No abstract

E26 transformation‐specific (ETS) gene family contains a common DNA‐binding domain, the ETS domain, responsible for sequence‐specific DNA recognition on target promoters. The Fli‐1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline‐like compounds including 4′‐demethoxy‐3′,4′‐methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli‐1 transactivation ability. These compounds altered expression of Fli‐1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline‐like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli‐1‐driven mouse model. Mechanistically, the compounds blocked c‐Raf‐MEK‐MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli‐1 protein synthesis. Consistent with its high expression in myelomas, B‐cell lymphoma, and B chronic lymphocytic leukemia (B‐CLL), pharmacological inhibition of Fli‐1 by the flavagline‐like compounds or genetic knock‐down via shRNA significantly hindered proliferation of corresponding cell lines and patients’ samples. These results uncover a critical role of Fli‐1 in growth and survival of various hematological malignancies and point to flavagline‐like agents as lead compounds for the development of anti‐Fli‐1 drugs to treat leukemias/lymphomas overexpressing Fli‐1.

The present study aimed to explore the association between immunohistochemical matrix metalloproteinase-9 (MMP-9) expression and the clinicopathological characteristics of patients with papillary thyroid carcinoma (PTC), and to determine whether it may be used as a diagnostic or prognostic tool for PTC. Immunohistochemical staining of MMP-9 was performed in thyroid tissues obtained from 112 patients with PTC and 42 subjects with benign thyroid nodules (BTNs). The receiver operating characteristic curve was used to evaluate the legitimacy of MMP-9 as a diagnostic tool for PTC, and a predictor for structurally persistent/recurrent disease (SPRD) and disease status. Cox regression was applied to identify the risk factors of disease status and SPRD. The present study revealed that MMP-9 was overexpressed in PTC tissues, compared with in BTN tissues. Furthermore, MMP-9 scores yielded an area under the curve (AUC) of 0.842 (95% CI, 0.776–0.908) for differentially diagnosing PTC from BTN. In addition, the MMP-9 score was greater if patients previously had central lymph node metastasis, lateral lymph node metastasis or an advanced tumor-node-metastasis stage (III+IV). When MMP-9 was employed to predict disease status and SPRD, an AUC of 0.811 (95% CI, 0.706–0.917) and 0.806 (95% CI, 0.620–0.992) was obtained, respectively. A tumor size of >2 cm and an MMP-9 staining score of ≥6 were independent risk factors for predicting disease status, whereas vascular invasion and an MMP-9 staining score of ≥8 were risk factors for predicting SPRD. Furthermore, an MMP-9 staining score of ≥6 and ≥8 indicated shortened disease-free survival and survival without SPRD, respectively. In conclusion, the assessment of MMP-9 expression in thyroid carcinoma samples may represent a potential and supplementary tool for the diagnosis and prognostic prediction of PTC.