| 1. |
- Dash, Pujarini, et al.
(författare)
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High PGD2 receptor 2 levels are associated with poor prognosis in colorectal cancer patients and induce VEGF expression in colon cancer cells and migration in a zebrafish xenograft model
- 2022
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 126:4, s. 586-597
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite intense research, the prognosis for patients with advanced colorectal cancer (CRC) remains poor. The prostaglandin D2 receptors DP1 and DP2 are explored here as potential therapeutic targets for advanced CRC. Methods: A CRC cohort was analysed to determine whether DP1 and DP2 receptor expression correlates with patient survival. Four colon cancer cell lines and a zebrafish metastasis model were used to explore how DP1/DP2 receptor expression correlates with CRC progression. Results: Analysis of the clinical CRC cohort revealed high DP2 expression in tumour tissue, whereas DP1 expression was low. High DP2 expression negatively correlated with overall survival. Other pathological indicators, such as TNM stage and metastasis, positively correlated with DP2 but not DP1 expression. In accordance, the in vitro results showed high DP2 expression in four CC-cell lines, but only one expressed DP1. DP2 stimulation resulted in increased proliferation, p-ERK1/2 and VEGF expression/secretion. DP2-stimulated cells exhibited increased migration in the zebrafish metastasis model. Conclusion: Our results support DP2 receptor expression and signalling as a therapeutic target in CRC progression based on its expression in CRC tissue correlating with poor patient survival and that it triggers proliferation, p-ERK1/2 and VEGF expression and release and increased metastatic activity in CC-cells.
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| 2. |
- Ghatak, Souvik, et al.
(författare)
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DNA Methylation and Gene Expression of the Cysteinyl Leukotriene Receptors as a Prognostic and Metastatic Factor for Colorectal Cancer Patients
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 24:4
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC), one of the leading causes of cancer-related deaths in the western world, is the third most common cancer for both men and women. As a heterogeneous disease, colon cancer (CC) is caused by both genetic and epigenetic changes. The prognosis for CRC is affected by a variety of features, including late diagnosis, lymph node and distant metastasis. The cysteinyl leukotrienes (CysLT), as leukotriene D4 and C4 (LTD4 and LTC4), are synthesized from arachidonic acid via the 5-lipoxygenase pathway, and play an important role in several types of diseases such as inflammation and cancer. Their effects are mediated via the two main G-protein-coupled receptors, CysLT1R and CysLT2R. Multiple studies from our group observed a significant increase in CysLT1R expression in the poor prognosis group, whereas CysLT2R expression was higher in the good prognosis group of CRC patients. Here, we systematically explored and established the role of the CysLTRs, cysteinyl leukotriene receptor 1(CYSLTR1) and cysteinyl leukotriene receptor 2 (CYSLTR2) gene expression and methylation in the progression and metastasis of CRC using three unique in silico cohorts and one clinical CRC cohort. Primary tumor tissues showed significant CYSLTR1 upregulation compared with matched normal tissues, whereas it was the opposite for the CYSLTR2. Univariate Cox proportional-hazards (CoxPH) analysis yielded a high expression of CYSLTR1 and accurately predicted high-risk patients in terms of overall survival (OS; hazard ratio (HR) = 1.87, p = 0.03) and disease-free survival [DFS] Hazard ratio [HR] = 1.54, p = 0.05). Hypomethylation of the CYSLTR1 gene and hypermethylation of the CYSLTR2 gene were found in CRC patients. The M values of the CpG probes for CYSLTR1 are significantly lower in primary tumor