8 demonstrated shorter OS in all BC sufferers.
CONCLUSIONS: Integrative bioinformatics analysis suggests that CXCL8/12/14 are potential suitable targets for precision therapy in BC patients compared to other CXC chemokines.

Hong SS, Zhang MX, Zhang M, et al.
Follicle-stimulating hormone peptide-conjugated nanoparticles for targeted shRNA delivery lead to effective gro-α silencing and antitumor activity against ovarian cancer.
Drug Deliv. 2018; 25(1):576-584 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
The distinct hormone molecules and receptors, such as follicle-stimulating hormone receptor (FSHR) in ovarian cancer, provide opportunities for more precisely targeted therapy. We previously developed FSHR-mediated nanoparticles and found that FSH peptides on the surface of nanoparticles improved the delivery of short interfering RNA (siRNA) into ovarian cancer cells. However, the high toxicity of the nanoparticles and the transient silencing of the siRNA in vivo limited further study. Here, we developed FSH peptide-conjugated nanoparticles with an increased amount of polyethylene glycol (PEG) grafting and encapsulated short hairpin RNA (shRNA) to silence the target gene, growth-regulated oncogene α (gro-α). The nanoparticle complexes exhibited good stability over three weeks. Expression of the target gene, gro-α, was significantly down-regulated by gro-α shRNA-loaded nanoparticles conjugated with FSH peptides (FSH33-G-NP) in FSHR-positive HEY cells. Cell proliferation, migration, and invasion were also inhibited by FSH33-G-NP. Tumor growth was delayed significantly in the mice treated with FSH33-G-NP. No significant loss of body weight or severe toxic effects were observed in any groups. In conclusion, gro-α shRNA-loaded nanoparticles conjugated with FSH peptides overcame the drawbacks of the in vivo application of RNAi therapeutics and polymer-based nanocarriers and showed safe antitumor efficacy. Our study might contribute to the application of FSHR-based targeted therapy and imaging in cancer.

Marazioti A, Lilis I, Vreka M, et al.
Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion.
Nat Commun. 2018; 9(1):672 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKKα-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1β. Indeed, IKKα is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-κB signaling. IL-1β fuels addiction of mutant KRAS to IKKα resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1β-mediated NF-κB induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKKα, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKKα-mediated responsiveness of tumor cells to host IL-1β, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.

Chung L, Thiele Orberg E, Geis AL, et al.
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Cell Host Microbe. 2018; 23(2):203-214.e5 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc

Song H, Wang W, Shen B, et al.
Pretreatment with probiotic Bifico ameliorates colitis-associated cancer in mice: Transcriptome and gut flora profiling.
Cancer Sci. 2018; 109(3):666-677 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Individuals with inflammatory bowel disease are at high risk of developing colitis-associated cancer (CAC). Strategies to block the process from inflammatory bowel disease to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane and dextran sodium sulphate-induced CAC in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of 35 C57BL/6 mice were collected and examined for the degree of inflammation and tumorigenesis. Comparative 16S rRNA sequencing was carried out to observe Bifico-target alterations in gene expression and microbiota structure. We found that pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including CXCL1, CXCL2, CXCL3, and CXCL5, which are all ligands of C-X-C motif receptor 2 (CXCR2). The 16S rRNA sequencing showed that Bifico decreased the abundance of genera Desulfovibrio, Mucispirillum, and Odoribacter, and a bloom of genus Lactobacillus was detected. Notably, we found that an abundance of these Bifico-target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies indicate that Bifico, given orally, can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus, and CXCR2 signaling.

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