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Expression of CXCL12: a Semi-quantitative RT-PCR showing expression of CXCL12 in normal cervical tissue and tumor biopsies (N = Normal cervical tissues, T = Tumor biopsies). b Scatter plot showing overall change in expression of CXCL12 in tumor biopsies (N = 62) compared to normal (N = 28). c Estimation of expression of CXCL12 in conditioned media of HEK293, NC29, NC30, CC cell lines and tissue lysates of normal (NC31, NC32) and tumor (T21-T25) biopsies by ELISA. d Cell surface expression of CXCR4 and CXCR7 was analysed by FACS analysis. e Scatter plot showing significant correlation of CXCL12 expression with size of tumor. f Survival curve showing correlation of percent survival with expression of CXCL12
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CXCL12 is a small pro-inflammatory chemo-attractant cytokine which signals through chemokine receptor CXCR4. The importance of CXCL12/CXCR4 axis is coming to the fore in several divergent signaling pathway-initiating signals related to cell survival and/or proliferation and cancer metastasis. In the present study we have investigated whether deregu...
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Cysteine X cysteine (CXC) chemokine receptor 4 (CXCR4) and C-X-C motif chemokine 12 (CXCL12) were originally identified as chemoattractants between immune cells and sites of inflammation. Since studies have validated an increased level of CXCL12 and its receptor in patients with colorectal cancers, CXCL12/CXCR4 axis has been considered as a valuabl...
Citations
... Of these, CXC chemokines as crucial and indispensable components producing and secreting by immune, stromal or tumor cells, are mainly concentrated in the tumor microenvironment and have been implicated in the tumor-specific immune responses [23][24][25]. They can modulate the tumor microenvironment and biological phenotypes of the malignant cells, thus affecting clinical characteristics, patients' outcomes and effectiveness of therapeutic interventions, including endometrial carcinoma [26], breast cancer [27], bladder cancer [28] and cervix cancer [29], etc. UCEC is one of the commonest malignancies of the female reproductive system. It is also the leading cause of death amongst gynecological cancers due to its high recurrence rate and molecular heterogeneity [30][31][32]. ...
Uterine corpus endometrial carcinoma (UCEC) is one of the most common type of gynecological malignancies. Multiple lines of evidence indicated that CXC chemokines exerted an anti-tumor immunological role in the tumor microenvironment which were critical regulators of cancer immunity. However, the relevance of CXC chemokines in the evaluation of prognosis and immune infiltration of UCEC remains to be explored. This study utilized various online databases, including TCGA, UALCAN, Kaplan-Meier Plotter, cBioPortal, TIMER2.0, TISIDB, and MethSurv to perform the analysis. Gene expression data from the TCGA-UCEC dataset indicated decreased expression of CXCL2/12 and increased expression of CXCL14/17. CXCL2/12 expression was negatively whereas CXCL14/17 expression was positively correlated with clinicopathological features of UCEC patients, including cancer stage, patients’ age, weight and menopause status. Patients with higher CXCL12/14 expression corresponded with better clinical outcomes, which were not influenced by the genetic alterations. The differential expression of CXCL2/12/14/17 was not only significantly correlated with immune infiltration levels, but also the abundance of immune checkpoint inhibitors. Heatmaps of DNA methylation of CXCL2/12/14/17 were investigated, and 4 CpGs of CXCL2, 16 CpGs of CXCL12, 3 CpGs of CXCL14/17 were identified where altered methylation affected the prognosis of UCEC patients. These findings provided novel insights into the immunologic features of UCEC and might pave the way toward the prognostic evaluation and immunotherapy selection based on CXCL2/12/14/17 expression status.
... It is widely speculated that specific chemokines secreted by cancer cells and conjugate receptors on MSCs are involved in MSCs migration [45]. One specific ligand CXCL12 has drawn particular interest and given its promoting function in cervical cancer progression [46]. A previous study has confirmed that CXCL12 is indeed upregulated in cervical cancer tissues [47]. ...
