BACKGROUND: Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes could alter miRNA expression levels or processing and, thus, may contribute to colorectal cancer (CRC) development. Therefore, this study aimed to examine whether the MIR181A1 genomic sequence possesses SNPs that can affect the expression of hsa-miR-181a-5p and, subsequently, impact its targets and associate with CRC risk.
METHODS: The NCBI dbSNP database was searched for possible SNPs associated with MIR181A1. One SNP with a minor allele frequency > 5%, rs12039395 G > T was identified. In silico analyses determined the effect of the SNP on the secondary structure of the miRNA and predicted the hsa-miR-181a-5p target genes. The SNP was genotyped using allelic discrimination assay, the relative hsa-miR-181a-5p expression level was determined using quantitative real-time PCR, and immunohistochemical staining was used to detect target genes in 192 paraffin-embedded specimens collected from 160 CRC patients and 32 healthy subjects.
RESULTS: The rs6505162 SNP conferred protection against CRC, and the G-allele presence provides may provide accessibility for the transcriptional machinery. Hsa-miR-181a-5p was significantly over-expressed in the CRC group compared to controls and in samples carrying the G-allele compared to those with T-allele. PTEN, identified as the only hsa-miR-181a-5p target implicated in CRC, was significantly diminished in the CRC group compared to controls and showed an inverse relationship with hsa-miR-181a-5p expression level as well as negatively associated with the G-allele presence in CRC.
CONCLUSIONS: This study highlights that rs12039395 G > T may protect against CRC by influencing the expression of hsa-mir-181a-5p and its target gene, PTEN.

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer in individuals under 50 years of age, has shown an alarming increase in incidence worldwide. We report a case of a twenty-four-year-old female with a strong family history of colorectal cancer (CRC) but without an identified underlying genetic predisposition syndrome. Two years after primary surgery and adjuvant chemotherapy, the patient developed new liver lesions. Extensive diagnostic imaging was conducted to investigate suspected liver metastases, ultimately leading to a diagnosis of focal nodular hyperplasia. The young age of the patient has prompted comprehensive genomic and transcriptomic profiling in order to identify potential oncogenic drivers and inform further clinical management of the patient. Besides a number of oncogenic mutations identified in the patient\'s tumour sample, including KRAS G12D, TP53 R248W and TTN L28470V, we have also identified a homozygous deletion of 24.5 MB on chromosome 8. A multivariate Cox regression analysis of this patient\'s mutation profile conferred a favourable prognosis when compared with the TCGA COADREAD database. Notably, the identified deletion on chromosome 8 includes the WRN gene, which could contribute to the patient\'s overall positive response to chemotherapy. The complex clinical presentation, including the need for emergency surgery, early age at diagnosis, strong family history, and unexpected findings on surveillance imaging, necessitated a multidisciplinary approach involving medical, radiation, and surgical oncologists, along with psychological support and reproductive medicine specialists. Molecular profiling of the tumour strongly indicates that patients with complex mutational profile and rare genomic rearrangements require a prolonged surveillance and personalised informed interventions.

Despite ongoing screening efforts, colorectal cancer (CRC) remains a leading cause of death in Canada. The aim of this study was to better understand the experiences of Canadian CRC patients with their family practitioners (FPs) during and after their CRC diagnosis. Patient-reported data were collected through an online questionnaire to understand their CRC diagnosis experiences and identify potential gaps in care. Various factors contributing to challenges throughout a patient\'s CRC diagnosis (e.g., delayed CRC diagnosis) were determined using descriptive, qualitative, and inferential analyses. These factors could be targeted to optimize CRC care. This study found that 40.6% of the 175 respondents were unaware of at least one of the following aspects of CRC prior to their diagnosis: early-age onset (EAO), symptoms, and screening procedures. While 84.6% had access to a family physician (FP) before their diagnosis, only 17.7% were diagnosed by FPs. Higher proportions of younger individuals experienced misdiagnoses and felt dismissed compared to older individuals. Only half felt fully informed about their diagnosis when it was explained to them by their FP, while 53.1% had their diagnosis explained in plain language. Transitioning towards patient-centred care would promote pre-diagnosis CRC awareness, address differences in management of CRC care (e.g., dismissal and support), and accommodate for age and health-literacy-related disparities, thereby improving CRC care pathways for patients. Future research should investigate FPs experiences in detecting CRC cases to develop educational resources and recommendations, enhancing early detection and improving patient outcomes (1).

