PTEN; phosphatase and tensin homolog (10q23.3)

Gene Summary

Gene:PTEN; phosphatase and tensin homolog
Aliases: BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del
Summary:This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
Updated:05 March, 2014


What does this gene/protein do?
PTEN is implicated in:
- activation of mitotic anaphase-promoting complex activity
- anaphase-promoting complex binding
- angiogenesis
- apoptotic process
- brain morphogenesis
- canonical Wnt receptor signaling pathway
- cardiac muscle tissue development
- cell migration
- cell projection
- cell proliferation
- central nervous system development
- central nervous system myelin maintenance
- central nervous system neuron axonogenesis
- cytoplasm
- cytosol
- dendritic spine morphogenesis
- dentate gyrus development
- endothelial cell migration
- enzyme binding
- epidermal growth factor receptor signaling pathway
- fibroblast growth factor receptor signaling pathway
- forebrain morphogenesis
- heart development
- induction of apoptosis
- inositol phosphate dephosphorylation
- inositol-1,3,4,5-tetrakisphosphate 3-phosphatase activity
- internal side of plasma membrane
- learning or memory
- lipid binding
- locomotor rhythm
- locomotory behavior
- long-term synaptic potentiation
- magnesium ion binding
- male mating behavior
- maternal behavior
- multicellular organismal response to stress
- myelin sheath adaxonal region
- negative regulation of apoptotic process
- negative regulation of axonogenesis
- negative regulation of cell aging
- negative regulation of cell migration
- negative regulation of cell proliferation
- negative regulation of cell size
- negative regulation of cyclin-dependent protein kinase activity involved in G1/S
- negative regulation of dendritic spine morphogenesis
- negative regulation of epithelial cell proliferation
- negative regulation of excitatory postsynaptic membrane potential
- negative regulation of focal adhesion assembly
- negative regulation of G1/S transition of mitotic cell cycle
- negative regulation of myelination
- negative regulation of organ growth
- negative regulation of phosphatidylinositol 3-kinase cascade
- negative regulation of protein kinase B signaling cascade
- negative regulation of protein phosphorylation
- negative regulation of ribosome biogenesis
- negative regulation of synaptic vesicle clustering
- nerve growth factor receptor signaling pathway
- neuron projection
- neuron-neuron synaptic transmission
- nucleus
- PDZ domain binding
- peptidyl-tyrosine dephosphorylation
- phosphatidylinositol biosynthetic process
- phosphatidylinositol dephosphorylation
- phosphatidylinositol-3-phosphatase activity
- phosphatidylinositol-3,4-bisphosphate 3-phosphatase activity
- phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
- phosphatidylinositol-mediated signaling
- phospholipid metabolic process
- phosphoprotein phosphatase activity
- plasma membrane
- PML body
- positive regulation of cell proliferation
- positive regulation of excitatory postsynaptic membrane potential
- positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process
- positive regulation of sequence-specific DNA binding transcription factor activity
- postsynaptic density assembly
- prepulse inhibition
- presynaptic membrane assembly
- prostate gland growth
- protein binding
- protein dephosphorylation
- protein kinase B signaling cascade
- protein kinase binding
- protein serine/threonine phosphatase activity
- protein stabilization
- protein tyrosine phosphatase activity
- protein tyrosine/serine/threonine phosphatase activity
- regulation of B cell apoptotic process
- regulation of cellular component size
- regulation of cyclin-dependent protein kinase activity
- regulation of myeloid cell apoptotic process
- regulation of neuron projection development
- regulation of protein stability
- rhythmic synaptic transmission
- Schmidt-Lanterman incisure
- small molecule metabolic process
- social behavior
- synapse assembly
- synapse maturation
- T cell receptor signaling pathway
Data from Gene Ontology via CGAP


What pathways are this gene/protein implicaed in?
- mTOR Signaling Pathway BIOCARTA
- PTEN dependent cell cycle arrest and apoptosis BIOCARTA
- Regulation of eIF4e and p70 S6 Kinase BIOCARTA
- Signaling of Hepatocyte Growth Factor Receptor BIOCARTA
- Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway BIOCARTA
- Focal adhesion KEGG
- Inositol phosphate metabolism KEGG
- Phosphatidylinositol signaling system KEGG
- Tight junction KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

