HMGB1-RAGE signaling facilitates Ras-dependent Yap1 expression to drive colorectal cancer stemness and development.

HMGB1-RAGE signaling plays an integral role in inflammation-driven carcinogenesis. In the present study, we showed that RAGE has direct association with K-Ras following HMGB1 exposure in colorectal cancer (CRC) cells. Immunofluorescence analysis revealed a significant co-localization between RAGE and K-Ras in HMGB1-exposed CRC cells. Moreover, we uncovered that HMGB1-mediated RAGE activation led to Yap1 accumulation in a Ras-dependent mechanism in CRC cells. HMGB1 activated the expression of Yap1 downstream stemness marker proteins CD44 and Sox2 in RAGE- and Ras-dependent manners. Furthermore, HMGB1 exposure led to the proliferation of CRC cells and the expansion of CRC stem cells. RAGE, Yap1 and CD44 were overexpressed in CRC specimens. Linear regression analysis revealed that the expression of RAGE was positively correlated with Yap1 in clinical CRC specimens. Both of RAGE and Yap1 expression were correlated with advanced histological grades, lymph node metastasis and TNM stages. Finally, we revealed that both of RAGE and Yap1 expression could predicted unfavorable prognosis in CRC patients. These findings implicated that HMGB1-RAGE signaling may promote Yap1 activation and CRC progression, shedding new light on the mechanisms underlying inflammation-driven CRC development.

(-)-Epicatechin gallate ameliorates cyprodinil-induced cardiac developmental defects through inhibiting aryl hydrocarbon receptor in zebrafish.

BACKGROUND: Cyprodinil is a widely used fungicide with broad-spectrum activity, but it has been associated with cardiac abnormalities. (-)-Epicatechin gallate (ECG), a natural polyphenolic compound, has been shown to possess protective properties in cardiac development. METHODS: In this study, we investigated whether ECG could mitigate cyprodinil-induced heart defects using zebrafish embryos as a model. Zebrafish embryos were exposed to cyprodinil with or without ECG. RESULTS: Our results demonstrated that ECG significantly improved the survival rate, embryo movement, and hatching delay induced by cyprodinil. Furthermore, ECG effectively ameliorated cyprodinil-induced cardiac developmental toxicity, including pericardial anomaly and impairment of cardiac function. Mechanistically, ECG attenuated the cyprodinil-induced alterations in mRNA expression related to cardiac development, such as amhc, vmhc, tbx5, and gata4, as well as calcium ion channels, such as ncx1h, atp2a2a, and cdh2. Additionally, ECG was found to inhibit the activity of the aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil. CONCLUSIONS: In conclusion, our findings provide evidence for the protective effects of ECG against cyprodinil-induced cardiac developmental toxicity, mediated through the inhibition of AhR activity. These findings contribute to a better understanding of the regulatory mechanisms and safe utilization of pesticide, such as cyprodinil.

High-quality reference genome sequences of two Cannaceae species provide insights into the evolution of Cannaceae.

Canna edulis Ker-Gawl and Canna indica L. are species belonging to the Cannaceae family and both have a very high economic value. Here, we aimed to assemble genomes of C. edulis and C. indica at the chromosome level to generate a reference genome for the Cannaceae family. We also comparatively analyzed the genomes of C. edulis and C. indica and examined the molecular mechanisms responsible for the remarkable differences in plant characteristics in C. edulis varieties. Our results indicated that genome-wide duplication events had recently occurred in C. edulis and C. indica. The comparative analysis of the genomes of C. edulis and C. indica revealed that C. edulis exhibited a remarkable level of replication of genes in the starch and sucrose metabolic pathways, especially during sucrose hydrolysis. This finding is consistent with the fact that the starch content of the C. edulis tuber is higher than that of C. indica. Simplified genome re-sequencing revealed the population structure of 241 C. edulis genes, and a genome-wide association study of leaf traits revealed the location of key genes related to leaf color and morphology. These findings extend our understanding of Cannaceade at the molecular level, and provide an effective theoretical basis for further study and utilization of Cannaceae plants.

Elevated Ras related GTP binding B (RRAGB) expression predicts poor overall survival and constructs a prognostic nomogram for colon adenocarcinoma.