and metastasis samples than in matched normal samples, but those for CYSLTR2 are significantly higher. The differentially upregulated genes between tumor and metastatic samples were uniformly expressed in the high-CYSLTR1 group. Two epithelial–mesenchymal transition (EMT) markers, E-cadherin (CDH1) and vimentin (VIM) were significantly downregulated and upregulated in the high-CYSLTR1 group, respectively, but the result was opposite to that of CYSLTR2 expression in CRC. CDH1 expression was high in patients with less methylated CYSLTR1 but low in those with more methylated CYSLTR2. The EMT-associated observations were also validated in CC SW620 cell-derived colonospheres, which showed decreased E-cadherin expression in the LTD4 stimulated cells, but not in the CysLT1R knockdown SW620 cells. The methylation profiles of the CpG probes for CysLTRs significantly predicted lymph node (area under the curve [AUC] = 0.76, p < 0.0001) and distant (AUC = 0.83, p < 0.0001) metastasis. Intriguingly, the CpG probes cg26848126 (HR = 1.51, p = 0.03) for CYSLTR1, and cg16299590 (HR = 2.14, p = 0.03) for CYSLTR2 significantly predicted poor prognosis in terms of OS, whereas the CpG probe cg16886259 for CYSLTR2 significantly predicts a poor prognosis group in terms of DFS (HR = 2.88, p = 0.03). The CYSLTR1 and CYSLTR2 gene expression and methylation results were successfully validated in a CC patient cohort. In this study, we have demonstrated that CysLTRs’ methylation and gene expression profile are associated with the progression, prognosis, and metastasis of CRC, which might be used for the assessment of high-risk CRC patients after validating the result in a larger CRC cohort.
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| 3. |
- Ghatak, Souvik, et al.
(författare)
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Identification of a Novel Five-Gene Signature as a Prognostic and Diagnostic Biomarker in Colorectal Cancers
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:2
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The current TNM (Tumor, Node, and Metastasis) classification approach is suboptimal in determining the prognosis of CRC patients. The prognosis for CRC is affected by a variety of features that are present at the initial diagnosis. Herein, we performed a systematic exploration and established a novel five-panel gene signature as a prognostic and early diagnosis biomarker after performing differential gene expression analyses in five independent in silico CRCs cohort and independently validating it in one clinical cohort, using immunohistochemistry. Four genes (BDNF, PTGS2, GSK3B, and CTNNB1) were significantly upregulated and one gene (HPGD) was significantly downregulated in primary tumor tissues compared with adjacent normal tissues throughout all the five in silico datasets. The univariate CoxPH analysis yielded a five-gene signature that accurately predicted overall survival (OS) and recurrence-free survival (RFS) in the in silico training (AUC = 0.73 and 0.69, respectively) and one independent in silico validation cohort (AUC = 0.69 and 0.74, respectively). This five-gene signature demonstrated significant associations with poor OS in independent clinical validation cohorts of colon cancer (CC) patients (AUC = 0.82). Intriguingly, a risk stratification model comprising of the five-gene signature together with TNM stage and gender status achieved an even superior AUC of 0.89 in the clinical cohorts. On the other hand, the circulating mRNA expression of the upregulated four-gene signature achieved a robust AUC = 0.83 with high sensitivity and specificity as a diagnosis marker in plasma from CRC patients. We have identified a novel, five-gene signature as an independent predictor of OS, which in combination with TNM stage and gender offers an easy-to-translate and facile assay for the personalized risk-assessment in CRC patients.
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| 4. |
- Mehdawi, Lubna M., et al.
