Activating internal tandem duplication (ITD) insertions in the juxtamembrane domain of the FLT3 tyrosine kinase are found in about one fourth of patients with acute myeloid leukemia and have been shown to be an independent negative prognostic factor for survival. We show that sorafenib (BAY 43-9006, Nexavar) potently inhibits FLT3 enzymatic and signaling activities. In HEK293 cells stably transfected with FLT3-WT or FLT3-ITD, sorafenib blocked basal and ligand dependent FLT3-mediated tyrosine autophosphorylation as well as extracellular signal-regulated kinase1/2 and Stat5 phosphorylation. In leukemia cell lines MV4-11 and EOL-1, sorafenib treatment resulted in decreased cell proliferation and inhibition of FLT3 signaling. The growth of the FLT3-independent RS4-11 cell line was only weakly inhibited by sorafenib. Cell cycle arrest and induction of apoptosis were observed upon treatment with sorafenib in MV4-11 and EOL-1 cells. The antitumor efficacy of sorafenib was evaluated against the MV4-11 leukemia grown subcutaneously in NCr nu/nu mice. Doses of 3 and 10 mg/kg administered orally for 14 days resulted in six and nine out of 10 animals with complete responses, respectively. The demonstration that sorafenib exhibits potent target inhibition and efficacy in FLT3-driven models suggests that this compound may have a therapeutic benefit for patients with FLT3-driven leukemias.

BACKGROUNDInternal tandem duplication of FMS-like tyrosine kinase (FLT3-ITD) is well known to be involved in acute myeloid leukemia (AML) progression, but FLT3-ITD–negative AML cases account for 70% to 80% of AML, and the mechanisms underlying their pathology remain unclear. This study identifies protein tyrosine phophatase PRL-3 as a key mediator of FLT3-ITD–negative AML.METHODSA total of 112 FLT3-ITD–negative AML patients were sampled between 2010 and 2013, and the occurrence of PRL-3 hyperexpression in FLT3-ITD–negative AML was evaluated by multivariate probit regression analysis. Overexpression or depletion of endogenous PRL-3 expression with the specific small interfering RNAs was performed to investigate the role of PRL-3 in AML progression. Xenograft models were also used to confirm the oncogenic role of PRL-3.RESULTSCompared to healthy donors, PRL-3 is upregulated more than 3-fold in 40.2% of FLT3-ITD–negative AML patients. PRL-3 expression level is adversely correlated to the overall survival of the AML patients, and the AML relapses accompany with re-upregulation of PRL-3. Mechanistically, aberrant PRL-3 expression promoted cell cycle progression and enhanced the antiapoptotic machinery of AML cells to drug cytotoxicity through downregulation of p21 and upregulation of Cyclin D1 and CDK2 and activation of STAT5 and AKT. Depletion of endogenous PRL-3 sensitizes AML cells to therapeutic drugs, concomitant with apoptosis by upregulation of cleaved PARP (poly ADP ribose polymerase) and apoptosis-related caspases. Xenograft assays further confirmed PRL-3’s oncogenic role in leukemogenesis.CONCLUSIONSOur results demonstrated that PRL-3 is a novel independent crucial player in both FLT3-ITD–positive and FLT3-ITD–negative AML and could be a potential therapeutic target. Cancer 2014;120:2130–2141. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.FLT3-ITD–negative acute myeloid leukemia (AML) accounts for up to approximately 70% to 80% of all cases. This study demonstrates that PRL-3, an independent driver in FLT3-ITD–negative AML, is adversely correlated to patient survival. Mechanistically, PRL-3 can promote AML cell cycle progression and render antiapoptosis features to AML cells, suggesting it could be an independent factor for AML diagnosis and therapy.