As tumours progress to more advanced stages, they tend to acquire an increasing number of genetic alterations. One common alteration seen in a range of different advanced cancers is mutation of the PTEN gene, a gene which is linked with cell regulation and apoptosis (programmed cell death). Mutations in the PTEN gene are documented in cancers of the breast, prostate, endometrium, ovary, colon, melanoma, glioblastoma. and lymphoma. Animal models have shown that the loss of just one copy of the PTEN gene is enough to interrupt cell signalling and begin the process of uncontrolled cell growth. However, the significance of PTEN alterations in carcinogenesis is controversial since aberrant transcripts of PTEN have also been identified in normal non-cancerous tissues.

Research Indicators

Publications Per Year (1989-2014)
Graph generated 05 March 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.


PTEN and Testicular Cancer

Related Publications (10)

PTEN and Thyroid Cancer

Related Publications (104)

PTEN and Soft Tissue Sarcoma

Related Publications (47)

PTEN and Prostate Cancer

Related Publications (326)

PTEN and Stomach Cancer

Related Publications (57)

PTEN mutations in Endometrial Cancer
Mutations of the PTEN suppressor gene are the most frequent genetic abnormality in endometrial cancers. They occur in 40-80% of endometrioid carcinomas, which account for the majority of endometrial cancers. PTEN mutations have also been detected in the precancerous condition endometrial intraepithelial neoplasia.
Related Publications (386)

PTEN and Lung Cancer

Related Publications (240)

PTEN and Astrocytoma

Related Publications (342)

PTEN and Glioblastoma

Related Publications (340)

PTEN in Precancerous Conditions
PTEN mutations are implicated in a number of precancerous conditions. For example Mutter and colleagues (JNCI, 2000) found 16/29 (55%) of endometrial intraepithelial neoplasia (a precancerous condition) had PTEN mutations compared to 25/30 (83%) of endometrioid adenocarcinomas. They suggest that PTEN may be a useful immunohistochemical biomarker for premalignant disease. The precancers were characterised by mutation of only 1 PTEN allele while the adenocarcinomas showed reduced or complete loss of PTEN protein expression.
Related Publications (48)

PTEN Amplification in Ewing's Sarcoma?
In a genome-wide copy-number analysis of Ewing's sarcoma, Lynn et al (2013) found localized copy-number alterations of PTEN.
Related Publications (1)

Related Links

Latest Publications: PTEN (cancer-related)

Saborowski M, Saborowski A, Morris JP, et al.
A modular and flexible ESC-based mouse model of pancreatic cancer.
Genes Dev. 2014; 28(1):85-97 [PubMed] Free Access to Full Article Related Publications
Genetically engineered mouse models (GEMMs) have greatly expanded our knowledge of pancreatic ductal adenocarcinoma (PDAC) and serve as a critical tool to identify and evaluate new treatment strategies. However, the cost and time required to generate conventional pancreatic cancer GEMMs limits their use for investigating novel genetic interactions in tumor development and maintenance. To address this problem, we developed flexible embryonic stem cell (ESC)-based GEMMs that facilitate the rapid generation of genetically defined multiallelic chimeric mice without further strain intercrossing. The ESCs harbor a latent Kras mutant (a nearly ubiquitous feature of pancreatic cancer), a homing cassette, and other genetic elements needed for rapid insertion and conditional expression of tetracycline-controlled transgenes, including fluorescence-coupled shRNAs capable of efficiently silencing gene function by RNAi. This system produces a disease that recapitulates the progression of pancreatic cancer in human patients and enables the study and visualization of the impact of gene perturbation at any stage of pancreas cancer progression. We describe the use of this approach to dissect temporal roles for the tumor suppressor Pten and the oncogene c-Myc in pancreatic cancer development and maintenance.