Metastasis is the primary cause of cancer-related deaths, and colorectal cancer (CRC) liver metastasis is a major poor prognostic factor in CRC. NAT1 (N-acetyltransferase 1) plays a crucial role in the invasive and metastatic processes of colorectal cancer. The role and molecular mechanism of NAT1 on tumor cells were verified by establishing a cell model of overexpression and knockdown of NAT1, and further verified by establishing a liver metastasis model of colorectal cancer for animal experiments. In vivo and in vitro experiments have demonstrated that overexpression of NAT1 reduces the ability of metastasis and invasion of colorectal cancer cells. NAT1 overexpression inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing the EMT (epithelial-mesenchymal transition) process and glycolytic ability of tumor cells. Additionally, decreased glycolytic ability results in reduced VEGF (Vascular endothelial growth factor) expression in colorectal cancer cells. The decreased VEGF expression leads to decreased angiogenesis and vascular permeability in liver metastases, ultimately reducing the occurrence of liver metastasis. Our findings highlight that overexpression of NAT1 significantly inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing EMT, glycolytic ability, and VEGF expression in colorectal cancer cells, collectively preventing the development of liver metastasis.

The signal transducer and activator of transcription 3 (STAT3) has been established as a crucial drug target in the development of antitumor agents. In this study, a series of 21 derivatives of the STAT3 inhibitor napabucasin were designed and synthesized. Through preliminary screening against tumor cell lines, SZ6 emerged as the most potent compound with half maximal inhibitory concentration (IC50) values of 46.3 nM, 66.4 nM, and 53.8 nM against HCT116, HepG2, and Hela cells respectively. Furthermore, SZ6 effectively suppressed tumor invasion and migration in HCT116 cell assays by inducing S-phase arrest and apoptosis through inhibition of Protein Kinase B (PKB/AKT) activity and induction of reactive oxygen species (ROS). The mechanism underlying SZ6\'s action involves inhibition of STAT3 phosphorylation, which was confirmed by western blotting analysis. Additionally, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) demonstrated direct binding between SZ6 and STAT3. Notably, in vivo studies revealed that SZ6 significantly inhibited tumor growth without any observed organ toxicity. Collectively, these findings identify SZ6 as a promising STAT3 inhibitor for colorectal cancer treatment.

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Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen\'s kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNLowPDPNLow); a PDPN-dominant group (DCNMidPDPNHigh); and a DCN-dominant group (DCNHighPDPNLow), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.

BACKGROUND: Colorectal cancer (CRC) is the third most malignant tumor in the world. 5-fluorouracil (5‑FU) -based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. Therefore, identification of genes associated with 5‑FU chemotherapy and seeking second-line treatment are necessary means to improve survival and prognosis of patients with CRC.
METHODS: The Cancer Therapeutics Response Portal (CTRP) database and Genomics of Drug Sensitivity in Cancer (GDSC) database were used to identify CRC-related genes and potential second-line therapies for 5-FU-resistant CRC. The single-cell RNA sequencing data for CRC tissues were obtained from a GEO dataset. The relationship between ITGA2 and 5-FU-resistant was investigated in vitro and in vivo models.
RESULTS: ACOX1 and ITGA2 were identified as risk biomarkers associated with 5-FU-resistance. We developed a risk signature, consisting of ACOX1 and ITGA2, that was able to distinguish well between 5-FU-resistance and 5-FU-sensitive. The single-cell sequencing data showed that ITGA2 was mainly enriched in malignant cells. ITGA2 was negatively correlated with IC50 values of most small molecule inhibitors, of which selumetinib had the highest negative correlation. Finally, knocking down ITGA2 can make 5-FU-resistant CRC cells sensitive to 5-FU and combining with selumetinib can improve the therapeutic effect of 5-FU resistant cells.
CONCLUSIONS: In summary, our findings demonstrated the critical role of ITGA2 in enhancing chemotherapy resistance in CRC cells and suggested that selumetinib can restore the sensitivity of chemotherapy-resistant CRC cells to 5-FU by inhibiting ITGA2 expression.

Colorectal cancer (CRC) stands second in terms of mortality and third among the highest prevalent kinds of cancer globally. CRC prevalence is rising in moderately and poorly developed regions and is greater in economically advanced regions. Despite breakthroughs in targeted therapy, resistance to chemotherapeutics remains a significant challenge in the long-term management of CRC. Circular RNAs (circRNAs) have been involved in growing cancer therapy resistance, particularly in CRC, according to an increasing number of studies in recent years. CircRNAs are one of the novel subclasses of non-coding RNAs, previously thought of as viroid. According to studies, circRNAs have been recommended as biological markers for therapeutic targets and diagnostic and prognostic purposes. That is particularly notable given that the expression of circRNAs has been linked to the hallmarks of CRC since they are responsible for drug resistance in CRC patients; thereby, circRNAs are significant for chemotherapy failure. Moreover, knowledge concerning circRNAs remains relatively unclear despite using all these advanced techniques. Here, in this study, we will go over the most recent published work to highlight the critical roles of circRNAs in CRC development and drug resistance and highlight the main strategies to overcome drug resistance to improve clinical outcomes.