Biophysical characterization of the CXC chemokine receptor 2 ligands.

The chemokines of the immune system act as first responders by operating as chemoattractants, directing immune cells to specific locations of inflamed tissues. This promiscuous network is comprised of 50 ligands and 18 receptors where the ligands may interact with the receptors in various oligomeric states i.e., monomers, homodimers, and heterodimers. Chemokine receptors are G-protein coupled receptors (GPCRs) present in the membrane of immune cells. The migration of immune cells occurs in response to a concentration gradient of the ligands. Chemotaxis of neutrophils is directed by CXC-ligand (CXCL) activation of the membrane bound CXC chemokine receptor 2 (CXCR2). CXCR2 plays an important role in human health and is linked to disorders such as autoimmune disorders, inflammation, and cancer. Yet, despite their important role, little is known about the biophysical characteristics controlling ligand:ligand and ligand:receptor interaction essential for biological activity. In this work, we study the homodimers of three of the CXCR2 cognate ligands, CXCL1, CXCL5, and CXCL8. The ligands share high structural integrity but a low sequence identity. We show that the sequence diversity has evolved different binding affinities and stabilities for the CXC-ligands resulting in diverse agonist/antagonist behavior. Furthermore, CXC-ligands fold through a three-state mechanism, populating a folded monomeric state before associating into an active dimer.

Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. METHODS: Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. RESULTS: It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. CONCLUSIONS: Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis.

[A tribute to François Gros, a committed scientist]. / Hommage à François Gros, savant engagé.

As an eminent scientist, fully aware of his social responsibilities, François Gros has been consulted on several occasions on how to make better use of science in the service of society. One of the first reports asked of him was by President Giscard d'Estaing on the social and industrial consequences of the rise of biology (1979). A few years later, at the request of President François Mitterrand, he chaired the National Conference on Research and Technology (1981-1982), which led to substantial changes in the way French public research was organised.

Éminent scientifique, pleinement conscient de ses responsabilités sociales, François Gros a été à plusieurs reprises consulté sur la façon de mieux utiliser la science au service de la société. L'un des premiers rapports qui lui ont été demandés l'a été par le Président Giscard d'Estaing sur les conséquences sociales et industrielle de l'essor de la biologie (1979). Et c'est quelques années plus tard qu'à la demande du Président François Mitterrand il a présidé le Colloque national Recherche et Technologie (1981­1982) dont les suites devaient modifier considérablement toute l'organisation de la recherche publique française.

H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis.

The role of the Immunoglobulin Superfamily (IgSF) as adhesion molecules in orchestrating inflammation is pivotal, yet its specific involvement in gastric cancer (GC) remains unknown. We analyzed IgSF components and discerned conspicuously elevated VCAM1 expression in GC, correlating with a poor prognosis. Remarkably, VCAM1 enhances GC cell proliferation and migration by activating AKT-mTOR signaling. Moreover, lactate in the tumor microenvironment (TME) promotes dynamic lactylation of H3K18 (H3K18la), leading to transcriptional activation of VCAM1 in GC cells. Furthermore, VCAM1 actively mediates intercellular communication in the TME. AKT-mTOR-mediated CXCL1 expression is increased by VCAM1, facilitating the recruitment of human GC-derived mesenchymal stem cells (hGC-MSCs), thereby fostering immunesuppression and accelerating cancer progression. In summary, H3K18 lactylation upregulated VCAM1 transcription, which activated AKT-mTOR signaling, and promoted tumor cell proliferation, EMT Transition and tumor metastasis. VCAM1 upregulated CXCL1 expression by AKT-mTOR pathway, so as to facilitate hGC-MSCs and M2 macrophage recruitment and infiltration. These findings provide novel therapeutic targets for GC.

Regulation of cancer stem cells by CXCL1, a chemokine whose secretion is controlled by MCM2.