In the last decade, there has been a rapid expansion in tumor targeted therapy using mesenchymal stem cells (MSCs) based on their unique tropism towards cancer cells. Despite similarities in morphology, immunophenotype, and differential potent in vitro, MSCs originated from different tissues do not necessarily have equivalent biological behaviors. It is important to screen the most chemotactic MSCs to cancer cells. In this study, different MSCs were isolated from various human tissues including adipose, umbilical cord, amniotic membrane, and chorion. The chemotaxis of human MSCs to cervical cancer cells was measured by CCK-8, ELISA and Transwell invasion assays. Western blotting was performed to explore the underlying mechanisms. MSCs derived from distinct sources can be differently recruited to cervical cancer cells, among which chorion-derived MSC (CD-MSC) possessed the strongest tropic capacity. CXCL12 was found to be highly secreted by cervical cancer cells, in parallel with the expression of CXCR4 in all MSCs. CD-MSC displayed the highest level of CXCR4. These results indicated that CXCL12/CXCR4 pathway contributed to the different chemotaxis to cervical cancer cells of each MSCs. This study proposed that CD-MSC with the highest CXCR4 expression is a promising therapeutic vehicle for targeted therapy in cervical cancer.
... Moreover, several mechanisms have been proposed to explain the loss of CXCL12 expression. Hypermethylation of the CXCL12 promoter in CRCs has been proposed by Wendt et al. [99], as well as in cervical tumor lines and biopsies, observed by Yadav et al. [156]. In our study of a cohort of 444 MSS CRCs, we showed that the CpG islands of the CXCL12 promoter are methylated in only 30% of tumors [82]. ...
Simple Summary
Many signaling pathways are involved in cancer progression, and among these pathways, the CXCL12 axis and its two receptors CXCR4 and CXCR7 are well described for many cancers. This review presents the current knowledge on the role played by each of the actors of this axis in colorectal cancer and on its consideration in the development of new therapeutic strategies.
Abstract
Colorectal cancer is one of the most common cancers, and diagnosis at late metastatic stages is the main cause of death related to this cancer. This progression to metastasis is complex and involves different molecules such as the chemokine CXCL12 and its two receptors CXCR4 and CXCR7. The high expression of receptors in CRC is often associated with a poor prognosis and aggressiveness of the tumor. The interaction of CXCL12 and its receptors activates signaling pathways that induce chemotaxis, proliferation, migration, and cell invasion. To this end, receptor inhibitors were developed, and their use in preclinical and clinical studies is ongoing. This review provides an overview of studies involving CXCR4 and CXCR7 in CRC with an update on their targeting in anti-cancer therapies.
... At least 27 different members of this subgroup have been described for mammals called CC chemokine ligands (CCL)-1 to -28; CCL10 is identical to CCL9 [6][7][8][9][10][11]. Members of the CXC chemokine subfamily, on the other hand, have an intermediate amino acid between the first two cysteine; members of the CC chemokine subfamily have two adjacent cysteine. Normally, and with only a few exceptions, members of CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and a small subset of lymphocytes [12][13][14][15][16][17]. Chemokine (C-motif) ligands (XCL1 and -2) are small cytokines from the family of C chemokines, also known as lymphotactin. ...
... Its gene is located on human chromosome 16 along with CCL17 and CCL22. CX3CL1 plays a role in the recruitment of cytotoxic cells and in the elimination of cells that may undergo malignant transformation [15][16][17][18][19][20][21][22][23]. ...
... In cervical cancer cell lines and primary tumor biopsies, CXCL12 is often downregulated and its promoter is hypermethylated [15]. Exogenous treatment with recombinant CXCL12 inhibited metastasis-promoting cell migration, cell invasion, and anchorageindependent cell growth events in cervical cancer cell lines (HeLa, SiHa and C-33A) [15]. ...
