The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers.

BackgroundA major challenge to the clinical utility of let-7 for hepatocellular carcinoma (HCC) therapy is the lack of an effective carrier to target tumours. We confirmed the high transfection efficiency of cholesterol-conjugated let-7a miRNA mimics (Chol-let-7a) in human HCC cells, as well as their high affinity for liver tissue in nude mice. However, their antitumor efficacy via systemic delivery remains unknown.MethodsWe explored the effects of Chol-let-7a on HCC in vitro and in vivo. Cell viability and mobility, let-7a abundance and the target ras genes was measured. Live-cell image and cell ultrastructure was observed. Antitumor efficacy in vivo was analyzed by ultrasonography, hispatholgogy and transmission electronic microscopy in a preclinical model of HCC orthotopic xenografts with systemic therapy.ResultsChol-let-7a inhibited the viability and mobility of HCC cells. Chol-let-7a was primarily observed in the cytoplasm and induced organelle changes, including autophagy. Mild changes were observed in the cells treated with negative control miRNA. Chol-let-7a reached HCC orthotopic tumours, significantly inhibited tumour growth, and prevented local invasion and metastasis. Compared to control tumours, Chol-let-7a-treated tumours showed more necrosis. Tumour cells showed no significant atypia, and mitoses were very rare after systemic Chol-let-7a therapy. Furthermore, let-7a abundance in orthotopic xenografts was coincident with a reduction in the expression of 3 human ras mRNAs and RAS proteins.ConclusionsChol-let-7a exerted significant antitumor effects by down-regulating all human ras genes at the transcriptional and translational levels. Chol-let-7a inhibited cell proliferation, growth, and metastasis, and mainly functioned in the cytoplasm. Chol-let-7a represents a potential useful modified molecule for systemic HCC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-889) contains supplementary material, which is available to authorized users.

Let-7 microRNA (miRNA) family members have been demonstrated to have potential therapeutic value in vitro and in vivo as tumor suppressors that act by regulating Ras at a posttranscriptional level. Previous studies on these miRNAs have primarily focused on certain cancers in which mutation and abnormal activation of k-ras/K-Ras occur, such as lung cancer and pancreatic cancers. However, the antitumor potential of let-7 in the case of hepatocellular carcinoma (HCC) has remained untested. Moreover, a major hurdle that limits the clinical use of miRNAs through systemic delivery, including the delivery of let-7 for HCC therapy, is the lack of an effective carrier for targeting tumors. Recently, we confirmed the antitumor efficacy of cholesterol-conjugated let-7a mimics ("Chol-let-7a") in vitro and in vivo and verified-for the first time-that Chol-let-7a can effectively carry let-7a to orthotopic tumors in the liver and successfully inhibit tumor growth in a preclinical model when delivered systemically. We also evaluated for the first time the potential damages that Chol-let-7a could cause to the liver and kidney at histological and ultrastructural levels after long-term systemic delivery, in which Chol-let-7a mainly reached and remained at these organs. Lastly, we showed that Chol-let-7a downregulated all 3 human ras/Ras at transcriptional and translational levels and primarily functioned in the cytoplasm. Overall, our data suggest that the use of cholesterol-conjugated miRNAs is a promising tool for HCC systemic therapy.