BACKGROUND: A high expression pattern of minichromosome maintenance 2 (MCM2) has been observed in various cancers. MCM2 is a protein involved in the cell cycle and plays a role in cancer growth and differentiation by binding to six members of the MCM subfamily. The MCM protein family includes MCM2 through MCM7. METHODS: MCM2 has shown high expression in both lung cancer stem cells (LCSCs) and glioma stem cells (GSCs). We investigated the characteristics of CSCs and the regulation of the epithelial-to-mesenchymal transition (EMT) phenomenon in LCSCs and GSCs by MCM2. Additionally, we explored secreted factors regulated by MCM2. RESULTS: There was a significant difference in survival rates between lung cancer patients and brain cancer patients based on MCM2 expression. MCM2 was found to regulate both markers and regulatory proteins in LCSCs. Moreover, MCM2 is thought to be involved in cancer metastasis by regulating cell migration and invasion, not limited to lung cancer but also identified in glioma. Among chemokines, chemokine (C-X-C motif) ligand 1 (CXCL1) was found to be regulated by MCM2. CONCLUSIONS: MCM2 not only participates in the cell cycle but also affects cancer cell growth by regulating the external microenvironment to create a favorable environment for cells. MCM2 is highly expressed in malignant carcinomas, including CSCs, and contributes to the malignancy of various cancers. Therefore, MCM2 may represent a crucial target for cancer therapeutics.

CXCL1-CXCR2 axis mediates inflammatory response after sciatic nerve injury by regulating macrophage infiltration.

Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1ß) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves.

The role of CXCL1 in crosstalk between endocrine resistant breast cancer and fibroblast.

BACKGROUND: ER positive breast cancer is currently targeted using various endocrine therapies. Despite the proven therapeutic efficacy, resistance to the drug and reoccurrence of tumor appears to be a complication that many patients deal with. Molecular pathways underlying the development of resistance are being widely studied. METHODS AND RESULTS: In this study, using four established endocrine resistant breast cancer (ERBC) cell lines, we characterized CXCL1 as a secreted factor in crosstalk between ERBC cells and fibroblasts. Protein array revealed upregulation of CXCL1 and we confirmed the CXCL1 expression by real-time qRT-PCR and U-Plex assay. Co-culturing ERBC cells with fibroblasts enhanced the cell growth and migration compared to monoculture. The crosstalk of ERBC cells with fibroblasts significantly activates ERK/MAPK signaling pathway while reparixin, CXCR1/2 receptor inhibitor, attenuates the activity. Reparixin displayed the ERBC cell growth inhibition and the combination treatment with reparixin and CDK4/6 inhibitor (palbociclib and ribociclib) increased these inhibitory effect. CONCLUSIONS: Taken together, our study implicates CXCL1 as a critical role in ERBC growth and metastasis via crosstalk with fibroblast and cotargeting CXCR1/2 and CDK4/6 could potentially overcome endocrine resistant breast cancer.

STS â ¡A inhibited angiogenesis of lung adenocarcinoma by activating FOXO3 to inhibit CXCL1/STAT3/VEGF pathway.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most popular type of lung cancer. Sulfotanshinone IIA sodium (STS IIA) has been proven to have an anticancer effect. However, its role in LUAD and its underlying mechanism remain unclear. OBJECTIVE: To investigate the role and mechanism of STS IIA in LUAD angiogenesis. METHODS: The mRNA levels of genes, including forkhead box O3 (FOXO3) and chemokine C-X-C motif ligand 1 (CXCL1), were detected by qRT-PCR. The levels of proteins, including FOXO3, CXCL1, and vascular endothelial growth factor (VEGF), were measured by Western blot. The proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) were detected by the EdU assay and the tubule formation assay, respectively. The binding relationship between FOXO3 and CXCL1 was detected by dual-luciferase reporter assay. RESULTS: Our results illustrated that different concentrations of STS IIA inhibited the proliferation and angiogenesis of HUVECs. FOXO3 regulated the proliferation and angiogenesis of HUVECs inhibited by STS ⅡA via targeting CXCL1. Subsequently, we proved that exogenous CXCL1 alleviated the inhibition of proliferation and angiogenesis of HUVECs regulated by STS IIA via activating the STAT3/VEGF pathway. Finally, we found that STS IIA inhibited the angiogenesis of lung adenocarcinoma though FOXO3 to inhibit the CXCL1/STAT3/VEGF pathway. CONCLUSION: Our study finally elucidated the underlying molecular mechanism by which STS ⅡA inhibits LUAD angiogenesis.