Both clinical-pathological and experimental studies have shown that chemokines play a key role in activating the immune checkpoint modulator in cervical cancer progression and are associated with prognosis in tumor cell proliferation, invasion, angiogenesis, chemoresistance, and immunosuppression. Therefore, a clear understanding of chemokines and immune checkpoint modulators is essential for the treatment of this disease. This review discusses the origins and categories of chemokines and the mechanisms that are responsible for activating immune checkpoints in cervical dysplasia and cancer, chemokines as biomarkers, and therapy development that targets immune checkpoints in cervical cancer research.
... Unfortunately, there was no statistically significant difference in the expression of CXCL12 between tumor and para-cancerous tissues. One possible interpretation is that cervical expression of CXCL12 is heterogeneous, tending to be inhibited as the tumor grows [30]. ...
... The hypermethylation of a single CpG dinucleotide in the promoter region of the CXCL13 gene promoted the migration of cervical cancer cells [38]. Silencing of CXCL12 altered the homeostatic autocrine and paracrine CXCR4 signaling to endocrine communication in the tumor microenvironment, leading to tumor progression and metastases [30]. In addition, TLRs are I intermembrane proteins, and TLR signaling pathways in tumor cells have been shown to influence cancer progression. ...
Background
The tumor microenvironment (TME) has received an increasing amount of attention. CXC chemokines can regulate immune cell transport and tumor cell activity to exert anti-tumor immunity. However, studies on the expression and prognosis of CXC chemokines in cervical cancer (CC) are more limited.
Methods
The study investigated the role of CXC chemokines in TME of CC by using public databases. Moreover, quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) of CXC chemokines were performed to further verify.
Results
The transcriptional levels of CXCL1/3/5/6/8/9/10/11/13/16/17 in CC tissues were significantly elevated while the transcriptional levels of CXCL12/14 were significantly reduced. We reached a consistent conclusion that the expression of CXCL9/10/11/13 was verified by quantitative real-time PCR and immunohistochemistry. Moreover, CC patients with low transcriptional levels of CXCL1/2/3/4/5/8 were significantly associated with longer overall survival (OS). The CCL family was related to CXC chemokines neighboring alteration. RELA, NFKB1, LCK and PAK2 were the key transcription factors and kinase targets of CXC chemokines, respectively. We also found there were significant correlations between the expression of CXCL9/10/11 and the infiltration of immune cells (CD8+ T cell, CD4+ T cell, neutrophils and dendritic cells).
Conclusions
In brief, we conducted a comprehensive analysis of CXC chemokines via clinical data and some online public databases. Our results may provide a new idea for the selection of immunotherapeutic targets and prognostic biomarkers for cervical cancer.
... The TME consists of fibroblasts, vascular endothelial cells, immune cells, cytokines, growth factors, hormones, extracellular matrix components, and so on [6]. The TME affects invasion, migration, proliferation, apoptosis, and response to drugs in CESC cells [7][8][9][10][11]. The Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm uses gene expression data to analyze the proportion of immune cells and stromal cells in the TME [12]. ...
Background
Previous studies have found that the microenvironment of cervical cancer (CESC) affects the progression and treatment of this disease. Thus, we constructed a multigene model to assess the survival of patients with cervical cancer.
Methods
We scored 307 CESC samples from The Cancer Genome Atlas (TCGA) and divided them into high and low matrix and immune scores using the ESTIMATE algorithm for differential gene analysis. Cervical cancer patients were randomly divided into a training group, testing group and combined group. The multigene signature prognostic model was constructed by Cox analyses. Multivariate Cox analysis was applied to evaluate the significance of the multigene signature for cervical cancer prognosis. Prognosis was assessed by Kaplan–Meier curves comparing the different groups, and the accuracy of the prognostic model was analyzed by receiver operating characteristic-area under the curve (ROC-AUC) analysis and calibration curve. The Tumor Immune Estimation Resource (TIMER) database was used to analyze the relationship between the multigene signature and immune cell infiltration.