(författare)
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LGR5 Expression Predicting Poor Prognosis Is Negatively Correlated with WNT5A in Colon Cancer
- 2023
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Ingår i: Cells. - 2073-4409. ; 12:22
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Tidskriftsartikel (refereegranskat)abstract
- WNT/β-catenin signaling is essential for colon cancer development and progression. WNT5A (ligand of non-canonical WNT signaling) and its mimicking peptide Foxy5 impair β-catenin signaling in colon cancer cells via unknown mechanisms. Therefore, we investigated whether and how WNT5A signaling affects two promoters of β-catenin signaling: the LGR5 receptor and its ligand RSPO3, as well as β-catenin activity and its target gene VEGFA. Protein and gene expression in colon cancer cohorts were analyzed by immunohistochemistry and qRT-PCR, respectively. Three colon cancer cell lines were used for in vitro and one cell line for in vivo experiments and results were analyzed by Western blotting, RT-PCR, clonogenic and sphere formation assays, immunofluorescence, and immunohistochemistry. Expression of WNT5A (a tumor suppressor) negatively correlated with that of LGR5/RSPO3 (tumor promoters) in colon cancer cohorts. Experimentally, WNT5A signaling suppressed β-catenin activity, LGR5, RSPO3, and VEGFA expression, and colony and spheroid formations. Since β-catenin signaling promotes colon cancer stemness, we explored how WNT5A expression is related to that of the cancer stem cell marker DCLK1. DCLK1 expression was negatively correlated with WNT5A expression in colon cancer cohorts and was experimentally reduced by WNT5A signaling. Thus, WNT5A and Foxy5 decrease LGR5/RSPO3 expression and β-catenin activity. This inhibits stemness and VEGFA expression, suggesting novel treatment strategies for the drug candidate Foxy5 in the handling of colon cancer patients.
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| 5. |
- Mehrabi, Syrina F., et al.
(författare)
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Brain-derived neurotrophic factor, neutrophils and cysteinyl leukotriene receptor 1 as potential prognostic biomarkers for patients with colon cancer
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:21
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Tidskriftsartikel (refereegranskat)abstract
- The tumor microenvironment has been recognized as a complex network in which immune cells play an important role in cancer progression. We found significantly higher CD66b neutrophil expression in tumor tissue than in matched normal mucosa in the Malmö colon cancer (CC) cohort and poorer survival of stage I-III patients with high CD66b expression. Additionally, mice lacking CysLT1 R expression (cysltr1−/− ) produce less brain-derived neurotrophic factor (BDNF) compared to WT mice and Montelukast (a CysLT1 R antagonist)-treated mice also reduced BDNF expression in a mouse xenograft model with human SW480 CC cells. CD66b and BDNF expression was significantly higher in patient tumor tissues than in the matched normal mucosa. The univariate Cox PH analysis yielded CD66b and BDNF as an independent predictor of overall survival, which was also found in the public TCGA-COAD dataset. We also discovered a strong positive correlation between CD66b, BDNF and CysLT1 R expression in the Malmö CC cohort and in the TCGA-COAD dataset. Our data suggest that CD66b/BDNF/CysLT1 R expression as a prognostic combined biomarker signature for CC patients.
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| 6. |
- Satapathy, Shakti Ranjan, et al.
(författare)
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The tumor promoter cysteinyl leukotriene receptor 1 regulates PD-L1 expression in colon cancer cells via the Wnt/β-catenin signaling axis
- 2023
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Ingår i: Cell Communication and Signaling. - 1478-811X. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy targeting programmed death-ligand 1 (PD-L1) or PD-1 in solid tumors has been shown to be clinically beneficial. However, in colorectal cancer (CRC), only a subset of patients benefit from PD-1/PD-L1 treatment. Previously, we showed that high cysteinyl leukotriene receptor 1 (CysLT1R) levels are associated with poor prognosis in CRC patients. Recently, we have revealed the role of the tumor promoter CysLT1R in drug resistance and stemness in colon cancer (CC) cells. Here, we show the role of the CysLT1R/Wnt/β-catenin signaling axis in the regulation of PD-L1 using both in vitro and in vivo preclinical model systems. Interestingly, we found that both endogenous and IFNγ-induced PD-L1 expression in CC cells is mediated through upregulation of CysLT1R, which enhances Wnt/β-catenin signaling. Therapeutic targeting of CysLT1R with its antagonist montelukast (Mo), as well as CRISPR/Cas9-mediated or doxycycline-inducible functional absence of CysLT1R, negatively regulated PD-L1 expression in CC cells. Interestingly, an anti-PD-L1 neutralizing antibody exhibited stronger effects together with the CysLT1R antagonist in cells (Apcmut or CTNNB1mut) with either endogenous or IFNγ-induced PD-L1 expression. Additionally, mice treated with Mo showed depletion of PD-L1 mRNA and protein. Moreover, in CC cells with combined treatment of a Wnt inhibitor and an anti-PD-L1 antibody was effective only in β-catenin-dependent (APCmut) context. Finally, analysis of public dataset showed positive correlations between the PD-L1 and CysLT1R mRNA levels. These results elucidate a previously underappreciated CysLT1R/Wnt/β-catenin signaling pathway in the context of PD-L1 inhibition in CC, which might be considered for improving the efficacy of anti-PD-L1 therapy in CC patients.