Involvement of CXC chemokines (CXCL1-CXCL17) in gastric cancer: Prognosis and therapeutic molecules.

Gastric cancer (GC) is the fifth-most prevalent and second-most deadly cancer worldwide. Due to the late onset of symptoms, GC is frequently treated at a mature stage. In order to improve the diagnostic and clinical decision-making processes, it is necessary to establish more specific and sensitive indicators valuable in the early detection of the disease whenever a cancer is asymptomatic. In this work, we gathered information about CXC chemokines and GC by using scientific search engines including Google Scholar, PubMed, SciFinder, and Web of Science. Researchers believe that GC chemokines, small proteins, class CXC chemokines, and chemokine receptors promote GC inflammation, initiation, and progression by facilitating angiogenesis, tumor transformation, invasion, survival, metastatic spread, host response safeguards, and inter-cell interaction. With our absolute best professionalism, the role of CXC chemokines and their respective receptors in GC diagnosis and prognosis has not been fully explained. This review article updates the general characteristics of CXC chemokines, their unique receptors, their function in the pathological process of GC, and their potential application as possible indicators for GC. Although there have only recently been a few studies focusing on the therapeutic efficacy of CXC chemokine inhibitors in GC, growing experimental evidence points to the inhibition of CXC chemokines as a promising targeted therapy. Therefore, further translational studies are warranted to determine whether specific antagonists or antibodies designed to target CXC chemokines alone or in combination with chemotherapy are useful for diagnosing advanced GC.

Tumor cell SPTBN1 inhibits M2 polarization of macrophages by suppressing CXCL1 expression.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, and the M2-type TAMs can promote tumor growth, invasion and angiogenesis, and suppress antitumor immune responses. It has been reported that spectrin beta, non-erythrocytic 1 (SPTBN1) may inhibit the infiltration of macrophages in Sptbn1+/-  mouse liver, but whether tumor SPTBN1 affects TAMs polarization remains unclear. This study investigated the effect and mechanism of tumor cell SPTBN1 on polarization and migration of TAMs in hepatoma and breast cancer. By analyzing tumor immune databases, we found a negative correlation between SPTBN1 and abundance of macrophages and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. By reverse transcription-quantitative real-time PCR assays and cell migration assays, the migration and M2 polarization of macrophages were enhanced by the culture medium from hepatocellular carcinoma cell line PLC/PRF/5, SNU449, and breast cancer cell line MDA-MB-231 with SPTBN1 suppression, which could be reversed by CXCL1 neutralizing antibody MAB275. Meanwhile, the ability of migration and colony formation of PLC/PRF/5, SNU449, and MDA-MB-231 cells were promoted when coculture with M2 macrophages. We also found that SPTBN1 regulated CXCL1 through p65 by cytoplasmic-nuclear protein isolation experiments and ChIP-qPCR. Our data suggest that tumor cell SPTBN1 inhibits migration and M2-type polarization of TAMs by reducing the expression and secretion of CXCL1 via inhibiting p65 nuclear localization.

Fucosylation deficiency enhances imiquimod-induced psoriasis-like skin inflammation by promoting CXCL1 expression.

