Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in ...mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.
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•mutp53 R248Q, the most common p53 mutant in human CRC, promotes CRC in mice•mutp53 R248Q binds to and deregulates Stat3, correlating with poor patient survival•Genetic ablation of mutp53 R248Q reduces growth and invasion of established CRCs•Hsp90 inhibition reduces the mutp53 R248Q level and inhibits CRC progression
Schulz-Heddergott et al. show that the most common p53 mutant R248Q (mutp53) enhances Stat3 activation by binding to Stat3 and displacing SHP2 in colorectal cancer cells. Reduction of mutp53 genetically or by using the HSP90 inhibitor 17AAG reduces Stat3 signaling and the growth of mutp53-driven tumors.
Colorectal cancer has served as a genetic and biological paradigm for the evolution of solid tumors, and these insights have illuminated early detection, risk stratification, prevention, and ...treatment principles. Employing the hallmarks of cancer framework, we provide a conceptual framework to understand how genetic alterations in colorectal cancer drive cancer cell biology properties and shape the heterotypic interactions across cells in the tumor microenvironment. This review details research advances pertaining to the genetics and biology of colorectal cancer, emerging concepts gleaned from immune and single-cell profiling, and critical advances and remaining knowledge gaps influencing the development of effective therapies for this cancer that remains a major public health burden.
As technology scales down, circuits are more prone to incur in faults and fault detection is necessary to ensure the system reliability. However, fault-detection circuits are also vulnerable to ...stuck-at faults due to, for example, manufacturing defects or ageing; a fault can cause an incorrect output in the fault-detection scheme; so concurrent fault detection is, therefore, needed. Cyclic redundancy checks (CRCs) are widely used to detect errors in many applications, for example, they are used in communication to detect errors on transmitted frames. In this study, an efficient method to implement concurrent fault detection for parallel CRC computation is proposed. The scheme relies on using a serial CRC computation circuit that is used to periodically check the results obtained from the main module to detect the faults. This introduces a lower circuit overhead than existing schemes. All CRC encoders and decoders that implement the CRC computation in parallel can employ the proposed scheme to detect faults.
Predicting the prognosis of colorectal cancer (CRC) is challenging since these tumors exhibit a wide range of biological behaviors. It has been hypothesized that caudal-related homeobox gene 2 ...(CDX2), which is vital for intestinal growth and maintenance, has a tumor-suppressing effect and promising role in CRC prognosis but studies are still controversial. This study used the immunohistochemical (IHC) staining method to determine the expression of the CDX2 protein in mucinous and non-mucinous CRC adenocarcinoma, as well as in normal colorectal tissues as a control, and correlate this expression with clinicopathological features such as grade, tumor distant metastasis, tumor site, histological type, lymph node metastasis, tumor invasion, sex, age, and rate of 4 years Overall survival (OS) after diagnosis. A total of sixty three tissue samples were obtained from CRC patients (58.90±14.94) years and embedded in wax and thirty-seven normal non-tumoural colorectal tissue samples with (56.43±12.28) years as a control group. CDX2 protein expression decreased significantly (p<0.05) in CRC patients than control, advanced age, mucinous pattern of CRC, moderate and poorly differentiated grades, lymph node metastasis, advanced tumor invasion (T3, T4), and organs metastasis. Moreover, the (OS) for patients with low CDX2 expression was (17.943±1.7) months compared to (33.431±2.7) months for those with high CDX2 expression (p = 0.0001). This study concluded that protein expression of CDX2 is regarded as a prognostic and diagnostic marker for CRC patients.
Each generation of CPU provides more resources and new features. These increase the ability to perform algorithms faster and with a higher degree of parallelism. The article discusses methods used to ...optimise CRC generation algorithms for long data blocks with consideration of the capabilities of contemporary systems. We analysed known software CRC algorithms and combined all known principles into a solution scalable in multiple CPU cores on single and multi-socket systems. Various algorithms were evaluated on contemporary multicore systems with 1 × 4, 1 × 64, 2 × 12, and 4 × 26 cores. The results show how the performance is affected by the architecture of the memory subsystem. Compared to the original sequential Sarwate algorithm, our algorithms are 48.0, 51.1, 38.0, and 28.8 times faster.
Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality globally. Therefore, a better understanding of the early molecular events of this disease is needed. Long noncoding ...RNAs (lncRNAs) play a critical role in the regulation of tumorigenesis and cancer progression. In this study, we investigated the characteristics of ZFAS1 in CRC. We analyzed three independent microarray datasets of CRC tissues from GEO and found that ZFAS1 expression was remarkably upregulated in all three datasets. Moreover, we validated the overexpression of ZFAS1 in CRC tissues compared with normal tissues and found that ZFAS1 was positively correlated with tumor size and metastasis in CRC. Knockdown of ZFAS1 significantly suppressed the malignant phenotype and lipogenesis of CRC cells. Mechanistically, ZFAS1 binds polyadenylate-binding protein 2 (PABP2) to stabilize SREBP1 mRNA, thereby increasing the expression of SREBP1 and its target genes stearoyl-CoA desaturase (SCD1) and fatty acid synthase (FASN), thus promoting CRC lipid accumulation. These data demonstrated that ZFAS1 could act as an oncogene for CRC and that ZFAS1 reprograms lipid metabolism by binding with PABP2 to stabilize SREBP1 mRNA accumulation, implicating it as a novel and potent target for the treatment of CRC.