Results
We obtained 420 differentially expressed genes in the tumor microenvironment from 307 patients with cervical cancer. A three-gene signature (SLAMF1, CD27, SELL) model related to the tumor microenvironment was constructed to assess patient survival. Kaplan–Meier analysis showed that patients with high risk scores had a poor prognosis. The ROC-AUC value indicated that the model was an accurate predictor of cervical cancer prognosis. Multivariate cox analysis showed the three-gene signature to be an independent risk factor for the prognosis of cervical cancer. A nomogram combining the three-gene signature and clinical features was constructed, and calibration plots showed that the nomogram resulted in an accurate prognosis for patients. The three-gene signature was associated with T stage, M stage and degree of immune infiltration in patients with cervical cancer.
Conclusions
This research suggests that the developed three-gene signature may be applied as a biomarker to predict the prognosis of and personalized therapy for CESC.
... Table 4 compares the expression of these seven key genes in cervical cancer, other cancers, and lymph node metastasis as reported in previous experimental studies and our calculated results. The decreased expression of CXCL12 in cervical cancer cells and its role in lymph node metastasis was confirmed in previous experiments (Yadav et al., 2016), and the decreased expression of IGF1 and the increased expression of WDHD1 were also experimentally validated in cervical cancer cells but only in lymph node metastasis of other cancers (Serrano et al., 2006;Kümmel et al., 2007;Huang et al., 2008;Zhou et al., 2016;Liu et al., 2019). Interestingly, the expression of RAD51B is also decreased in cervical cancer cells, but experiments showed that its expression is increased in other cancer lymph node metastases (Cheng et al., 2016;Hang et al., 2016). ...
... CXCL12 is the ligand for the G-protein coupled receptor-like chemokine (C-X-C motif) receptors 4 and 7. It affects many cellular processes such as immune monitoring, inflammatory response, tumor growth, and metastasis (Colamussi et al., 2001;Yadav et al., 2016). Yadav et al. (2016) demonstrated that CXCL12 expression is absent in cervical cancer. ...
... It affects many cellular processes such as immune monitoring, inflammatory response, tumor growth, and metastasis (Colamussi et al., 2001;Yadav et al., 2016). Yadav et al. (2016) demonstrated that CXCL12 expression is absent in cervical cancer. They also illustrated that CXCL12 silencing enables cells to evade apoptosis and leads to the progression and metastasis of cervical cancer (Yadav et al., 2016). ...
Background
miRNAs and genes can serve as biomarkers for the prognosis and therapy of cervical tumors whose metastasis into lymph nodes is closely associated with disease progression and poor prognosis.
Methods
R software and Bioconductor packages were employed to identify differentially expressed miRNAs (DEMs) from The Cancer Genome Atlas (TCGA) database. GEO2R detected differentially expressed genes (DEGs) in the GSE7410 dataset originating from the Gene Expression Omnibus (GEO). A Cox proportional hazard regression model was established to select prognostic miRNA biomarkers. Online tools such as TargetScan and miRDB predicted target genes, and overlapping DEGs and target genes were defined as consensus genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) function annotations were performed to discern the potential functions of consensus genes. STRING and Cytoscape screened key genes and constructed a regulatory network.
Results
A combination of four miRNAs (down-regulated miR-502 and miR-145, up-regulated miR-142 and miR-33b) was identified as an independent prognostic signature of cervical cancer. A total of 94 consensus genes were significantly enriched in 7 KEGG pathways and 19 GO function annotations including the cAMP signaling pathway, the plasma membrane, integral components of the plasma membrane, cell adhesion, etc. The module analysis suggested that CXCL12, IGF1, PTPRC CDH5, RAD51B, REV3L, and WDHD1 are key genes that significantly correlate with cervical cancer lymph node metastasis.
Conclusions
This study demonstrates that a four-miRNA signature can be a prognostic biomarker, and seven key genes are significantly associated with lymph node metastasis in cervical cancer patients. These miRNAs and key genes have the potential to be therapeutic targets for cervical cancer. Among them, two miRNAs (miR-502 and miR-33b) and two key genes (PTPRC and CDH5) were first reported to be potential novel biomarkers for cervical cancer. The current study further characterizes the progression of lymph node metastasis and mechanism of cervical tumors; therefore, it provides a novel diagnostic indicator and therapeutic targets for future clinical treatments.