Related: Cancer of the Pancreas Pancreatic Cancer

Chomczyk MA, Czajka P
[PIK3CA mutations in the most common types of cancer].
Postepy Biochem. 2013; 59(3):280-4 [PubMed] Related Publications
Continuous improvement of appropriate methods of dealing with cancer require active search for the possibility of applying more and newer targeted therapies. Scientific reports, in addition to best-described proteins KRAS, PI3K emphasize the important role in carcinogenesis. This paper presents overview PIK3CA mutations in the path PI3K/PTEN/Akt the most common cancers. Targeted to stop the most important components of this path can be used to create targeted therapies. PIK3CA mutation may also be a predictive factor in the selection of targeted therapies. A lot of questions remain unanswered such as: how the structure and biochemical effects of intracellular affect different mutations in PIK3CA, and all mutations in the gene lead to the activation of p110a subunit? Additional research on the biochemical structure and cell structure are necessary to complete the discovery of PIK3CA gene function and, in particular subunits of p110a.

Related: Cancer Prevention and Risk Reduction

Lee KS, Wu Z, Song Y, et al.
Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway.
Genes Dev. 2013; 27(24):2642-7 [PubMed] Article available free on PMC after 15/06/2014 Related Publications
The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.

Related: Mitochondrial Mutations in Cancer Signal Transduction

White AC, Khuu JK, Dang CY, et al.
Stem cell quiescence acts as a tumour suppressor in squamous tumours.
Nat Cell Biol. 2014; 16(1):99-107 [PubMed] Article available free on PMC after 01/07/2014 Related Publications
In some organs, adult stem cells are uniquely poised to serve as cancer cells of origin. It is unclear, however, whether tumorigenesis is influenced by the activation state of the adult stem cell. Hair follicle stem cells (HFSCs) act as cancer cells of origin for cutaneous squamous cell carcinoma and undergo defined cycles of quiescence and activation. The data presented here show that HFSCs are unable to initiate tumours during the quiescent phase of the hair cycle, indicating that the mechanisms that keep HFSCs dormant are dominant over the gain of oncogenes (such as Ras) or the loss of tumour suppressors (such as p53). Furthermore, Pten activity is necessary for quiescence-based tumour suppression, as its deletion alleviates tumour suppression without affecting proliferation. These data demonstrate that stem cell quiescence is a form of tumour suppression in HFSCs, and that Pten plays a role in maintaining quiescence in the presence of tumorigenic stimuli.

Related: Signal Transduction Skin Cancer TP53 KRAS gene

Perets R, Wyant GA, Muto KW, et al.
Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models.
Cancer Cell. 2013; 24(6):751-65 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations.

Related: Fallopian Tube Cancer BRCA1 BRCA2 Ovarian Cancer

Kim Y, Hammerman PS, Kim J, et al.
Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients.
J Clin Oncol. 2014; 32(2):121-8 [PubMed] Related Publications
PURPOSE: Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients.
PATIENTS AND METHODS: We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.
RESULTS: This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC.
CONCLUSION: These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.

Related: Lung Cancer TP53 USA

Wong CC, Martincorena I, Rust AG, et al.
Inactivating CUX1 mutations promote tumorigenesis.
Nat Genet. 2014; 46(1):33-8 [PubMed] Article available free on PMC after 01/07/2014 Related Publications
A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.

Related: Cancer Prevention and Risk Reduction Signal Transduction CUX1

Piovan E, Yu J, Tosello V, et al.
Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia.
Cancer Cell. 2013; 24(6):766-76 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.

Related: AKT1

Zhang J, Zhang P, Wei Y, et al.
Deubiquitylation and stabilization of PTEN by USP13.
Nat Cell Biol. 2013; 15(12):1486-94 [PubMed] Related Publications
The tumour suppressor PTEN is frequently lost in human cancers. In addition to gene mutations and deletions, recent studies have revealed the importance of post-translational modifications, such as ubiquitylation, in the regulation of PTEN stability, activity and localization. However, the deubiquitylase that regulates PTEN polyubiquitylation and protein stability remains unknown. Here we screened a total of 30 deubiquitylating enzymes (DUBs) and identified five DUBs that physically associate with PTEN. One of them, USP13, stabilizes the PTEN protein through direct binding and deubiquitylation of PTEN. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage-independent growth, glycolysis and tumour growth through downregulation of PTEN. Conversely, overexpression of USP13 suppresses tumorigenesis and glycolysis in PTEN-positive but not PTEN-null breast cancer cells. Importantly, USP13 protein is downregulated in human breast tumours and correlates with PTEN protein levels. These findings identify USP13 as a tumour-suppressing protein that functions through deubiquitylation and stabilization of PTEN.

