👤 Michael T Lotze

IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma. Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma. The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development. IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development. Show less

Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure-activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of fibroblast growth factor signaling [(E)-2-benzylidene-5-bromo-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI-215)] that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian cells. Here, we hypothesized that BCI-215 could selectively affect survival of transformed cells. In MDA-MB-231 human breast cancer cells, BCI-215 inhibited cell motility, caused apoptosis but not primary necrosis, and sensitized cells to lymphokine-activated killer cell activity. Mechanistically, BCI-215 induced rapid and sustained phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) in the absence of reactive oxygen species, and its toxicity was partially rescued by inhibition of p38 but not JNK or ERK. BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses. Kinase phosphorylation profiling documented BCI-215 selectively activated MAPKs and their downstream substrates, but not receptor tyrosine kinases, SRC family kinases, AKT, mTOR, or DNA damage pathways. Our findings support the hypothesis that BCI-215 causes selective cancer cell cytotoxicity in part through non-redox-mediated activation of MAPK signaling, and the findings also identify an intersection with immune cell killing that is worthy of further exploration. Show less