Differential expression of angiogenesis-related genes 'VEGF' and 'angiopoietin-1' in metastatic and EMAST-positive colorectal cancer patients.

Abnormal angiogenesis leads to tumor progression and metastasis in colorectal cancer (CRC). This study aimed to elucidate the association between angiogenesis-related genes, including VEGF-A, ANGPT-1, and ANGPT-2 with both metastatic and microsatellite alterations at selected tetranucleotide repeats (EMAST) subtypes of CRC. We conducted a thorough assessment of the ANGPT-1, ANGPT-2, and VEGF-A gene expression utilizing publicly available RNA sequencing and microarray datasets. Then, the experimental validation was performed in 122 CRC patients, considering their disease metastasis and EMAST+/- profile by using reverse transcription polymerase chain reaction (RT-PCR). Subsequently, a competing endogenous RNA (ceRNA) network associated with these angiogenesis-related genes was constructed and analyzed. The expression level of VEGF-A and ANGPT-2 genes were significantly higher in tumor tissues as compared with normal adjacent tissues (P-value < 0.001). Nevertheless, ANGPT-1 had a significantly lower expression in tumor samples than in normal colon tissue (P-value < 0.01). We identified a significantly increased VEGF-A (P-value = 0.002) and decreased ANGPT-1 (P-value = 0.04) expression in EMAST+ colorectal tumors. Regarding metastasis, a significantly increased VEGF-A and ANGPT-2 expression (P-value = 0.001) and decreased ANGPT-1 expression (P-value < 0.05) were established in metastatic CRC patients. Remarkably, co-expression analysis also showed a strong correlation between ANGPT-2 and VEGF-A gene expressions. The ceRNA network was constructed by ANGPT-1, ANGPT-2, VEGF-A, and experimentally validated miRNAs (hsa-miR-190a-3p, hsa-miR-374c-5p, hsa-miR-452-5p, and hsa-miR-889-3p), lncRNAs (AFAP1-AS1, KCNQ1OT1 and MALAT1), and TFs (Sp1, E2F1, and STAT3). Network analysis revealed that colorectal cancer is amongst the 82 significant pathways. We demonstrated a significant differential expression of VEGF-A and ANGPT-1 in colorectal cancer patients exhibiting the EMAST+ phenotype. This finding provides novel insights into the molecular pathogenesis of colorectal cancer, specifically in EMAST subtypes. Yet, the generalization of in silico findings to EMAST+ colorectal cancer warrants future experimental investigations. In the end, this study proposes that the EMAST biomarker could serve as an additional perspective on CMS4 biology which is well-defined by activated angiogenesis and worse overall survival.

Non-coding RNAs in Precursor Lesions of Colorectal Cancer: Their Role in Cancer Initiation and Formation.

Colorectal cancer (CRC) is one of the world's most common types of malignancy. The proliferation of precancerous lesions causes this type of cancer. Two distinct pathways for CRC carcinogenesis have been identified: the conventional adenoma-carcinoma pathway and the serrated neoplasia pathway. Recently, evidence has demonstrated the regulatory roles of noncoding RNAs (ncRNAs) in the initiation and progression of precancerous lesions, especially in the adenoma-carcinoma pathway and serrated neoplasia pathway. By expanding the science of molecular genetics and bioinformatics, several studies have identified dysregulated ncRNAs that function as oncogenes or tumor suppressors in cancer initiation and formation by diverse mechanisms via intracellular signaling pathways known to act on tumor cells. However, many of their roles are still unclear. This review summarizes the functions and mechanisms of ncRNAs (such as long non-coding RNAs, microRNAs, long intergenic non-coding RNAs, small interfering RNAs, and circRNAs) in the initiation and formation of precancerous lesions.

An updated review of the association of host genetic factors with susceptibility and resistance to COVID-19.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human populations sparked a global pandemic of the coronavirus disease 2019 (COVID-19). According to preliminary data, about 14% of cases are considered severe and 5% of cases result in critical illness and, reported case fatality rates vary from 1% to more than 7%. However, the symptoms of the disease and the clinical outcome are very different in infected people. In view of these differences, it is clearly apparent that to gain insight into the biology of the SARS-CoV-2, it is important to study not just the infectious particle in itself but also to investigate the virus-host cell interactions that occur during infection. This review seeks to consider the various aspects of genetic factors in determining the susceptibility and host resistance to SARS-CoV-2 throughout the recently published literature.

MSI-L/EMAST is a predictive biomarker for metastasis in colorectal cancer patients.

