[Show abstract][Hide abstract] ABSTRACT: It has been reported that persistent or excessive autophagy promotes cancer cell death during chemotherapy, either by enhancing the induction of apoptosis or mediating autophagic cell death. Here, we show that miR-15a and miR-16 are potent inducers of autophagy. Rictor, a component of mTORC2 complex, is directly targeted by miR-15a/16. Overexpression of miR-15a/16 or depletion of endogenous Rictor attenuates the phosphorylation of mTORC1 and p70S6K, inhibits cell proliferation and G1/S cell cycle transition in human cervical carcinoma HeLa cells. Moreover, miR-15a/16 dramatically enhances anticancer drug camptothecin (CPT)-induced autophagy and apoptotic cell death in HeLa cells. Collectively, these data demonstrate that miR-15a/16 induced autophagy contribute partly to their inhibition of cell proliferation and enhanced chemotherapeutic efficacy of CPT.
[Show abstract][Hide abstract] ABSTRACT: Steatosis is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD) which can be driven by peroxisome proliferator-activated receptor-α (PPAR-α) dysregulation. Through examining the effect of PPAR-α on fatty liver development, we found that PPAR-α is a target of miR-17-5p. Transgenic mice expressing miR-17 developed fatty liver and produced higher levels of triglyceride and cholesterol but lower levels of PPAR-α. Ectopic expression of miR-17 enhanced cellular steatosis. Gain-of-function and loss-of-function experiments confirmed PPAR-α as a target of miR-17-5p. On the other hand, PPAR-α bound to the promoter of miR-17 and promoted its expression. The feed-back loop between miR-17-5p and PPAR-α played a key role in the induction of steatosis and fatty liver development. Mice with high levels of miR-17-5p were sensitive to Dexamethasone-induced fatty liver formation. Inhibition of miR-17-5p suppressed this process and enhanced PPAR-α expression in mice treated with Dexamethasone. Clofibrate, Ciprofibrate, and WY-14643: three agents used for treatment of metabolic disorders, were found to promote PPAR-α expression whilst decreasing miR-17-5p levels and inhibiting steatosis. Our studies show that miR-17-5p inhibitor and agents used in metabolic disorders may be applied in combination with Dexamethasone in the treatment of anti-inflammation, immunosuppression, and cancer patients.Molecular Therapy (2015); doi:10.1038/mt.2015.64.
[Show abstract][Hide abstract] ABSTRACT: Tumor-resident proteases (TRPs) are regarded as informative biomarkers for staging cancer progression and evaluating therapeutic efficacy. Currently in the clinic, measurement of TRP is dependent on invasive biopsies, limiting their usefulness as monitoring tools. Here we identified circulating peptides naturally produced by TRPs, and evaluated their potential to monitor the efficacy of anti-tumor treatments. We established a mouse model for ovarian cancer development and treatment by orthotopic implantation of the human drug-resistant ovarian cancer cell line HeyA8-MDR, followed by porous silicon particle- or multistage vector (MSV) - enabled EphA2 siRNA therapy. Immunohistochemistry staining of tumor tissue revealed decreased expression of matrix metallopeptidase 9 (MMP-9) in mice exhibiting positive responses to MSV-EphA2 siRNA treatment. We demonstrated, via an ex vivo proteolysis assay, that C3f peptides can act as substrates of MMP-9, which cleaves C3f at L1311-L1312 into two peptides (SSATTFRL and LWENGNLLR). Importantly, we showed that these two C3f-derived fragments detected in serum were primarily generated by tumor-resident, but not blood-circulating, MMP-9. Our results suggested that the presence of the circulating fragments specially derived from the localized cleavage in tumor microenvironment can be used to evaluate therapeutic efficacy of anti-cancer treatment, assessed through a relatively noninvasive and user-friendly proteomics approach.