... The colonies were incubated for 10 days. 22 The experiment was performed three times independently for each cell line. ...
Pre-B-cell leukemia homeobox 3 (PBX3) is upregulated in various malignancies; however, the role of PBX3 in cervical cancer (CC) is unknown. The purpose of this study was to explore the expression characteristics, clinicopathological significance, and molecular biological function of PBX3 in CC. The expression levels of PBX3 were analyzed in CC cell lines and tumor specimens by real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical staining. The clinicopathological characteristics associated with PBX3 expression were evaluated. An RNA interference approach was employed to suppress PBX3 expression in CC in vitro and in vivo, determine its role in cell proliferation and analyze its molecular function. We found that PBX3 expression was significantly upregulated in CC cell lines and clinical specimens compared with normal cells and adjacent nontumorous cervical tissues. PBX3 was an independent predictive factor of poor prognosis, and its expression was correlated with tumor diameter, pathological grading, lymph node metastasis, invasion depth, vascular invasion, and clinical stage of CC. Multivariate analysis suggested that PBX3 expression may represent an independent prognostic indicator of the survival of CC patients. CC patients with high PBX3 expression exhibited reduced overall survival compared with those with low PBX3 expression. Additionally, stable downregulation of PBX3 expression in CC cell lines suppressed cell proliferation and decreased p-AKT protein expression levels in vitro. Similarly, in vivo assays demonstrated that PBX3 downregulation in CC cells markedly inhibited tumor size and weight. Overall, we demonstrated that PBX3 can promote CC cell proliferation via the AKT signaling pathway and that it may serve as a prognostic marker. Our data indicate that inactivation of PBX3 may be an effective clinical treatment for CC.
... A recent paper indicated that in cervical cancer cells, epigenetic reactivation of CXCL12 was observed when cells are treated with both methylation-inhibiting and acetylating agents, suggesting that in cervical cancer also, methylation and histone acetylation may participate to control the CXCL12 expression level [26]. ...
CXCL12 has been shown to be involved in colon cancer metastasis, but its expression level and molecular mechanisms regulating its expression remain controversial. We thus evaluated CXCL12 expression in a large cohort of colon adenomas and carcinomas, investigated for an epigenetic mechanism controlling its expression and evaluated the impact of CXCL12 levels on cell migration and tumor growth. CXCL12 expression was measured in human colon adenomas and carcinomas with transcriptome array and RT-qPCR. The promoter methylation was analyzed with whole-genome DNA methylation chips and protein expression by immunohistochemistry. We confirm a reduced expression of CXCL12 in 75% of MSS carcinomas and show that the decrease is an early event as already present in adenomas. The methylome analysis shows that the CXCL12 promoter is methylated in only 30% of microsatellite-stable tumors. In vitro, treatments with HDAC inhibitors, butyrate and valproate restored CXCL12 expression in three colon cell lines, increased acetylation of histone H3 within the CXCL12 promoter and inhibited cell migration. In vivo, valproate diminished (65%) the number of intestinal tumors in APC mutant mice, slowed down xenograft tumor growth concomitant to restored CXCL12 expression. Finally we identified loss of PCAF expression in tumor samples and showed that forced expression of PCAF in colon cancer cell lines restored CXCL12 expression. Thus, reduced PCAF expression may participate to CXCL12 promoter hypoacetylation and its subsequent loss of expression. Our study is of potential clinical interest because agents that promote or maintain histone acetylation through HDAC inhibition and/or HAT stimulation, may help to lower colon adenoma/carcinoma incidence, especially in high-risk families, or could be included in therapeutic protocols to treat advanced colon cancer.
... Some genes related to the immune system, such as CXCL12 and IL1b, were hypermethylated in CIN III and cervical cancer. Recently, CXCL12 has been shown hypermethylated in cervical cancer biopsies and in established cell lines (HeLa, SiHa) and its expression down regulated [35]. ...