BACKGROUND: Microsatellite instability (MSI) is a prognostic marker in colorectal cancer (CRC). The biological significance of MSI-low (MSI-L) phenotype and its differences with microsatellite stable (MSS) phenotype remains unclear. The aim of this study is indicating the role of mononucleotide repeat in identifying MSI-L and revealing the association of MSI-L with elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and oncologic outcome in CRC patients. METHODS: MSI and EMAST status were analyzed using three quasimonomorphic panel (BAT-25, BAT-26, and NR-27) and five tetranucleotide repeats (D20S82, D20S85, D9S242, D8S321, and MYCL1), respectively, by capillary electrophoresis method without the need to fluorescent primers. The associations of MSI status with clinicopathological features, EMAST status, metastasis, and overall survival (OS) were investigated. RESULTS: Among 159 CRC patient 22.0% were MSI-H, 40.3% were MSS, 37.7% were MSI-L, and 41.5% showed EMAST + phenotype. MSI-L were associated with advanced stages, EMAST+ tumors and worse OS ( p ≤ 0.001). Metastasis was relatively common in MSI-L/EMAST + CRCs and BAT-25 were the most unstable marker in these tumors. CONCLUSIONS: MSI-L tumors have different clinicopathological features from MSS and MSI-H tumors. The MSI-L phenotype is a worse prognostic biomarker in CRC and when accompanied by EMAST could be a predictor for metastasis.

Prevalence and prognostic role of PIK3CA E545K mutation in Iranian colorectal cancer patients.

AIM: This study aimed to evaluate the distribution of PIK3CA E545K mutation in Iranian CRC patients and explored its roles in disease prognosis. BACKGROUND: Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the progression of tumors. The p110a (PIK3CA), a catalytic subunit of PIK3, is mutated in many types of cancers. Exon 9 (E545K) is the most frequently mutated hotspot in PIK3CA in colorectal cancer (CRC). However, the prognostic role of PIK3CA E545K mutation needs to be elucidated. METHODS: Tumors from 187 CRC patients were retrospectively collected from the Taleghani and Shohada Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran, between 2010 and 2017. PIK3CA E545K status was detected in Formalin-fixed paraffin-embedded (FFPE) tissues using PCR-RFLP methods, and validated by pyrosequencing. Correlations between PIK3CA E545K mutation clinicopathological features were analyzed. RESULTS: The frequency of PIK3CA E545K gene mutations in CRC patients was 10.7%. Significant correlations were observed in PIK3CA E545K mutation with tumor differentiation and TNM stage (p < 0.042 and p = 0.033, respectively). Kaplan-Meier analysis showed a worse prognosis in overall survival (OS) in patients with PIK3CA E545K mutation (p < 0.001). Multivariate analysis indicated that PIK3CA E545K mutation was a detrimental factor for OS (HR = 6.497, 95% CI: 2.859-14.768, p < 0.021). CONCLUSION: A high frequency of PIK3CA E545K mutation was detected in Iranian CRC patients. The results of the present study suggested that PIK3CA E545K mutation may be associated with poor prognosis. These findings require further confirmation via prospective studies with larger samples.

High expression of Snail1 is associated with EMAST and poor prognosis in CRC patients.

AIM: This study aimed to determine the link between Snail1 expression and CRC patients' survival as well as its significant association with EMAST status. BACKGROUND: Snail1 is an evolutionary preserved zinc-finger transcription protein which contributes to Epithelial-to-mesenchymal transition (EMT). EMT initiates invasion and proliferation in many tumors. Elevated microsatellite alteration at selected tetranucleotide repeats (EMAST) is a marker of poor prognosis in patients with colorectal cancer (CRC). We hypothesized that Snail1 overexpression is an important mediator of metastasis and decreased survival in CRCs that characteristically have EMAST phenotype. METHODS: Quantitative real-time polymerase chain reactions were carried out to analyze the expression levels of Snail1 in both normal and tumor specimens from a total of 122 paraffin-embedded tissues (FFPE) of CRC sample with known EMAST status. The correlation between Snail1 expression and clinicopathological characteristics, survival, and EMAST status were examined. RESULTS: Snail1 overexpression was detected in tumor tissues in 32% of all examined patients and its positive expression was related to metastasis (p=0.001) and EMAST+ phenotype (P=0.017). Further, positive Snail1 expression correlates with poor overall survival in CRC patients (P=0.01). CONCLUSION: Our findings suggest that Snail1 overexpression is not only associated with EMAST but also with clinicopathological variables of poor prognosis. These results indicate that Snail1 expression levels may be useful for establishing novel therapeutic strategies and could help survival improvement in CRC patients.