Related: Breast Cancer AKT1 Signal Transduction

Sellitto C, Li L, Gao J, et al.
AKT activation promotes PTEN hamartoma tumor syndrome-associated cataract development.
J Clin Invest. 2013; 123(12):5401-9 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
Mutations in the human phosphatase and tensin homolog (PTEN) gene cause PTEN hamartoma tumor syndrome (PHTS), which includes cataract development among its diverse clinical pathologies. Currently, it is not known whether cataract formation in PHTS patients is secondary to other systemic problems, or the result of the loss of a critical function of PTEN within the lens. We generated a mouse line with a lens-specific deletion of Pten (PTEN KO) and identified a regulatory function for PTEN in lens ion transport. Specific loss of PTEN in the lens resulted in cataract. PTEN KO lenses exhibited a progressive age-related increase in intracellular hydrostatic pressure, along with, increased intracellular sodium concentrations, and reduced Na+/K+-ATPase activity. Collectively, these defects lead to lens swelling, opacities and ultimately organ rupture. Activation of AKT was highly elevated in PTEN KO lenses compared to WT mice. Additionally, pharmacological inhibition of AKT restored normal Na+/K+-ATPase activity in primary cultured lens cells and reduced lens pressure in intact lenses from PTEN KO animals. These findings identify a direct role for PTEN in the regulation of lens ion transport through an AKT-dependent modulation of Na+/K+-ATPase activity, and provide a new animal model to investigate cataract development in PHTS patients.

Related: AKT1

Drake LE, Macleod KF
Tumour suppressor gene function in carcinoma-associated fibroblasts: from tumour cells via EMT and back again?
J Pathol. 2014; 232(3):283-8 [PubMed] Related Publications
Recent reports indicate that inactivation of the RB, TP53 or PTEN tumour suppressor genes is detected in tumour stroma of oropharyngeal, breast and other human cancers. Mouse models have validated the tumour-promoting effects of deleting Rb, Pten or p53 in fibroblasts that converts them from normal fibroblasts to carcinoma associated fibroblasts (CAFs). The tumour-promoting activity of CAFs in these contexts was associated with increased paracrine signaling to tumour cells through production of specific growth factors, chemokines and MMPs by CAFs. The conversion of NOFs into CAFs through acquisition of specific mutations, such as loss of tumour suppressors, or deregulated expression of microRNAs or key epigenetic events, can clearly occur independently of genetic and epigenetic changes in tumour cells but an alternative source of CAFs that is being reconsidered is that CAFs derive from the tumour cells by EMT. Recent mouse models employing lineage-tracing techniques have suggested that this can take place in vivo and the extent to which this is relevant more broadly is discussed.

Kaplan R, Maughan T, Crook A, et al.
Evaluating many treatments and biomarkers in oncology: a new design.
J Clin Oncol. 2013; 31(36):4562-8 [PubMed] Related Publications
There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.