[Show abstract][Hide abstract] ABSTRACT: Network cross-talks between microRNAs (miRNAs) and mRNAs may be useful to elucidate the pathological mechanisms of pancreatic islet cells in diabetic individuals. The aim of the present study was to investigate the cross-talks between miRNAs and mRNAs in pancreatic tissues of streptozotocin-induced diabetic mice through microarray and bioinformatic methods. Based on the miRNA microarray, 64 upregulated and 72 downregulated miRNAs were observed in pancreatic tissues in diabetic mice compared to the normal controls. Based on the mRNA microarrray, 507 upregulated mRNAs and 570 downregulated mRNAs were identified in pancreatic tissues in diabetic mice compared to the normal controls. Notably, there were 246 binding points between upregulated miRNA and downregulated mRNAs; simultaneously, there were 583 binding points between downregulated miRNA and upregulated mRNAs. These changed mRNA may potentially involve the following signaling pathways: Insulin secretion, pancreatic secretion, mammalian target of rapamycin signaling pathway, forkhead box O signaling pathway and phosphatidylinositol 3-kinase-protein kinase B signaling. The fluctuating effects of miRNAs and matched mRNAs indicated that miRNAs may have wide cross-talks with mRNAs in pancreatic tissues of type 1 diabetic mice. The cross-talks may play important roles in contributing to impaired islet functions and the development of diabetes. However, further functional validation should be conducted in the future.
[Show abstract][Hide abstract] ABSTRACT: (Macro)autophagy delivers cellular constituents to lysosomes for degradation. Although a cytoplasmic process, autophagy-deficient cells accumulate genomic damage, but an explanation for this effect is currently unclear. We report here that inhibition of autophagy causes elevated proteasomal activity leading to enhanced degradation of checkpoint kinase 1 (Chk1), a pivotal factor for the error-free DNA repair process, homologous recombination (HR). We show that loss of autophagy critically impairs HR and that autophagy-deficient cells accrue micronuclei and sub-G1 DNA, indicators of diminished genomic integrity. Moreover, due to impaired HR, autophagy-deficient cells are hyperdependent on nonhomologous end joining (NHEJ) for repair of DNA double-strand breaks. Consequently, inhibition of NHEJ following DNA damage in the absence of autophagy results in persistence of genomic lesions and rapid cell death. Because autophagy deficiency occurs in several diseases, these findings constitute an important link between autophagy and DNA repair and highlight a synthetic lethal strategy to kill autophagy-deficient cells.
Proceedings of the National Academy of Sciences 01/2015; 112(3):773-8. DOI:10.1073/pnas.1409563112 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Accelerated cell cycle progression is the common feature of most cancers. MiRNAs can act as oncogenes or tumor suppressors by directly modulating cell cycle machinery. It has been shown that miR-188 is upregulated in UVB-irradiated mouse skin and human nasopharyngeal carcinoma CNE cells under hypoxic stress. However, little is known about the function of miR-188 in cell proliferation and growth control.ResultsOverexpression of miR-188 inhibits cell proliferation, tumor colony formation and G1/S cell cycle transition in human nasopharyngeal carcinoma CNE cells. Using bioinformatics approach, we identify a series of genes regulating G1/S transition as putative miR-188 targets. MiR-188 inhibits both mRNA and protein expression of CCND1, CCND3, CCNE1, CCNA2, CDK4 and CDK2, suppresses Rb phosphorylation and downregulates E2F target genes. The expression level of miR-188 also inversely correlates with the expression of miR-188 targets in human nasopharyngeal carcinoma (NPC) tissues. Moreover, studies in xenograft mouse model reveal that miR-188 is capable of inhibiting tumor initiation and progression by suppressing target genes expression and Rb phosphorylation.Conclusions
This study demonstrates that miR-188 exerts anticancer effects, via downregulation of multiple G1/S related cyclin/CDKs and Rb/E2F signaling pathway.
