Description: Nature Genetics 47, 1061 (2015). doi:10.1038/ng.3358 Authors: Lu Jiang, Zhao-Hui Gu, Zi-Xun Yan, Xia Zhao, Yin-Yin Xie, Zi-Guan Zhang, Chun-Ming Pan, Yuan Hu, Chang-Ping Cai, Ying Dong, Jin-Yan Huang, Li Wang, Yang Shen, Guoyu Meng, Jian-Feng Zhou, Jian-Da Hu, Jin-Fen Wang, Yuan-Hua Liu, Lin-Hua Yang, Feng Zhang, Jian-Min Wang, Zhao Wang, Zhi-Gang Peng, Fang-Yuan Chen, Zi-Min Sun, Hao Ding, Ju-Mei Shi, Jian Hou, Jin-Song Yan, Jing-Yi Shi, Lan Xu, Yang Li, Jing Lu, Zhong Zheng, Wen Xue, Wei-Li Zhao, Zhu Chen & Sai-Juan Chen Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56+ and cytoCD3+ lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.

Description: BACKGROUND Prostate cancer is one of the most prevalent cancers in men worldwide. Aberrant activation of c-Met/signal transducer and activator of transcription-3 (STAT3) signaling is involved in prostate carcinogenesis, underscoring the demand for developing c-Met/STAT3-targeting drugs. Thus, we first utilized virtual screening strategy to identify STAT3-inhibiting marine compound, heteronemin, and then validated the STAT3-inhibiting function of heteronemin in prostate cancer cells. METHODS Human prostate cancer LNCaP, DU145, and PC-3 cell lines were treated with heteronemin for 24 hr, then the cell viability was evaluated by MTT assay. Flow cytometry was performed to analyze the apoptosis in heteronemin-treated cells. Western blot and quantitative real-time PCR were executed to further confirm the c-Met/STAT3 signaling inhibition by heteronemin in DU145 and PC-3 cells. RESULTS In this study, we employed the virtual screening strategy to identify heteronemin, a spongean sesterterpene, as a potential STAT3 inhibitor from Taiwan marine drugs library. Application of heteronemin potently suppressed the viability and anchorage-independent growth of human prostate cancer cells. Besides, heteronemin induced apoptosis in prostate cancer cells by activation of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways. By luciferase assay and expression analysis, it was confirmed that heteronemin inhibited the phosphorylation of c-Met/src/STAT3 signaling axis, STAT3-driven luciferase activities and expression of STAT3-regulated genes including Bcl-xL, Bcl-2, and Cyclin D1. Finally, heteronemin effectively antagonized the hepatocyte growth factor (HGF)-stimulated c-Met/STAT3 activation as well as the proliferation and colonies formation in refractory prostate cancer cells. CONCLUSIONS These findings suggest that heteronemin may constitute a novel c-Met/STAT3-targeting agent for prostate cancer. Prostate © 2016 Wiley Periodicals, Inc.