Related: Colorectal (Bowel) Cancer Cancer Prevention and Risk Reduction

Li P, Mao WM, Zheng ZG, et al.
Down-regulation of PTEN expression modulated by dysregulated miR-21 contributes to the progression of esophageal cancer.
Dig Dis Sci. 2013; 58(12):3483-93 [PubMed] Related Publications
BACKGROUND AND AIM: miR-21, a putative tumor oncomiR, is a frequently overexpressed miRNA in a variety of tumors. Because it targets tumor-suppressor genes it has been linked to tumor progression. In this study we investigated the role of miR-21 in esophageal squamous cell carcinoma (ESCC), and its possible mechanism.
METHODS: Expression of miR-21 was detected by stem-loop RT-PCR in tissue from 76 invasive ESCC at stage I-IV and in their corresponding para-cancerous histological normal tissues (PCHNT). Thirty endoscopic esophageal mucosal biopsy specimens from non-tumor patients were used as controls. Expression of PTEN in 76 paired ESCC and PCHNT was investigated by real-time RT-PCR and an immunohistochemical method, respectively. Paired tumor and PCHNT specimens of 20 ESCC cases were randomly selected for western blot analysis. The effect of miR-21 on PTEN expression was assessed in the ESCC cell line with an miR-21 inhibitor to reduce miR-21 expression. Furthermore, the roles of miR-21 in cell biology were analyzed by use of miR-21 inhibitor-transfected cells.
RESULTS: Stem-loop RT-PCR revealed miR-21 was significantly overexpressed in ESCC tissues and cell lines. Overexpression of miR-21 correlated with tumor status, lymph node metastasis, and clinical stage. We demonstrated that knockdown of miR-21 significantly increased expression of PTEN protein. Consequent PTEN expression reduced cell proliferation, invasion, and migration.
CONCLUSIONS: Our findings suggest that miR-21 could be a potential oncomiR, probably by regulation of PTEN, and a novel prognostic factor for ESCC patients.

Related: Cancer of the Esophagus Esophageal Cancer miR-21

Marsh Durban V, Deuker MM, Bosenberg MW, et al.
Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma.
J Clin Invest. 2013; 123(12):5104-18 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase-dependent and -independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway-targeted inhibitors. These experiments revealed that mutationally activated PIK3CAH1047R cooperates with BRAFV600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAFV600E/PTENNull melanomas in vivo and in tissue culture. Combined inhibition of BRAFV600E and PI3K had more potent effects on the regression of established BRAFV600E/PTENNull melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAFV600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFV600E/PTENNull melanomas. These data indicate that PTEN silencing contributes a PI3K-dependent, but AKT-independent, function in melanomagenesis. Our findings enhance our knowledge of how BRAFV600E and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway-targeted inhibition of PI3K and BRAFV600E in the therapeutic management of BRAFV600E/PTENNull melanomas.

Related: Apoptosis Melanoma AKT1 Signal Transduction

Sun B, Meng J, Xiang T, et al.
Jianpijiedu fang improves survival of hepatocarcinoma mice by affecting phosphatase and tensin homolog, phosphoinositide 3-kinase, and focal adhesion kinase.
J Tradit Chin Med. 2013; 33(4):479-85 [PubMed] Related Publications
OBJECTIVE: To investigate the effect of Jianpijiedu Fang (JPJDF) on phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and focal adhesion kinase (FAK), and on the survival of hepatocellular carcinoma (HCC) nude mice.
METHODS: Forty male nude mice were randomly divided into 4 groups. Human HCC tissue was implanted in the livers of three groups. After 24 h, the three groups were treated respectively with JPJDF (37.5 g/kg), saline (20 mL/kg) and Tegafur (FT-207, 160 mg/kg) once a day for 10 weeks. The control group without implanting the tissue was concurrently treated with saline (20 mL/kg). The survival data and body weight of all mice were recorded, and expression levels of PTEN, PI3K and FAK in normal tissue and cancer tissue of the livers were evaluated with immunohistochemical method.
RESULTS: The cumulative survival rate of the mice in the JPJDF group was higher than those of the other groups. The rate of weight loss was the lowest in JPJDF group. The survivability and weight loss rate in FT-207 group were the poorest in all groups. The expression intensity of PTEN was higher in normal tissues than in cancer tissues, and lower in the normal tissues of HCC models than in that of mice without HCC. The PTEN expression intensity in normal tissue and cancer tissue from mice treated with FT-207 were lower than that from the mice treated with JPJDF or saline. The expression intensity of PI3K was higher in cancer tissue than in normal tissue. The PI3K expression intensity was the lowest in normal tissue and cancer tissue from mice treated with JPJDF, and the intensity from mice treated with FT-207 was the highest. In mice treated with JPJDF, the expression intensity of FAK was higher in the normal tissue and lower in the cancer tissue than those of the other treatment groups.
CONCLUSION: The mechanism accounting for the prolonged survival of HCC-bearing mice treated with JPJDF might be related to the reduction in weight loss and the benign regulation of PTEN, PI3K, and FAK.

