ABSTRACT
INTRODUCTION: Although colon (COAD) and rectal adenocarcinoma (READ) combined to refer to colorectal cancer (CRC), substantial clinical evidence urged that CRC should be treated as two different cancers due to compared with READ, COAD showed higher morbidity and worse 5-year survival. OBJECTIVES: This study has tried to screen for the crucial gene that caused the worse prognosis and investigate its mechanism for mediating tumor growth and metastases in COAD. Meanwhile, the potential anti-COAD compound implicated in this mechanism was identified and testified from 1,855 food-borne chemical kits. This study aims to bring a new perspective to the development of new anti-COAD drugs and personalized medicine for patients with COAD. METHODS AND RESULTS: The survival-related hub genes in COAD and READ were screened out from The Cancer Genome Atlas (TCGA) database and the results showed that HIGD1A, lower expressed in COAD than in READ, was associated with poor prognosis in COAD patients, but not in READ. Over-expressed HIGD1A suppressed CRC cell proliferation, invasion, and migration in vitro and in vivo. Meanwhile, the different expressed microRNA profiles between COAD and READ showed that miR-501-3p was highly expressed in COAD and inhibited HIGD1A expression by targeting 3'UTR of HIGD1A. MiR-501-3p mimics promoted cell proliferation and metastasis in CRC cells. In addition, Procyanidin C1 (PCC1), a kind of natural polyphenol has been verified as a potential miR-501-3p inhibitor. In vitro and in vivo, PCC1 promoted HIGD1A expression by suppressing miR-501-3p and resulted in inhibited tumor growth and metastasis. CONCLUSION: The present study verified that miR-501-3p/HIGD1A axis mediated tumor growth and metastasis in COAD. PCC1, a flavonoid that riched in food exerts anti-COAD effects by inhibiting miR-501-3p and results in the latter losing the ability to suppress HIGD1A expression. Subsequently, unfettered HIGD1A inhibited tumor growth and metastasis in COAD.
ABSTRACT
Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral CFTR mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced CFTR expression in this population, we investigated association of tumoral CFTR expression with overall and disease-specific mortality in CRC patients. CFTR mRNA expression, clinical factors and survival data from 1177 CRC patients reported in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus studies GSE39582 and GSE17538 were included. Log-transformed and z-normalized [mean = 0, standard deviation (SD) = 1] CFTR expression values were modeled as quartiles or dichotomized at the median. Univariate and multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall and disease-specific mortality in individual studies and meta-analyses. Analyses of each of the three individual datasets showed a robust association of decreased CFTR expression with increased mortality. In meta-analyses adjusted for stage at diagnosis, age and sex, CFTR expression was inversely associated with risk of overall death [pooled HR (95% CI): 0.70 (0.57-0.86)] and disease-specific death [pooled HR (95% CI): 0.68 (0.47-0.99)]. Associations did not differ by stage at diagnosis, age, or sex. Meta-analysis of overall death stratified by microsatellite instable (MSI) versus microsatellite stable (MSS) status indicated potential interaction between MSI/MSS status and CFTR expression, (p-interaction: 0.06). The findings from these three datasets support the hypothesis that low CFTR expression is associated with increased CRC mortality.
ABSTRACT
Background: The early diagnosis of colorectal cancer (CRC) is very important for the prognosis of patients. It has been suggested that the cytosine-phosphate-guanine (CpG) island of itga4 is highly methylated in colorectal adenoma cell lines AA/C1, Vaco 235 and so on. So the purpose of our study is to explore the diagnostic accuracy and related mechanism of integrin alpha 4 (ITGA4) in early CRC. Methods: The Cancer Genome Atlas (TCGA) database was used to analyze the relationship between the expression of ITGA4 and the clinicopathological features and the overall survival rate of the disease. Then, the interaction protein and function enrichment region of ITGA4 were analyzed. Finally, the infiltration of related immune cells was analyzed. Results: Compared with normal tissues, the expression of ITGA4 in colon adenocarcinoma and rectum adenocarcinoma (COAD-READ) tumor tissues was lower (P<0.05). The overall survival rate of COAD-READ patients with low ITGA4 level was lower than that of patients with high ITGA4 expression (P<0.05), and expression of ITGA4 had a more significant predictive effect in the early stage of tumor development. The results of protein network and enrichment analysis suggested that ITGA4 was closely related to ITGB2 and might be involved in the inflammatory reaction and inflammatory tumor transformation process in the carcinogenesis of inflammatory bowel disease (IBD), which was verified by another independent sequence. In terms of immune infiltration, the expression level of ITGA4 was positively correlated with the infiltration level of intestinal macrophages (Th17), immature dendritic cells (IDC), dendritic cells (DC), mast cells, and eosinophils in COAD-READ, and significantly negatively correlated with CD56bright natural killer (NK) cells. Conclusions: The low expression of ITGA4 was related to the poor prognosis of COAD-READ. Findings showed that ITGA4 might participate in the inflammatory reaction and inflammatory tumor transformation process in the carcinogenesis of IBD, and that ITGA4 was related to the infiltration of immune cells, macrophages, syndactyls, and CD56bright NK cells. The expression of ITGA4 could be used as an early predictor of CRC. However, the mechanism of ITGA4 promoting tumor progression in CRC still needs further research.