Cell Communication and Signaling 10/2014; 12(1):66. DOI:10.1186/PREACCEPT-1482274339133333 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have increasingly linked microRNAs to colorectal cancer (CRC). MiR-194 has been reported deregulated in different tumor types, whereas the function of miR-194 in CRC largely remains unexplored. Here we investigated the biological effects, mechanisms and clinical significance of miR-194. Functional assay revealed that overexpression of miR-194 inhibited CRC cell viability and invasion in vitro and suppressed CRC xenograft tumor growth in vivo. Conversely, block of miR-194 in APC(Min/+) mice promoted tumor growth. Furthermore, miR-194 reduced the expression of AKT2 both in vitro and in vivo. Clinically, the expression of miR-194 gradually decreased from 20 normal colorectal mucosa (N-N) cases through 40 colorectal adenomas (CRA) cases and then to 40 CRC cases, and was negatively correlated with AKT2 and pAKT2 expression. Furthermore, expression of miR-194 in stool samples was gradually decreased from 20 healthy cases, 20 CRA cases, then to 28 CRC cases. Low expression of miR-194 in CRC tissues was associated with large tumor size (P=0.006), lymph node metastasis (P=0.012) and shorter survival (HR =2.349, 95% CI = 1.242 to 4.442; P=0.009). In conclusion, our data indicated that miR-194 acted as a tumor suppressor in the colorectal carcinogenesis via targeting PDK1/AKT2/XIAP pathway, and could be a significant diagnostic and prognostic biomarker for CRC.
[Show abstract][Hide abstract] ABSTRACT: The regulation of gene expression by microRNAs (miRNAs) is complex due to a number of variables involved. The potential for one miRNA to target many genes, the presence of multiple miRNA response elements (MREs) in one mRNA molecule and the interplay between RNAs that share common MREs each add a layer of complexity to the process; making it difficult to determine how regulation of gene expression by miRNAs works within the context of the system as a whole. In this study, we used luciferase report vectors inserted with different 3’UTR fragments as probes to detect the repressive effect of miRNA pool on gene expression and uncovered some essential characteristics of gene regulation mediated by the miRNA pool, such as the nonlinear correlative relationship between the regulatory potential of a miRNA pool and the number of potential MREs, the buffering effect and saturating effect of miRNA pool, and the restrictive effect caused by the density of MREs. Through expressing gradient concentration of 3’UTR fragments, we indirectly detected the regulatory potential of competing endogenous RNA (ceRNA) pool and analysed its effect on the regulatory potential of the miRNA pool. Our results provide some new insights about miRNA pool mediated gene regulation.
[Show abstract][Hide abstract] ABSTRACT: The checkpoint kinase 1 (Chk1) functions not only in genotoxic stresses but also in normal cell cycle progression, particularly the initiation, progression and fidelity of unperturbed mitosis. In this study, we investigated the role of Chk1 in regulating the metaphase-anaphase transition in mammalian cells.
The mitotic progression was monitored by flow cytometry analysis. The levels of cyclin B1, Cdc20 and Mad2 were measured by western blotting. Metaphase chromosome alignment and the subcellular localization of Cdc20 and Mad2 were analyzed by immunofluorecence and confocal microscopy.
Cyclin B1 degradation and the metaphase-anaphase transition were severely blocked by Chk1 siRNA. Depletion of Chk1 induced chromosome alignment defect in metaphase cells. The kinetochore localization of Cdc20, Mad2 was disrupted in Chk1 depleted cells. Chk1 abrogation also dramatically reduced the protein expression levels of Cdc20 and Mad2.
These results strongly suggest that Chk1 is required for the metaphase-anaphase transition via regulating the subcellular localization and the expression of Cdc20 and Mad2.
Life sciences 04/2014; 106(1). DOI:10.1016/j.lfs.2014.04.011 · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Metabolic stress induces autophagy as an alternative source of energy and metabolites. Insufficient autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. Here, we performed a functional screen in search of novel autophagy regulators from natural products. We showed that oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes and impaired degradation of SQSTM1/p62. Costaining of GFP-LC3B with LysoTracker Red or LAMP1 antibody demonstrates that autophagosome-lysosome fusion is blocked by OC treatment. Furthermore, OC inhibits lysosomal proteolytic activity by altering lysosomal acidification and downregulating the expression of lysosomal cathepsins. Importantly, OC can eliminate the tolerance of cancer cells to nutrient starvation. Starvation dramatically increases the susceptibility of cancer cells to OC-induced CASP3-dependent apoptosis in vitro. Subsequent studies in xenograft mouse model showed that OC has anticancer potency as revealed by increased staining of cleaved CASP3, LC3 puncta, and SQSTM1, as well as reduced expression of lysosomal cathepsins. Combined treatment with OC and caloric restriction potentiates anticancer efficacy of OC in vivo. Collectively, these data demonstrated that OC is a novel autophagic flux inhibitor and might be useful in anticancer therapy.