Related: Liver Cancer

Shroff S, Overman MJ, Rashid A, et al.
The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy.
Arch Pathol Lab Med. 2013; 137(11):1619-26 [PubMed] Related Publications
CONTEXT: Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Somatic mutations of PTEN occur in many tumors including those of the gastrointestinal and hepatobiliary tracts. Loss of PTEN expression is associated with poor prognosis in patients with metastatic colonic adenocarcinoma, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, and pancreatic ductal adenocarcinoma.
OBJECTIVE: To study the expression of PTEN and its significance in ampullary adenocarcinoma (AA).
DESIGN: We constructed tissue microarrays by using archival tissue from 92 patients (55 males, 37 females; median age, 63 years; age range, 37 to 87 years) with previously untreated AA who underwent pancreaticoduodenectomy at our institution. PTEN expression was evaluated by immunohistochemistry, scored semiquantitatively (based on staining intensity and percentage positive tumor cells), and correlated with clinicopathologic features and survival.
RESULTS: Of 92 cases, 23 (25.0%) were PTEN negative. Loss of PTEN expression correlated with lymph node metastasis (P = .004), advanced American Joint Committee on Cancer (AJCC) stage (P = .02), and higher frequency of recurrence (P = .03). Patients with PTEN-negative tumors had shorter disease-free survival (DFS, mean: 89.0 ± 20.8 months) and overall survival (OS, mean: 93.1 ± 19.1 months) than those with PTEN-positive tumors (DFS, mean: 161.4 ± 11.7 months, P = .01; OS, mean: 175.4 ± 11.0 months, P = .001). In multivariate analyses, PTEN expression was a prognostic factor for both DFS and OS, independent of AJCC stage, lymph node status, pathologic tumor (pT) stage, and differentiation.
CONCLUSIONS: Loss of PTEN expression is associated with poor DFS and OS in patients with AA after curative surgery. PTEN expression may be used as a prognostic marker for patients with resected AA.

Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, et al.
Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.
J Clin Oncol. 2013; 31(34):4333-42 [PubMed] Related Publications
PURPOSE: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse.
PATIENTS AND METHODS: In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion).
RESULTS: N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001).
CONCLUSION: These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

Related: KRAS gene NOTCH1 gene NRAS gene FBXW7 gene

Metcalfe C, Alicke B, Crow A, et al.
PTEN loss mitigates the response of medulloblastoma to Hedgehog pathway inhibition.
Cancer Res. 2013; 73(23):7034-42 [PubMed] Related Publications
Medulloblastoma is a cancer of the cerebellum, for which there is currently no approved targeted therapy. Recent transcriptomics approaches have demonstrated that medulloblastoma is composed of molecularly distinct subgroups, one of which is characterized by activation of the Hedgehog pathway, which in mouse models is sufficient to drive medulloblastoma development. There is thus considerable interest in targeting the Hedgehog pathway for therapeutic benefit in medulloblastoma, particularly given the recent approval of the Hedgehog pathway inhibitor vismodegib for metastatic and locally advanced basal cell carcinoma. Like other molecularly targeted therapies, however, there have been reports of acquired resistance to vismodegib, driven by secondary Hedgehog pathway mutations and potentially by activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Given that acquired resistance to vismodegib may occur as a result of inappropriate PI3K pathway activation, we asked if loss of the PI3K pathway regulator, phosphatase and tensin homologue (Pten), which has been reported to occur in patients within the Hedgehog subgroup, would constitute a mechanism of innate resistance to vismodegib in Hedgehog-driven medulloblastoma. We find that Hedgehog pathway inhibition successfully restrains growth of Pten-deficient medulloblastoma in this mouse model, but does not drive tumor regression, as it does in Pten-wild-type medulloblastoma. Combined inhibition of the Hedgehog and PI3K pathways may lead to superior antitumor activity in PTEN-deficient medulloblastoma in the clinic.

