Girdin influences pancreatic cancer progression by regulating c-MYC expression.

Pancreatic ductal adenocarcinoma is a complex gastrointestinal tumor with high metastatic potential and poor prognosis. Actin-binding protein Girdin is highly expressed in a variety of tumors and promotes tumorigenesis and progression. However, the mechanisms underlying the involvement of Girdin in pancreatic cancer have not been clarified. In this study, we observed that the expression of Girdin was upregulated in pancreatic cancer cells. The siRNA-mediated gene knockdown experiments showed that reduced expression of Girdin in pancreatic cancer cells inhibited cell proliferation, migration, and invasion while promoting cell apoptosis. Functional assays revealed that c-MYC overexpression in pancreatic cancer cells could significantly increase the cell proliferation ability and rates of cell migration and invasion while decreasing the apoptosis rate. It has been shown that phosphorylation plays a role in the functional regulation of the c-MYC gene. Subsequently, we examined the expression level of c-MYC in cells with manipulated expression of Girdin and identified a positive correlation between Girdin expression and c-MYC expression. Moreover, we found that Girdin knockdown in c-MYC-overexpressing pancreatic cancer cells slowed cell growth, blocked the cell cycle progression, significantly promoted apoptosis, and markedly decreased the cell migration and invasion. This finding indicated that silencing Girdin could mitigate the effect of c-MYC on promoting proliferation and metastasis of pancreatic cancer. Overall, this study provided evidence that Girdin promoted pancreatic cancer development presumably by regulating the c-MYC overexpression.

Chrysin inhibits hepatocellular carcinoma progression through suppressing programmed death ligand 1 expression.

BACKGROUNDS: The aberrant PD-L1 expression on cancer cells was confirmed to participate in immune evasion of hepatocellular carcinoma (HCC). Previous studies had documented that there were anti-tumorigenic effects of chrysin on HCC. However, whether chrysin can act on the over-expressed PD-L1 on HCC cells to exert the therapeutic effectiveness and the involved mechanisms has not yet been deciphered. PURPOSE: Herein, we aimed to explore the regulatory effects of chrysin on the PD-1/PD-L1 immune checkpoint and investigate its possible mechanisms in vivo and in vitro. METHODS: H22 xenograft mouse model was used to investigate the effects of chrysin on tumor growth and PD-L1 expression in tumors. In interferon-gamma (IFN-γ)-induced HepG2 cells, the cytotoxicity of chrysin was detected by MTT assay. Flow cytometry, ELISA and RT-PCR were carried out to evaluate the expression of PD-L1, and the expression of proteins in STAT3 and NF-κB pathways was also determined by Western blot. In HepG2 cells and Jurkat T cell co-culture system, ELISA kit was used to detect the level of IL-2, and T cell proliferation was further evaluated by CCK-8 method. RESULTS: Our data suggested that chrysin could effectively inhibit the progression of tumor, and promote the anti-tumor immunity of mice concomitant with enhanced CD4/CD8-positive T cell proportion in tumor tissues of H22 xenograft mouse model. Additionally, chrysin significantly down-regulated the expression of PD-L1 in vivo and in vitro, which was closely associated with the blockage of STAT3 and NF-κB pathways. Moreover, in the co-culture system, chrysin could increase the proliferation of T cells and the concentration of IL-2. CONCLUSION: These results indicate that chrysin may have the potential to be an immune checkpoint inhibitor for preventive or as an adjunctive curative agent for HCC.

HRD1 suppresses the growth and metastasis of breast cancer cells by promoting IGF-1R degradation.

HRD1 (3-hydroxy-3-methylglutaryl reductase degradation) is an E3 ubiquitin ligase. We found that HRD1 was significantly downregulated in 170 breast cancer tissues. Low tumoral HRD1 expression was correlated with clinicopathological characteristics and a shorter survival in breast cancer patients. P65 specifically bound to the HRD1 promoter and inhibited HRD1 expression. Suppression of NF-κB activity reversed IL-6-induced downregulation of HRD1 expression. HRD1 interacted with IGF-1R and promoted its ubiquitination and degradation by the proteasome. Overexpression of HRD1 resulted in the inhibition of growth, migration and invasion of breast cancer cells in vitro and in vivo. Furthermore, HRD1 attenuated IL-6-induced epithelial-mesenchymal transition in MCF10A cells. These findings uncover a novel role for HRD1 in breast cancer.