Crosstalk between CCL7 and CCR3 promotes metastasis of colon cancer cells via ERK-JNK signaling pathways

Background: Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRAS ^mut) tumors. Methods: The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRAS^mut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment. Results: Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRAS ^mut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRAS ^mut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRAS ^mut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRAS ^mut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRAS ^mut tumor models. Conclusions: Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.

Correlation between tumor engraftment in patient-derived xenograft models and clinical outcomes in colorectal cancer patients

Background: Epithelial–mesenchymal transition (EMT) is the most common cause of death in colorectal cancer (CRC). In this study, we investigated the functional roles of miRNA-17-5p in EMT of CRC cells. Methods: In order to determine if miRNA-17-5p regulated EMT, the precursors and inhibitors of miR-17-5p were transduced into four CRC cells. To evaluate the regulatory mechanism, we performed argonaute 2 (Ago2) immunoprecipitation (IP) and luciferase assay. In addition, we used an intra-splenic injection mouse model of BALB/c nude mice to investigate the metastatic potential of miRNA-17-5p in vivo. Results: The miRNA-17-5p expression was lower in primary CRC tissues with metastasis than in primary CRC tissues without metastasis in our RNA sequencing data of patient tissue. Real-time quantitative PCR revealed that miRNA-17-5p was inversely correlated with that of vimentin in five CRC cell lines. Over-expression of miRNA-17-5p decreased vimentin expression and inhibited cell migration and invasion in both LoVo and HT29 cells. However, inhibition of miRNA-17-5p showed the opposite effect. Ago2 IP and luciferase assay revealed that miRNA-17-5p directly bound to the 3′UTR of VIM mRNA. Furthermore, miRNA-17-5p inhibited the metastasis of CRC into liver in vivo. Conclusions: Our results demonstrated that miRNA-17-5p regulates vimentin expression, thereby regulating metastasis of CRC.