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| 7. |
- Topi, Geriolda, et al.
(författare)
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Combined Estrogen Alpha and Beta Receptor Expression Has a Prognostic Significance for Colorectal Cancer Patients
- 2022
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- We reported that high estrogen receptor beta (ERβ) expression is independently associated with better prognosis in female colorectal cancer (CRC) patients. However, estrogen receptor alpha (ERα) is expressed at very low levels in normal colon mucosa, and its prognostic role in CRC has not been explored. Herein, we investigated the combined role of ERα and ERβ expression in the prognosis of female patients with CRC, which, to the best of our knowledge, is the first study to investigate this topic. A total number of 306 primary CRCs were immunostained for ERα and ERβ expression. A Cox regression model was used to evaluate overall survival (OS) and disease-free survival (DFS). The combined expression of high ERβ + negative ERα correlates with longer OS (HR = 0.23; 95% CI: 0.11–0.45, P <0.0001) and DFS (HR = 0.10; 95% CI: 0.03–0.26, P < 0.0001) and a more favorable tumor outcome, as well as significantly higher expression of antitumorigenic proteins than combined expression of low ERβ + positive ERα. Importantly, we found that low ERβ expression was associated with local recurrence of CRC, whereas ERα expression was correlated with liver metastasis. Overall, our results show that the combined high ERβ + negative ERα expression correlated with a better prognosis for CRC patients. Our results suggest that the combined expression of ERα and ERβ could be used as a predictive combination marker for CRC patients, especially for predicting DFS.
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| 8. |
- Topi, Geriolda, et al.
(författare)
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High Oestrogen receptor alpha expression correlates with adverse prognosis and promotes metastasis in colorectal cancer
- 2024
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Ingår i: Cell Communication and Signaling. - 1478-811X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- In normal colon tissue, oestrogen receptor alpha (ERα) is expressed at low levels, while oestrogen receptor beta (ERβ) is considered the dominant subtype. However, in colon carcinomas, the ERα/β ratio is often increased, an observation that prompted us to further investigate ERα’s role in colorectal cancer (CRC). Here, we assessed ERα nuclear expression in 351 CRC patients. Among them, 119 exhibited positive ERα nuclear expression, which was significantly higher in cancer tissues than in matched normal tissues. Importantly, patients with positive nuclear ERα expression had a poor prognosis. Furthermore, positive ERα expression correlated with increased levels of the G-protein coupled cysteinyl leukotriene receptor 1 (CysLT1R) and nuclear β-catenin, both known tumour promoters. In mouse models, ERα expression was decreased in Cysltr1−/− CAC (colitis-associated colon cancer) mice but increased in ApcMin/+ mice with wild-type Cysltr1. In cell experiments, an ERα-specific agonist (PPT) increased cell survival via WNT/β-catenin signalling. ERα activation also promoted metastasis in a zebrafish xenograft model by affecting the tight junction proteins ZO-1 and Occludin. Pharmacological blockade or siRNA silencing of ERα limited cell survival and metastasis while restoring tight junction protein expression. In conclusion, these findings highlight the potential of ERα as a prognostic marker for CRC and its role in metastasis.
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