Synergistic effects of glycated chitosan with high-intensity focused ultrasound on suppression of metastases in a syngeneic breast tumor model

Stimulation of the host immune system is crucial in cancer treatment. In particular, nonspecific immunotherapies, when combined with other traditional therapies such as radiation and chemotherapy, may induce immunity against primary and metastatic tumors. In this study, we demonstrate that a novel, non-toxic immunoadjuvant, glycated chitosan (GC), decreases the motility and invasion of mammalian breast cancer cells in vitro and in vivo. Lung metastatic ratios were reduced in 4T1 tumor-bearing mice when intratumoral GC injection was combined with local high-intensity focused ultrasound (HIFU) treatment. We postulate that this treatment modality stimulates the host immune system to combat cancer cells, as macrophage accumulation in tumor lesions was detected after GC-HIFU treatment. In addition, plasma collected from GC-HIFU-treated tumor-bearing mice exhibited tumor-specific cytotoxicity. We also investigated the effect of GC on epithelial–mesenchymal transition-related markers. Our results showed that GC decreased the expression of Twist-1 and Slug, proto-oncogenes commonly implicated in metastasis. Epithelial-cadherin, which is regulated by these genes, was also upregulated. Taken together, our current data suggest that GC alone can reduce cancer cell motility and invasion, whereas GC-HIFU treatment can induce immune responses to suppress tumor metastasis in vivo.     

miR‐200/375 control epithelial plasticity‐associated alternative splicing by repressing the RNA‐binding protein Quaking

Members of the miR‐200 family are critical gatekeepers of the epithelial state, restraining expression of pro‐mesenchymal genes that drive epithelial–mesenchymal transition (EMT) and contribute to metastatic cancer progression. Here, we show that miR‐200c and another epithelial‐enriched miRNA, miR‐375, exert widespread control of alternative splicing in cancer cells by suppressing the RNA‐binding protein Quaking (QKI). During EMT, QKI‐5 directly binds to and regulates hundreds of alternative splicing targets and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI‐5 is both necessary and sufficient to direct EMT‐associated alternative splicing changes, and this splicing signature is broadly conserved across many epithelial‐derived cancer types. Importantly, several actin cytoskeleton‐associated genes are directly targeted by both QKI and miR‐200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT. These findings demonstrate the existence of a miR‐200/miR‐375/QKI axis that impacts cancer‐associated epithelial cell plasticity through widespread control of alternative splicing.     

Enhanced myeloid differentiation factor 88 promotes tumor metastasis via induction of epithelial–mesenchymal transition in human hepatocellular carcinoma

Metastasis is the leading cause of death in patients with hepatocellular carcinoma (HCC) after curative resection. Therefore, it is critical to understand the mechanisms underlying tumor metastasis in HCC. We have previously shown that elevated expression of myeloid differentiation factor 88 (MyD88) may promote tumor growth and metastasis in HCC. In this study, we reported that enhanced expression of MyD88 promoted epithelial–mesenchymal transition (EMT) properties and tumor-initiating capabilities in HCC cells. MyD88 was found to be able to interact with p85, a regulatory subunit of phosphoinositide 3-kinase (PI3-K), independent of TLR/IL-1R-mediated response and caused PI3-K/v-akt murine thymoma viral oncogene homolog (Akt) activation, which resulted in subsequent phosphorylation of glycogen synthase kinase-3β and stabilization of Snail, a critical EMT mediator. Consistently, we observed a significant correlation between MyD88 expression and p-Akt levels in a cohort of HCC patients, and found that the combination of these two parameters have better prognostic value for HCC patients. Taken together, these results suggest that elevated MyD88 may facilitate HCC metastasis by promoting EMT properties and tumor-initiating capabilities via PI3–K/Akt pathway.