Currently, no articles have explored the roles of RRAGB gene in the occurrence and development of cancer. By means of The Cancer Genome Atlas (TCGA) data mining, we found that this gene might be a novel prognostic predictor for colon adenocarcinoma (COAD). Hence, this article was carried out to explore its roles in COAD and associations with immunity. RRAGB single-gene expression matrix and corresponding clinical information were extracted from TCGA database. Univariate/multivariate cox regression analyses and gene set enrichment analysis (GSEA) were utilized to identify independent prognostic factors and RRAGB related pathways, respectively. Relationships between RRAGB and immunity were also analyzed. Boxplot and K-M survival analysis indicated that RRAGB was not only differently expressed in COAD (P < 0.05), but also significantly associated with overall survival (OS; P < 0.05). Univariate and multivariate Cox hazard regression analyses indicated that RRAGB could serve as an independent prognostic factor for COAD (both P < 0.05). GSEA identified five signaling pathways significantly enriched in the high-RRAGB expression phenotype. Moreover, a RRAGB-based nomogram was successfully constructed and displayed a satisfactory performance. In addition, RRAGB expression was found to be significantly associated with microsatellite instability (MSI), tumor mutational burden (TMB) and immunity. Our results revealed that RRAGB could be a prognostic biomarker for COAD in terms of OS and markedly related to MSI, TMB, and immunity. We also constructed an RRAGB-based nomogram with a satisfactory performance. Further researches should be carried out to validate our findings.

High expression of P2X7R is an independent postoperative indicator of poor prognosis in colorectal cancer.

The purinergic P2X7 receptor (P2X7R) is a master regulator of inflammation and inflammation-related diseases. Recently, P2X7R has been reportedly involved in carcinogenesis and tumor progression. In this study, we investigated the expression pattern and prognostic merit of P2X7R in human colorectal cancer (CRC). The expression profile of P2X7R in 12 pairs of CRC and non-tumorous specimens was evaluated using Western blotting analysis. Additionally, we performed immunohistochemistry (IHC) on 116 paraffin-embedded CRC specimens, and evaluated the correlation between P2X7R expression and clinicopathological factors. P2X7R was overexpressed in CRC samples, compared with adjacent non-tumorous ones. High P2X7R expression significantly correlated with tumor size (P = .0177), Lymph node metastasis (P = .0128), and TNM stage (P = .0081). Furthermore, univariate and multivariate Cox regression analyses revealed that P2X7R expression could serve as an independent prognostic factor for poor overall survival (P = .0197). Treatment with P2X7R agonist BzATP led to the activation of Akt and NF-κB pathways. Consequently, we revealed that BzATP accelerated the proliferation of CRC cells, whereas co-incubation with PI3K/Akt inhibitor LY294002 significantly impaired BzATP-induced proliferation of CRC cells. Our findings implied that P2X7R may serve as a valuable prognostic indicator and promising therapeutic target of CRC.

Cortactin promotes colon cancer progression by regulating ERK pathway.

Cortactin is upregulated in various cancers including breast cancer, head and neck squamous cell carcinoma and gastric cancer. However, the role of cortactin in the pathogenesis of colon cancer remains unclear. mRNA expression of cortactin in colon cancer samples and cell lines was detected by quantitative real-time PCR (qRT-PCR), while protein expression of cortactin in colon cancer tissues and adjacent non-cancer tissues was assessed by immunohistochemistry. The role of cortactin in regulation of the proliferation of colon cancer derived cells were investigated both in vitro and in vivo. In the total of 60 paired colon cancer specimens, compared with the adjacent non-cancer tissues, the expression of cortactin mRNA was upregulated in 45 (75.0%). Immunohistochemical analysis showed significantly increased cortactin expression in colon cancer (42/60, 70.0%) compared to control tissues (18/60, 30.0%). Overexpression of cortactin promoted HCT116 cellular colony formation and tumor growth. Conversely, cortactin knockdown inhibited these effects in SW480 cells. Mechanistic analyses indicated that cortactin was able to activate the EGFR-ERK signaling pathway. Additionally, cortactin expression was associated with tumor size, tumor stages and lymphatic invasion, increased cortactin expression predicts poor prognosis in patients with colon cancer. In summary, cortactin demonstrated the promotive effect in human colon cancer cell growth and tumorigenicity. These results indicated that cortactin may serve as an effective target for gene therapy.