[Show abstract][Hide abstract] ABSTRACT: Hypoxia activates autophagy, an evolutionarily conserved cellular catabolic process. Dysfunction in the autophagy pathway has been implicated in an increasing number of human diseases, including cancer. Hypoxia induces upregulation of a specific set of microRNAs (miRNAs) in a variety of cell types. Here, we describe hypoxia-induced MIR155 as a potent inducer of autophagy. Enforced expression of MIR155 increases autophagic activity in human nasopharyngeal cancer and cervical cancer cells. Knocking down endogenous MIR155 inhibits hypoxia-induced autophagy. We demonstrated that MIR155 targets multiple players in MTOR signaling, including RHEB, RICTOR, and RPS6KB2. MIR155 suppresses target-gene expression by directly interacting with their 3' untranslated regions (UTRs), mutations of the binding sites abolish their MIR155 responsiveness. Furthermore, by downregulating MTOR signaling, MIR155 also attenuates cell proliferation and induces G 1/S cell cycle arrest. Collectively, these data present a new role for MIR155 as a key regulator of autophagy via dysregulation of MTOR pathway.
[Show abstract][Hide abstract] ABSTRACT: One criterion for microRNA identification is based on their conservation across species, and prediction of miRNA targets by empirical approaches using computational analysis relies on the presence of conservative mRNA 3'UTR. Because most miRNA target sites identified are highly conserved across different species, it is not clear whether miRNA targeting is species-specific. To predict miRNAs targeting, we aligned all available fibronectin 3'UTRs and observed significant conservation of all 20 species. Twelve miRNAs were predicted to target most fibronectin 3'UTRs, but rodent fibronectin showed potential binding sites specific for five different miRNAs. One of them, the miR-378a-5p, contained a complete matching seed-region for all rodent fibronectin, which could not be found in any other species. We designed experiments to test whether the species-specific targeting possessed biological function and found that expression of miR-378a-5p decreased cancer cell proliferation, migration, invasion, resulting in inhibition of tumor growth. Silencing fibronectin expression produced similar effects as miR-378a-5p, while transfection with a construct targeting miR-378-5p produced opposite results. Tumor formation assay showed that enhanced expression of fibronectin in the stromal tissues as a background environment suppressed tumor growth, while increased fibronectin expression inside the tumor cells promoted tumor growth. This was likely due to the different signaling direction, either inside-out or outside-in signal. Our results demonstrated that species-specific targeting by miRNA could also exert functional effects. Thus, one layer of regulation has been added to the complex network of miRNA signaling.
[Show abstract][Hide abstract] ABSTRACT: miR-181a has been presumed to target the 3'-untranslated regions (3'-UTR) of IL1a based on software predictions. miR-181a and IL1a have opposite expression levels in monocytes and macrophages in the inflammatory state. This led us to suspect that mir-181a has an important function in regulating inflammatory response by targeting IL1a. Fluorescence reporter assays showed that miR-181a effectively binds to the 3'-UTR of IL1a. The anti-inflammatory functions of miR-181a were investigated in lipopolysaccharides (LPS)-induced Raw264.7 and phorbol 12-myristate 13-acetate (PMA)/LPS-induced THP-1 cells. We found that miR-181a mimics significantly lowered IL1a expression levels in these cells and, interestingly, miR-181a inhibitors reversed this decrease. In addition, miR-181a mimics significantly inhibited increase in the levels of inflammatory factors (IL1b, IL6, and TNFa) in these cells. Furthermore, miR-181a mimics and inhibitors decreased and increased, respectively, production of reactive oxygen species in PMA/LPS-induced THP-1 cells. These results indicate that miR-181a regulates inflammatory responses by directly targeting the 3'-UTR of IL1a and down-regulating IL1a levels. Interestingly, we found that miR-181a inhibited production of inflammatory factors even in IL1a-induced THP-1 cells, suggesting that the anti-inflammatory effects of miR-181a possibly involves other targets in addition to IL1a. Thus, we provide the first evidence for anti-inflammatory effects of miR-181a mediated at least in part by down-regulating IL1a.
