RESUMO
Menin is necessary for the formation of the menin/mixed lineage leukemia (MLL) complex and is recruited directly to chromatin. Menin is an important tumor suppressor in several cancer types, including lung cancer. Here, we investigated the role of MLL in menin-regulated lung tumorigenesis. Ablation of MLL suppressed KrasG12D-induced lung tumorigenesis in a genetically engineered mouse model. MLL deficiency decreased histone H3 lysine 4 trimethylation (H3K4me3) and subsequently suppressed expression of the Ras protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene. Rasgrf1 was essential for the GTP-bound active state of Kras and the activation of Kras downstream pathways as well as their cancer-promoting activities. MI-3, a small-molecule inhibitor targeting MLL, specifically inhibited the growth of Kras-mutated lung cancer cells in vitro and in vivo with minimal effect on wild-type Kras lung cancer growth. Together, these results demonstrate a novel tumor promoter function of MLL in mutant Kras-induced lung tumorigenesis and further indicate that specific blockade of the MLL-Rasgrf1 pathway may be a potential therapeutic strategy for the treatment of tumors containing Kras mutations. SIGNIFICANCE: Activation of mutant Kras is dependent on MLL-mediated epigenetic regulation of Rasgrf1, conferring sensitivity to small-molecule inhibition of MLL in Kras-driven lung cancer.
Assuntos
Epigênese Genética , Neoplasias Pulmonares , Proteína de Leucina Linfoide-Mieloide , ras-GRF1 , Animais , Camundongos , Transformação Celular Neoplásica/metabolismo , Epigênese Genética/genética , Epigênese Genética/fisiologia , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia/genética , Leucemia/patologia , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , ras-GRF1/genética , ras-GRF1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , MutaçãoRESUMO
Preoperative elevation of serum C-reactive protein (CRP) is reportedly associated with poor prognosis in several types of cancer. This study investigated the role of serum CRP as a prognostic factor in early-stage esophageal squamous cell carcinoma (ESCC). The preoperative serum CRP levels were measured in 156 newly diagnosed pT1-2N0M0 patients using an enzyme-linked immunosorbent assay. Correlations between serum CRP levels and other clinical parameters were analyzed. Multivariate analyses were performed to find prognostic markers using Cox's proportional hazards model. CRP concentrations were within the normal range in 117 (75%) individuals, but were elevated in 39 (25%) patients. Serum CRP levels were significantly correlated with the tumor length (p = 0.032), depth (T classification, p = 0.0157), or histologic grade (p = 0.034). The overall 5-year survival rates were 76.3% and 50.2% in the low- and high-CRP groups, respectively (p = 0.005). By multivariate analyses, the elevated serum CRP level was found to be an independent prognostic factor for poor survival (hazard ratio = 2.131; p = 0.007), regardless of tumor classification or other prognostic factors. In conclusion, preoperative, high serum CRP is an independent determinant of poor prognosis in early-stage ESCC.