BackgroundPoly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive.MethodsWe performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay. Cell proliferation, cell cycle, tumorigenesis and cell apoptosis were also evaluated in ovary and colon cancer cell lines. The mechanism that PCBP1 affects p27 was analyzed by mRNA stability and ribosome profiling assays. We analyzed PCBP1 and p27 expression in ovary, colon and renal tumor samples and adjacent non-tumor tissues using RT-PCR, Western Blotting and immunohistochemistry. The prognostic significance of PCBP1 and p27 also analyzed using online databases.ResultsWe identified cell cycle inhibitor p27Kip1 (p27) as a novel PCBP1-bound transcript. We then demonstrated that binding of PCBP1 to p27 3’UTR via its KH1 domain mainly stabilizes p27 mRNA, while enhances its translation to fuel p27 expression, prior to p27 protein degradation. The upregulated p27 consequently inhibits cell proliferation, cell cycle progression and tumorigenesis, whereas promotes cell apoptosis under paclitaxel treatment. Conversely, knockdown of PCBP1 in turn compromises p27 mRNA stability, leading to lower p27 level and tumorigenesis in vivo. Moreover, forced depletion of p27 counteracts the tumor suppressive ability of PCBP1 in the same PCBP1 over-expressing cells. Physiologically, we showed that decreases of both p27 mRNA and its protein expressions are well correlated to PCBP1 depletion in ovary, colon and renal tumor samples, independent of the p27 ubiquitin ligase Skp2 level. Correlation of PCBP1 with p27 is also found in the tamoxifen, doxorubincin and lapatinib resistant breast cancer cells of GEO database.ConclusionOur results thereby indicate that loss of PCBP1 expression firstly attenuates p27 expression at post-transcriptional level, and subsequently promotes carcinogenesis. PCBP1 could be used as a diagnostic marker to cancer patients.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0840-1) contains supplementary material, which is available to authorized users.

Hepatitis B e antigen (HBeAg) is a viral strategy of immune response evasion associated with hepatitis B virus (HBV) persistence. Spontaneous HBeAg seroconversion is usually accompanied by liver disease remission. Unfortunately, this goal is difficult to achieve and requires expensive and time-consuming treatment. Furin, a proprotein convertase, is involved in HBeAg maturation and is therefore a potential therapeutic target or indicator for predicting disease progression and antiviral response. Here we demonstrate that healthy Han Chinese from southern China (an endemic area of HBV infection) harbor a common single nucleotide polymorphism (SNP; ؊229 C/T) in a 1268-bp region of the P1 promoter of the furin gene [FES upstream region (Fur)]. A luciferase reporter gene assay showed that transcription activity is about 3 times higher in allele T carriers than in allele C carriers of this SNP. Allele T includes a suboptimal transcription factor NF-E2 [i.e., nuclear factor (erythroid-derived 2)]-binding motif according to bioinformatics and studies using site-directed mutagenesis. We also observed that individuals carrying allele T were more likely to become persistently infected. When persistently infected patients were divided into subgroups according to recent guidelines and HBeAg-defective virus infection was taken into account, patients with allele T or genotype TT had a decreased likelihood of HBeAg seroconversion or an increased likelihood of progressing to HBeAg-negative chronic hepatitis B or liver cirrhosis if accompanied by HBeAg-defective virus infection. Conclusion: The common SNP in the P1 promoter of the Fur gene affects furin transcription activity and HBV infection outcome, possibly by increasing furin messenger RNA expression, and this suggests that furin is a potential therapeutic target and that this SNP is a potential predictor of disease progression or therapeutic response. (HEPATOLOGY 2009;50:763-771.)

Accumulating evidences indicate that poly C binding protein (PCBP1) is downregulated in various carcinomas as a tumor suppressor, but the underlying mechanism in suppression of tumorigenesis still remains elusive. Here, we found that PCBP1 overexpression attenuates tumor cell growth upon serum-free starvation. Notably, the autophagic degradation inhibitor, chloroquine, could mimic this suppressive effect in tumor cell growth. Autophagy analyses demonstrated that PCBP1 overexpression blocked autophagic flux of tumor cells under starvation conditions, while PCBP1 downregulation in turn refueled this autophagic flux, protecting cells from death. Mechanistically, PCBP1 overexpression attenuated microtubule-associated protein Light chain 3 (LC3B) mRNA stability to repress LC3B expression, resulting in the autophagy inhibition. Consequently, PCBP1 overexpression strongly triggered the caspase 3 and 8-mediated apoptosis of tumor cells and downregulated anti-apoptotic Bcl-2 expression upon starvation, which could be further synergized by autophagic inhibitor, indicating that PCBP1 not only inhibits tumor cell autophagy, but also renders them to apoptosis. Taken together, our results uncovered a novel mechanism of PCBP1 in repressing autophagy-mediated cell survival and indicated that inhibition of tumor cell autophagy by PCBP1 upregulation or with autophagic inhibitors could be an effective therapeutical strategy to colon and ovary tumors with low PCBP1 expression.