Psoriasis is a multifaceted chronic inflammatory skin disease; however, its underlying molecular mechanisms remain unclear. In this study, we explored the role of fucosylation in psoriasis using an imiquimod-induced psoriasis-like mouse model. ABH antigen and fucosyltransferase 1 (Fut1) expression was reduced in the granular layer of lesional skin of patients with psoriasis. In particular, the blood group H antigen type 2 (H2 antigen)-a precursor of blood group A and B antigens-and FUT1 were highly expressed throughout the spinous layer in both patients with psoriasis and the skin of imiquimod-treated mice. Upon the application of imiquimod, Fut1-deficient mice, which lacked the H2 antigen, exhibited higher clinical scores based on erythema, induration, and scaling than those of wild-type mice. Imiquimod-treated Fut1-deficient mice displayed increased skin thickness, trans-epidermal water loss, and Gr-1+ cell infiltration compared with wild-type mice. Notably, the levels of CXCL1 protein and mRNA were significantly higher in Fut1-deficient mice than those in wild-type mice; however, there were no significant differences in other psoriasis-related markers, such as IL-1ß, IL-6, IL-17A, and IL-23. Fut1-deficient primary keratinocytes treated with IL-17A also showed a significant increase in both mRNA and protein levels of CXCL1 compared with IL-17A-treated wild-type primary keratinocytes. Further mechanistic studies revealed that this increased Cxcl1 mRNA in Fut1-deficient keratinocytes was caused by enhanced Cxcl1 mRNA stabilization. In summary, our findings indicated that fucosylation, which is essential for ABH antigen synthesis in humans, plays a protective role in psoriasis-like skin inflammation and is a potential therapeutic target for psoriasis.

Memories of Professor François Gros.

I joined the laboratory of Professor Francois Gros in 1987 and worked there as a postdoc with Robert Whalen until 1992. I recount the research we carried out and mention that of the other scientists also working on skeletal muscle on the 6th floor of the Molecular Biology Department of the Institut Pasteur at that time. I then present my subsequent research when I returned to Japan. I pay tribute to the influence of Professor Gros and to his support in establishing Japanese/French meetings on muscle biology and muscular dystrophy. I also invoke personal memories of Robert Whalen and Margaret Buckingham and remember the occasions when I returned to Paris to honour François Gros.

J'ai rejoint le laboratoire du professeur François Gros en 1987 et j'y ai travaillé en tant que postdoc avec Robert Whalen jusqu'en 1992. Je raconte les recherches que nous avons menées et je mentionne celles des autres scientifiques qui travaillaient également sur le muscle squelettique au 6 e étage du Département de biologie moléculaire de l'Institut Pasteur à cette époque. Je présente ensuite les recherches ultérieures que j'ai menées de retour au Japon. Je rends hommage à l'influence du professeur Gros et à son soutien lors de la mise en place de réunions franco-japonaises autour de la biologie musculaire et de la dystrophie musculaire. J'évoque également des souvenirs personnels de Robert Whalen et de Margaret Buckingham et je me rappelle les moments où je suis retourné à Paris pour rendre hommage à François Gros.

Cxcl1 monomer-dimer equilibrium controls neutrophil extravasation.

The chemokine Cxcl1 plays a crucial role in recruiting neutrophils in response to infection. The early events in chemokine-mediated neutrophil extravasation involve a sequence of highly orchestrated steps including rolling, adhesion, arrest, and diapedesis. Cxcl1 function is determined by its properties of reversible monomer-dimer equilibrium and binding to Cxcr2 and glycosaminoglycans. Here, we characterized how these properties orchestrate extravasation using intravital microscopy of the cremaster. Compared to WT Cxcl1, which exists as both a monomer and a dimer, the trapped dimer caused faster rolling, less adhesion, and less extravasation. Whole-mount immunofluorescence of the cremaster and arrest assays confirmed these data. Moreover, the Cxcl1 dimer showed impaired LFA-1-mediated neutrophil arrest that could be attributed to impaired Cxcr2-mediated ERK signaling. We conclude that Cxcl1 monomer-dimer equilibrium and potent Cxcr2 activity of the monomer together coordinate the early events in neutrophil recruitment.

