Complement in Tumourigenesis and the Response to Cancer Therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: O'Brien RM
PROVIDER: S-EPMC7998562 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aneuploidy and chromosomal instability (CIN) are common features of gastric cancer (GC), but their contribution to carcinogenesis and antitumour therapy response is still poorly understood. Failures in the mitotic checkpoint induced by changes in expression levels of the spindle assembly checkpoint (SAC) proteins cause the missegregation of chromosomes in mitosis as well as aneuploidy. To evaluate the possible contribution of SAC to GC, we analyzed the expression levels of proteins of the mitotic checkpoint complex in a cohort of GC cell lines. We found that the central SAC proteins, Mad2 and BubR1, were the more prominently expressed members in disseminated GC cell lines. Silencing of Mad2 and BubR1 in MKN45 and ST2957 cells decreased their cell proliferation, migration and invasion abilities, indicating that Mad2 and BubR1 could contribute to cellular transformation and tumor progression in GC. We next evaluated whether silencing of SAC proteins could affect the response to microtubule poisons. We discovered that paclitaxel treatment increased cell survival in MKN45 cells interfered for Mad2 or BubR1 expression. However, apoptosis (assessed by caspase-3 activation, PARP proteolysis and levels of antiapoptotic Bcl 2-family members), the DNA damage response (assessed by H2Ax phosphorylation) and exit from mitosis (assessed by Cyclin B degradation and Cdk1 regulation) were activated equally between cells, independently of Mad2 or BubR1-protein levels. In contrast, we observed that the silencing of Mad2 or BubR1 in MKN45 cells showed the induction of a senescence-like phenotype accompanied by cell enlargement, increased senescence-associated ?-galactosidase activity and increased IL-6 and IL-8 expression. In addition, the senescent phenotype is highly increased after treatment with PTX, indicating that senescence could prevent tumorigenesis in GC. In conclusion, the results presented here suggest that Mad2 and BubR1 could be used as prognostic markers of tumor progression and new pharmacological targets in the treatment for GC.
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Project description:BackgroundAlthough mammary microcalcification is frequently observed and has been associated with poor survival in patients with breast cancer, the genesis of calcification remains unclear. Carbonic anhydrase I (CA1) has been shown to promote calcification by catalysing the hydration of CO2. This study aimed to determine whether CA1 was correlated with microcalcification and with other processes that are involved in breast cancer tumourigenesis.MethodsCA1 expression in breast cancer tissues and blood samples was detected using western blotting, real-time PCR, immunohistochemistry and ELISA. Calcification was induced in the cultured 4T1 cell line originating from mouse breast tumours, using ascorbic acid and β-glycerophosphate. Acetazolamide, a chemical inhibitor of CA1, was also added to the culture to determine the role of CA1 in calcification. The MCF-7 human breast cancer cell line was treated with anti-CA1 siRNA and was assessed using a CCK-8 cell proliferation assay, an annexin V cell apoptosis assay, transwell migration assay and a human breast cancer PCR array. The tag SNP rs725605, which is located in the CA1 locus, was genotyped using TaqMan® genotyping.ResultsIncreased CA1 expression was detected in samples of breast carcinoma tissues and blood obtained from patients with breast cancer. A total of 15.3 % of these blood samples exhibited a 2.1-fold or higher level of CA1 expression, compared to the average level of CA1 expression in samples from healthy controls. Following the induction of calcification of 4T1 cells, both the number of calcium-rich deposits and the expression of CA1 increased, whereas the calcification and CA1 expression were significantly supressed in the presence of acetazolamide. Increased migration and apoptosis were observed in MCF-7 cells that were treated with anti-CA1 siRNA. The PCR array detected up-regulation of the androgen receptor (AR) and down-regulation of X-box binding protein 1 (XBP1) in the treated MCF-7 cells. Significant differences in the allele and genotype frequencies of rs725605 were detected in the cohort of patients with breast cancer but not in other tumours.ConclusionThe results of this study suggested that CA1 is a potential oncogene and that it contributes to abnormal cell calcification, apoptosis and migration in breast cancer.
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Project description:Recent studies have reported that long non-coding RNAs (lncRNAs) are associated with the tumourigenesis of colorectal cancer (CRC); however, several of these are yet to be identified and characterised. In this study, we report a novel lncRNA, LINC00467, which was significantly up-regulated in CRC; we investigated its function and mechanism in CRC. Our study demonstrated that LINC00467 levels in 45 pairs of CRC tissues were higher than those in the corresponding normal colon mucosal tissues. We used the Gene Expression Omnibus (GEO) and Gene Expression Profiling Interactive Analysis (GEPIA) databases for the analysis and measurement of clinical samples, and observed that the CRC patients with high LINC00467 expression levels showed poor overall survival (OS) and recurrent-free survival (RFS) rates. Furthermore, following the short interfering RNA (siRNA) knockdown of LINC00467 in the CRC cell line, the results demonstrated that LINC00467 suppresses the proliferation, invasion and metastasis of CRC cells in vitro. Moreover, its molecular mechanism of LINC00467 decreased the expression of Cyclin D1, Cyclin A1, CDK2, CDK4 and Twist1 as well as enhanced the expression of E?cadherin. Collectively, these findings suggest that LINC00467 may be crucial in the progression and development of CRC, and may serve as a potential therapeutic target for CRC patients.
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Project description:Purpose: Anti-CD20 mAb therapies, including rituximab and obinutuzumab (GA101), are common treatments for follicular lymphoma. In an effort to better understand the role of complement in mAb action, we recently performed germline SNP profiling on 142 follicular lymphoma patients and found rs3766404 genotype correlated with patient response to rituximab. To assess the role of three SNP-associated complement-regulatory proteins (CFH, CFHR1, and CFHR3) in clinical response to anti-CD20 mAb, we studied two cohorts of patients treated with anti-CD20 mAb.Experimental Design: Cohorts included the Iowa/Mayo Lymphoma SPORE observational cohort of subjects with a new diagnosis of follicular lymphoma treated with rituximab and the GAUSS prospective randomized trial cohort of follicular lymphoma subjects randomized to receive single-agent rituximab or obinutuzumab. Circulating protein expression was measured for CFH, CFHR1, and CFHR3 and correlated to clinical outcome.Results: rs3766404 genotype correlated with expression of the related downstream genes CFHR1 and CFHR3 Loss of CFHR1 expression correlated with inferior patient outcome in the observational cohort, but not in the GAUSS cohort. Loss of CFHR3 correlated with superior event-free survival in GAUSS subjects treated with obinutuzumab, but not rituximab.Conclusions: We conclude that the relationship between complement-regulatory proteins CFHR1 and CFHR3 and response to anti-CD20 mAb therapy varies based on the specific anti-CD20 mAb used. We propose that CFHR3 is a candidate biomarker for obinutuzumab response. Further studies are needed to validate these findings and to better understand how complement pathways and complement-regulatory proteins impact on the efficacy of anti-CD20 mAb therapy. Clin Cancer Res; 23(4); 954-61. ©2016 AACR.
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