PLoS ONE 03/2013; 8(3):e58639. DOI:10.1371/journal.pone.0058639 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Versican is highly expressed during the early stages of tissue development and its expression is elevated during wound repair and tumor growth. There is little literature on the potential role of breast cancer stem cells on the cellular-extracellular matrix interactions involving versican. An anti-versican shRNA was used to observe the effect of reduction of versican on breast cancer self-renewal. A versican G3 construct was exogenously expressed in breast cancer cell lines. Colony formation and mammosphere formation assays were performed; flow cytometry was applied to analyze the prevalence of side population (SP) cells. The versican G3- and vector-transfected 66c14 cells were injected transdermally into BALB/c mice as a 10-fold dilution series from 1 x 105 to 1 x 102 cells per mouse. Versican G3 domain enhanced breast cancer self-renewal in both experimental in vitro and in vivo models. Versican G3 transfected cells contained high levels of SP cells, formed more mammospheres when cultured in the serum-free medium, and formed a greater number and larger colonies. Reduction of versican's functionality through anti-versican shRNA or knocking out the EGF-like motifs reduced the effect of versican on enhancing mammosphere and colony formation. Versican enhanced self-renewal played a role in enhanced chemotherapeutic drug resistance, relating partly to the up-regulated expression of EGFR signaling. Versican is highly expressed in breast cancer progenitor cells and was maintained at high levels before cell differentiation. Over-expression of versican enhanced breast cancer self-renewal through EGFR/AKT/GSK-3β (S9P) signaling, and conferred resistant to chemotherapeutic drugs tested.
Molecular Cancer Research 02/2013; 11(5). DOI:10.1158/1541-7786.MCR-12-0461 · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammatory stimuli are usually associated with homeostatic responses, which have an important function in protecting the body from excessive inflammatory damage. Previous studies reported the anti-inflammatory effect of miR-181a. The current study utilized two animal models of inflammation, induced by either lipopolysaccharides (LPS) or streptozotocin. We demonstrated that inflammatory stimuli significantly increase miR-181a expression, concurrently with inflammatory factors. In addition, the knock down of toll-like receptor 4 (TLR-4) by small interfering RNA in LPS-induced Raw264.7 cells significantly reduces the expression of both miR-181a and inflammatory factors. Furthermore, patients with inflammatory response show increased expression of miR-181a, which is strongly correlated with the expression of interleukin (IL)-1, IL-6, and tumor necrosis factor alpha. These data indicate that the up-regulation of miR-181a may be associated with homeostatic response to inflammatory stimuli by TLR-4 pathway activation. Therefore, miR-181a may serve as a novel marker for inflammatory response.
Biochemical and Biophysical Research Communications 12/2012; 430(2). DOI:10.1016/j.bbrc.2012.11.097 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MiR-210 is up-regulated in multiple cancer types but its function is disputable and further investigation is necessary. Using a bioinformatics approach, we identified the putative target genes of miR-210 in hypoxia-induced CNE cells from genome-wide scale. Two functional gene groups related to cell cycle and RNA processing were recognized as the major targets of miR-210. Here, we investigated the molecular mechanism and biological consequence of miR-210 in cell cycle regulation, particularly mitosis. Hypoxia-induced up-regulation of miR-210 was highly correlated with the down-regulation of a group of mitosis-related genes, including Plk1, Cdc25B, Cyclin F, Bub1B and Fam83D. MiR-210 suppressed the expression of these genes by directly targeting their 3'-UTRs. Over-expression of exogenous miR-210 disturbed mitotic progression and caused aberrant mitosis. Furthermore, miR-210 mimic with pharmacological doses reduced tumor formation in a mouse metastatic tumor model. Taken together, these results implicate that miR-210 disturbs mitosis through targeting multi-genes involved in mitotic progression, which may contribute to its inhibitory role on tumor formation.
Nucleic Acids Research 11/2012; 41(1). DOI:10.1093/nar/gks995 · 9.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Versican is detected in the interstitial tissues at the invasive margins of breast carcinoma, is predictive of relapse, and negatively impacts overall survival rates. The versican G3 domain is important in breast cancer cell growth, migration and bone metastasis. However, mechanistic studies evaluating versican G3 enhanced breast cancer bone metastasis are limited.