The Role and Mechanism of Spinal NF-κB-CXCL1/CXCR2 in Rats with Nucleus Pulposus-induced Radicular Pain.

STUDY DESIGN: Experimental study of the role and mechanism of spinal NFκB-CXCL1/CXCR2 in rats with nucleus pulposus-induced radicular pain. OBJECTIVE: This study investigated the role and mechanism of spinal NFκB-CXCL1/CXCR2 in autologous nucleus pulposus-induced pain behavior in rats and to clarify the involvement and regulation of spinal NFκB as an upstream molecule of CXCL1 in autologous nucleus pulposus-induced radicular pain in rats. SUMMARY OF BACKGROUND DATA: The inflammatory response of nerve roots is an important mechanism for the occurrence of chronic pain. NFκB-CXCL1/CXCR2 pathway plays an important role in the development of radicular pain, but its regulatory mechanism in the model of radicular pain induced by autologous nucleus pulposus is still unclear. MATERIALS AND METHODS: We established a rat model of autologous medullary nucleus transplantation. We observed and recorded the changes in 50% mechanical withdrawal threshold and thermal withdrawal latency before and after the administration of CXCL1-neutralizing antibodies, CXCR2 inhibitor, and NFκB inhibitor in each group of rats and evaluated the expression of NFκB, CXCL1, and CXCR2 in the spinal dorsal horn using immunofluorescence and Western blot. To compare differences between groups in behavioral testing, analysis of variance was employed. Dunnett's method was used to compare differences at different time points within a group and between different groups at the same time point. A comparison of the relative concentration of protein, relative concentration of mRNA, and semiquantitative data from immunofluorescence staining was conducted utilizing one-way ANOVA and Dunnett's pairwise comparison. RESULTS: Autologous nucleus pulposus transplantation can induce radicular pain in rats and upregulate the expression of CXCL1, CXCR2, and NFκB in the spinal cord. CXCL1 is co-expressed with astrocytes, CXCR2 with neurons, and NFκB with both astrocytes and neurons. The application of CXCL1 neutralizing antibodies, CXCR2 inhibitors, and NFκB inhibitors can alleviate pain hypersensitivity induced by autologous nucleus pulposus transplantation in rats. Inhibitors of NFκB could downregulate the expression of CXCL1 and CXCR2. CONCLUSIONS: We found that spinal NFκB is involved in NP-induced radicular pain in rats through the activation of CXCL1/CXCR2, enriching the mechanism of medullary-derived radicular pain and providing a possible new target and theoretical basis for the development of more effective anti-inflammatory and analgesic drugs for patients with chronic pain following LDH.

TGFß1 induces CXCL1 to promote stemness features in lung cancer.

Chemokines critically orchestrate the tumorigenesis, metastasis, and stemness features of cancer cells that lead to poor outcomes. High plasma levels of transforming growth factor-ß1 (TGFß1) correlate with poor prognostic features in advanced lung cancer patients, thus suggesting the importance of TGFß1 in the lung tumor microenvironment. However, the role of chemokines in TGFß1-induced tumor stemness features remains unclear. Here, we clarify the previously undocumented role of CXCL1 in TGFß1-induced lung cancer stemness features. CXCL1 and its receptor CXCR2 were significantly upregulated in TGFß1-induced lung cancer stem cells (CSCs). CXCL1 silencing (shCXCL1) suppressed stemness gene expression, tumorsphere formation, colony formation, drug resistance, and in vivo tumorigenicity in TGFß1-induced lung tumorspheres. Immunohistochemistry staining showed that patients with stage II/III lung cancer had higher expression levels of CXCL1. The levels of CXCL1 were positively associated with lymph node metastasis and correlated with the expression of the CSC transcription factor Oct-4. Furthermore, online database analysis revealed that CXCL1 expression was negatively correlated with lung cancer survival in patients. Patients with high TGFß1/CXCL1/CD44 co-expression had a worse survival rate. We suggest that CXCL1 serves as a crucial factor in TGFß1-induced stemness features of lung cancer.

