SummaryThis study describes a novel mechanism of the inflammatory cytokine IL-6 induced Fra-1 upregulation through activating STAT3 by phosphorylation and acetylation, and demonstrates that this signaling pathway plays a critical role in promoting epithelial–mesenchymal transition and aggressiveness of colorectal cancer.
PRSS3 plays an important role in the progression, metastasis and prognosis of human pancreatic cancer. Targeting the PRSS3 signalling pathway may be an effective and feasible approach for treatment of this lethal cancer.
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
Basal-like breast cancer (BLBC) is associated with a poor clinical outcome due to the few treatment options and absence of effective targeted agents. Here, we show that malic enzyme 1 (ME1) is dramatically upregulated in BLBC due to ME1 copy number amplification. ME1 expression increases glucose uptake and lactate production, and reduces oxygen consumption, leading to aerobic glycolysis. ME1 expression promotes, whereas knockdown of ME1 expression suppresses tumorigenicity. In breast cancer patients, ME1 expression is positively correlated with large tumor size, high grade, poor survival, and chemotherapy resistance. Our study not only contributes to a new understanding of how metabolic reprogramming contributes to BLBC progression, but also provides a potential prognostic marker and therapeutic target for this challenging disease.
Cao et al. show that UGT8 promotes BLBC progression through activating sulfatide–αVβ5 axis. ZA is identified as a direct inhibitor of UGT8 and suppresses BLBC progression, suggesting that inhibition of UGT8 offers a promising opportunity for treating BLBC.
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