A versican G3 construct was exogenously expressed in the 66c14 and the MC3T3-E1 cell line. Cells were observed through light microscopy and viability analyzed by Coulter Counter or determined with colorimetric proliferation assays. The Annexin V-FITC apoptosis detection kit was used to detect apoptotic activity. Modified Chemotactic Boyden chamber migration invasion assays were applied to observe tumor migration and invasion to bone stromal cells and MC3T3-E1 cells. Alkaline phosphatase (ALP) staining and ALP ELISA assays were performed to observe ALP activity in MC3T3-E1 cells.
In the four mouse breast cancer cell lines 67NR, 66c14, 4T07, and 4T1, 4T1 cells expressed higher levels of versican, and showed higher migration and invasion ability to MC3T3-E1 cells and primary bone stromal cells. 4T1 conditioned medium (CM) inhibited MC3T3-E1 cell growth, and even lead to apoptosis. Only 4T1 CM prevented MC3T3-E1 cell differentiation, noted by inhibition of alkaline phosphatase (ALP) activity. We exogenously expressed a versican G3 construct in a cell line that expresses low versican levels (66c14), and observed that the G3-expressing 66c14 cells showed enhanced cell migration and invasion to bone stromal and MC3T3-E1 cells. This observation was prevented by selective EGFR inhibitor AG1478, selective MEK inhibitor PD 98059, and selective AKT inhibitor Triciribine, but not by selective JNK inhibitor SP 600125. Versican G3 enhanced breast cancer cell invasion to bone stromal cells or osteoblast cells appears to occur through enhancing EGFR/ERK or AKT signaling. G3 expressing MC3T3-E1 cells showed inhibited cell growth and cell differentiation when cultured with TGF-β1 (1 ng/ml), and expressed enhanced cell apoptosis when cultured with TNF-α (2 ng/ml). Enhanced EGFR/JNK signaling appears to be responsible for G3 enhanced osteoblast apoptosis and inhibited osteoblast differentiation. Whereas repressed expression of GSK-3β (S9P) contributes to G3 inhibited osteoblast growth. Versican G3 functionality was dependent on its EGF-like motifs. Without the structure of EGF-like repeats, the G3 domain would not confer enhancement of tumor cell migration and invasion to bone with concordant inhibition of osteoblast differentiation and promotion of osteoblast apoptosis.
Versican enhances breast cancer bone metastasis not only through enhancing tumor cell mobility, invasion, and survival in bone tissues, but also by inhibiting pre-osteoblast cell growth, differentiation, which supply favorable microenvironments for tumor metastasis.
BMC Cancer 08/2012; 12(1):341. DOI:10.1186/1471-2407-12-341 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Akt family of serine/threonine protein kinases are key regulators of multiple aspects of cell behaviour, including proliferation, survival, metabolism, and tumorigenesis. Growth-factor-activated Akt signalling promotes progression through normal, unperturbed cell cycles by acting on diverse downstream factors involved in controlling the G1/S and G2/M transitions. Remarkably, several recent studies have also implicated Akt in modulating DNA damage responses and genome stability. High Akt activity can suppress ATR/Chk1 signalling and homologous recombination repair (HRR) via direct phosphorylation of Chk1 or TopBP1 or, indirectly, by inhibiting recruitment of double-strand break (DSB) resection factors, such as RPA, Brca1, and Rad51, to sites of damage. Loss of checkpoint and/or HRR proficiency is therefore a potential cause of genomic instability in tumor cells with high Akt. Conversely, Akt is activated by DNA double-strand breaks (DSBs) in a DNA-PK- or ATM/ATR-dependent manner and in some circumstances can contribute to radioresistance by stimulating DNA repair by nonhomologous end joining (NHEJ). Akt therefore modifies both the response to and repair of genotoxic damage in complex ways that are likely to have important consequences for the therapy of tumors with deregulation of the PI3K-Akt-PTEN pathway.
Journal of Oncology 03/2012; 2012:951724. DOI:10.1155/2012/951724