CXCL1 promotes immune escape in colorectal cancer by autophagy-mediated MHC-I degradation.

BACKGROUND: Immunotherapy is now seen as a potential remedy for colorectal cancer (CRC). Chemokines play a crucial role in tumors, including CRC, which contains CXCL1. We attempted to study how CXCL1 impacts immune escape in CRC. METHODS: Bioinformatics analysis was used to examine CXCL1 level in CRC. qRT-PCR was used to assess CXCL1 and MHC-I (HLA-A, B, C) levels. Cell Counting Kit-8 (CCK-8) was used to measure cell viability. Cytotoxicity assay kit was utilized to assay CD8+ T cell cytotoxicity against CRC. Flow cytometry tested proliferation and apoptosis of CD8+ T cells. Chemotaxis assay evaluated chemotaxis of CD8+ T cells towards CRC. Immunofluorescence examined expression of autophagy marker LC3 and localization of NBR1/MHC-I. Western blot analysis measured protein levels of chemokines CXCL9 and CXCL10, autophagy-related proteins LC3-I and LC3-II, and MHC-I (HLA-A, B, C). RESULTS: Bioinformatics analysis and qRT-PCR presented that CXCL1 was upregulated in CRC. Cell experiments demonstrated that CXCL1 overexpression promoted immune escape in CRC. Rescue experiments revealed that the autophagy inducer Rapa could attenuate the inhibitory effect of CXCL1 low expression on immune escape in CRC. Further studies showed that CXCL1 promoted immune escape in CRC by autophagy-mediated MHC-I degradation. CONCLUSION: CXCL1 promoted immune escape in CRC by autophagy-mediated MHC-I degradation, suggesting that CXCL1 may be a possible immunotherapeutic target for CRC.

Collagen 1-mediated CXCL1 secretion in tumor cells activates fibroblasts to promote radioresistance of esophageal cancer.

Esophageal squamous-cell carcinoma (ESCC) is commonly treated with radiotherapy; however, radioresistance hinders its clinical effectiveness, and the underlying mechanism remains elusive. Here, we develop patient-derived xenografts (PDXs) from 19 patients with ESCC to investigate the mechanisms driving radioresistance. Using RNA sequencing, cytokine arrays, and single-cell RNA sequencing, we reveal an enrichment of cancer-associated fibroblast (CAF)-derived collagen type 1 (Col1) and tumor-cell-derived CXCL1 in non-responsive PDXs. Col1 not only promotes radioresistance by augmenting DNA repair capacity but also induces CXCL1 secretion in tumor cells. Additionally, CXCL1 further activates CAFs via the CXCR2-STAT3 pathway, establishing a positive feedback loop. Directly interfering with tumor-cell-derived CXCL1 or inhibiting the CXCL1-CXCR2 pathway effectively restores the radiosensitivity of radioresistant xenografts in vivo. Collectively, our study provides a comprehensive understanding of the molecular mechanisms underlying radioresistance and identifies potential targets to improve the efficacy of radiotherapy for ESCC.

Biological function of C-X-C Motif Chemokine Ligand 1 gene (CXCL1) in ovarian malignant tumors.