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Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Liu et al. report that long noncoding RNA ZFAS1 regulates fatty acid synthesis, thereby providing survival advantages for malignant phenotype transformation of CRC, and may be a potential therapeutic target for CRC.
Abstract
Background
Colorectal cancer is a significant public health concern globally, with high incidence and mortality rates. Despite the implementation of CRC screening guidelines, the uptake of ...screening among adults in the UAE remains low. This study aimed to assess the practice, factors associated, barriers, and knowledge gaps among adults in the UAE.
Materials and methods
2100 residents of the UAE, aged > = 40 years, participated in the study. A validated questionnaire was used to collect data. Data was collected through online platforms and face-to-face interviews in healthcare settings. Chi-Square test and binary logistic regression were used for data analysis.
Results
The study revealed a low CRC screening rate of 9.1%. Factors analyzed included age groups, health insurance coverage, regular physician checkups, family history of CRC, awareness of CRC, and knowledge levels about CRC and its signs and symptoms. Participants in the 50–59 age group showed a slightly higher likelihood of CRC screening, but the difference was not statistically significant. However, individuals in the 60–69 and > = 70 age groups were more likely to undergo screening. Regular physician checkups, family history of CRC, prior knowledge of CRC, and knowledge about the disease and its signs and symptoms were associated with a higher likelihood of screening, with statistically significant OR.
Conclusion
A low CRC screening rate of 9.1% among adults. Barriers to screening included not being offered a test by physicians, fear of positive results, discomfort with the screening process, perception of pain, and lack of knowledge. Identifying particulate barriers and developing targeted measures requires larger-scale research.
Alterations in the glycomic profile are a hallmark of cancer, including colorectal cancer (CRC). While, the glycosylation of glycoproteins and glycolipids has been widely studied for CRC cell lines ...and tissues, a comprehensive overview of CRC glycomics is still lacking due to the usage of different samples and analytical methods. In this study, we compared glycosylation features of N-, O-glycans, and glycosphingolipid glycans for a set of 22 CRC cell lines, all measured by porous graphitized carbon nano-liquid chromatography-tandem mass spectrometry. An overall, high abundance of (sialyl)Lewis antigens for colon-like cell lines was found, while undifferentiated cell lines showed high expression of H blood group antigens and α2-3/6 sialylation. Moreover, significant associations of glycosylation features were found between the three classes of glycans, such as (sialyl)Lewis and H blood group antigens. Integration of the datasets with transcriptomics data revealed positive correlations between (sialyl)Lewis antigens, the corresponding glycosyltransferase FUT3 and transcription factors CDX1, ETS, HNF1/4A, MECOM, and MYB. This indicates a possible role of these transcription factors in the upregulation of (sialyl)Lewis antigens, particularly on glycosphingolipid glycans, via FUT3/4 expression in colon-like cell lines. In conclusion, our study provides insights into the possible regulation of glycans in CRC and can serve as a guide for the development of diagnostic and therapeutic biomarkers.
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•Glycosylation motifs are compared for a set of 22 colorectal cancer cell lines.•For (sialyl)Lewis and H blood group antigens significant associations are found across the three glycan classes.•Colon-like cell lines present high abundance of (sialyl)Lewis antigens.•High expression of (sialyl)Lewis antigens might result from the regulation of FUT3.
An integrated analysis of glycosylation features including (sialyl)Lewis structure and blood group antigens was performed across N-, O-glycans, and glycosphingolipid glycans. Colon-like lines exhibited abundant (sialyl)Lewis antigens, while undifferentiated lines expressed H blood group antigens and α2-3/6 sialylation. The observed associations across glycan classes along with correlations with glycosyltransferases and transcription factors suggest that certain transcription factors like CDX1 contribute to the upregulation of (sialyl)Lewis antigens on all three glycan classes via regulation of glycosyltransferases FUT3/4.
Constitutional methylation of the MLH1 promoter is implicated in colorectal cancer (CRC) susceptibility by silencing the expression of the MLH1 protein. While MLH1 promoter methylation has been ...identified in variable frequencies among various populations, no data exist for CRC patients from Pakistan. In this study, we investigated constitutional MLH1 promoter methylation in Pakistani CRC patients. We screened 210 CRC patients belonging to HNPCC/suspected-HNPCC (n = 27) and non-HNPCC (n = 183) groups and 100 healthy controls for constitutional MLH1 promoter methylation using a methylation-sensitive high-resolution melting (MS-HRM) assay with methylated and unmethylated standards. Of the 210 CRC patients, 12.9 % (n = 27) had a family history of HNPCC-associated cancers, and 87.1 % (n = 183) had CRC with no family history (non-HNPCC group). The mean age at disease onset was 43.1 years (range 14–77), while controls had a mean age at enrollment of 40.0 years (range 19–74.4). Constitutional MLH1 promoter methylation was not identified in 210 CRC patients and 100 healthy controls. Constitutional MLH1 promoter methylation does not appear to be associated with CRC susceptibility in Pakistani patients.
•This is the first report on MLH1 promoter methylation among Pakistani CRC patients.•MLH1 promoter methylation was not identified in CRC patients or healthy controls.•Methylated and unmethylated standards were included to ensure the assay's integrity.
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