OBJECTIVE: To determine the function of the chemokine (C-X-C motif) ligand 1 (CXCL1) gene in ovarian cancer cells and to investigate the relationship between CXCL1 gene mRNA expression and ovarian tumor clinical pathology. METHODS: Using bioinformatics methods to identify common differentially expressed genes associated with ovarian cancer in the GEO database. Growth curves of A2780 cells with or without CXCL1 expression were plotted by MTT assay. Cell cycles were measured by flow cytometry. Cell colony formation was enumerated in Transwell chambers. Migration and invasion in vitro were investigated using Cell Counting Kit-8 (CCK8), wound healing and Transwell, respectively. The relationship between CXCL1 gene mRNA expression and ovarian tumor clinical pathology was analyzed. RESULTS: CXCL1 was found to be one of the co-upregulated differentially expressed genes in the GEO database. The migration of A2780 cells expressing CXCL1 was significantly higher than that of A2780 cells without CXCL1 expression. CXCL1 mRNA expression in ovarian malignancy was significantly higher than those in benign lesions and the normal control (p < .01). In advanced ovarian cancer (Stages III-IV), CXCL1 mRNA expression was also significantly higher than that in patients with early-stage ovarian cancer (Stages I-II) (p = .005). Kaplan-Meier survival curve showed no correlation between CXCL1 mRNA expression and ovarian cancer prognosis. A Cox proportional hazard model also showed that CXCL1 expression was not an independent prognostic factor for ovarian cancer patients. CONCLUSIONS: CXCL1 gene could promotes ovarian cancer A2780 cell proliferation and invasion in vitro, and contributed theoretical knowledge for the target selection in molecular targeted therapy. CXCL1 mRNA over-expression may be correlated with the occurrence and development of ovarian malignancy. Level of plasma CXCL1 might serve as a biomarker for prognosis in ovarian carcinoma patients.

Bioinformatic Analysis of the CXCR2 Ligands in Cancer Processes.

Human CXCR2 has seven ligands, i.e., CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8/IL-8-chemokines with nearly identical properties. However, no available study has compared the contribution of all CXCR2 ligands to cancer progression. That is why, in this study, we conducted a bioinformatic analysis using the GEPIA, UALCAN, and TIMER2.0 databases to investigate the role of CXCR2 ligands in 31 different types of cancer, including glioblastoma, melanoma, and colon, esophageal, gastric, kidney, liver, lung, ovarian, pancreatic, and prostate cancer. We focused on the differences in the regulation of expression (using the Tfsitescan and miRDB databases) and analyzed mutation types in CXCR2 ligand genes in cancers (using the cBioPortal). The data showed that the effect of CXCR2 ligands on prognosis depends on the type of cancer. CXCR2 ligands were associated with EMT, angiogenesis, recruiting neutrophils to the tumor microenvironment, and the count of M1 macrophages. The regulation of the expression of each CXCR2 ligand was different and, thus, each analyzed chemokine may have a different function in cancer processes. Our findings suggest that each type of cancer has a unique pattern of CXCR2 ligand involvement in cancer progression, with each ligand having a unique regulation of expression.

CXCL1 enhances COX-II expression in rheumatoid arthritis synovial fibroblasts by CXCR2, PLC, PKC, and NF-κB signal pathway.

Rheumatoid arthritis (RA) is the most common autoimmune disease, affecting the joints of the hands and feet. Several chemokines and their receptors are crucial in RA pathogenesis through immune cell recruitment. C-X-C Motif Chemokine Ligand 1 (CXCL1), a chemokine for the recruitment of various immune cells, can be upregulated in patients with RA. However, the discussion on the role of CXCL1 in RA pathogenesis is insufficient. Here, we found that CXCL1 promoted cyclooxygenase-2 (COX-II) expression in a dose- and time-dependent manner in rheumatoid arthritis synovial fibroblasts (RASFs). CXCL1 overexpression in RASFs led to a significant increase in COX-II expression, while the transfection of RASFs with the shRNA plasmid resulted in a noticeable decrease in COX-II expression. Next, we delineated the molecular mechanism underlying CXCL1-promoted COX-II expression and noted that CXC chemokine receptor 2 (CXCR2), phospholipase C (PLC), and protein kinase C (PKC) signal transduction were responsible for COX-II expression after CXCL1 incubation for RASFs. Finally, we confirmed the transcriptional activation of nuclear factor κB (NF-κB) in RASFs after incubation with CXCL1. In conclusion, the current study provided a novel insight into the role of CXCL1 in RA pathogenesis.