Related: Childhood Medulloblastoma / PNET Signal Transduction

Chen X, Pan M, Han L, et al.
miR-338-3p suppresses neuroblastoma proliferation, invasion and migration through targeting PREX2a.
FEBS Lett. 2013; 587(22):3729-37 [PubMed] Related Publications
MicroRNAs (miRNA) can regulate cancer cell proliferation and metastasis. Here, we show that miR-338-3p is down-regulated in metastatic tumor tissues compared to primary tumors, and that that miR-338-3p can inhibit cell proliferation by inducing cell cycle arrest, as well as restrain cell migration and invasion. PREX2a is confirmed as a direct target of miR-338-3p. Knockdown of PREX2a inhibits cell proliferation, migration and invasion through the PTEN/Akt pathway. miR-338-3p-dependent inhibition of proliferation and invasion can be rescued by PREXa. Overall, this study demonstrates that miR-338-3p affects the PTEN/Akt pathway by down-regulating PREX2a. This newly identified function of miR-338-3p provides novel insights into neuroblastoma and may foster therapeutic applications.

Related: AKT1 Signal Transduction

Guo P, Nie Q, Lan J, et al.
C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells.
Biochem Biophys Res Commun. 2013; 441(1):186-90 [PubMed] Related Publications
The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc-miR-26a-PTEN signaling pathway. This may be of clinical relevance.

Related: AKT1 Signal Transduction

Pilarski R, Burt R, Kohlman W, et al.
Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.
J Natl Cancer Inst. 2013; 105(21):1607-16 [PubMed] Related Publications
BACKGROUND: PTEN hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders caused by mutations in the phosphatase and tensin homolog (PTEN) gene. Diagnostic criteria for Cowden syndrome, the principal PTEN-related disorder, were first established in 1996 before the identification of the PTEN gene and the ability to molecularly confirm a clinical diagnosis. These consortium criteria were based on clinical experience and case reports in the existing literature, with their inherent selection biases. Although it was initially reported that approximately 80% of patients with Cowden syndrome had an identifiable germline PTEN mutation, more recent work has shown these diagnostic criteria to be far less specific. In addition, increasing evidence has documented the association of a broader spectrum of clinical features with PTEN mutations. Our goal was to develop revised, evidence-based diagnostic criteria and to include features of the broader spectrum of PTEN-related clinical syndromes.
METHODS: We performed a systematic search and review of the medical literature related to clinical features reported in individuals with a PTEN mutation and/or a related clinical diagnosis.
RESULTS: We found no sufficient evidence to support inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as diagnostic criteria. There was evidence to include autism spectrum disorders, colon cancer, esophageal glycogenic acanthosis, penile macules, renal cell carcinoma, testicular lipomatosis, and vascular anomalies.
CONCLUSIONS: We propose revised, evidence-based criteria covering the spectrum of PTEN-related clinical disorders. Additional research on clinical features associated with PTEN mutations is warranted.

Related: Breast Cancer Gastrointestinal System Cancers Skin Cancer Thyroid Cancer

Liu D, Yang C, Bojdani E, et al.
Identification of RASAL1 as a major tumor suppressor gene in thyroid cancer.
J Natl Cancer Inst. 2013; 105(21):1617-27 [PubMed] Article available free on PMC after 06/11/2014 Related Publications
BACKGROUND: RAS-coupled MAPK and PI3K pathways play a fundamental role in thyroid tumorigenesis, and classical genetic alterations upregulating these pathways are well characterized. We hypothesized that gene abnormality of negative modulators of these signaling pathways might be an important alternative genetic background for thyroid cancer.
METHODS: By examining gene expression patterns of negative modulators of RAS signaling, we attempted to identify potential tumor suppressor genes. We then analyzed the methylation and mutation patterns of the identified gene in 101 thyroid tumors and tested its functions in vitro and in vivo to establish the tumor suppressor role in thyroid cancer.
RESULTS: Among 13 negative modulators of the RAS pathway screened, RASAL1, encoding a RAS GTPase-activating protein, was frequently hypermethylated in thyroid cancers, which was coupled to its silencing in thyroid cancer cells. We also, for the first time, identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in follicular thyroid cancer (FTC) and 16.67% (n = 5 of 30) in anaplastic thyroid cancer (ATC). RASAL1 displayed MAPK- and PI3K-suppressing and thyroid tumor-suppressing activities, which were all impaired by the mutations. Hypermethylation and mutations of RASAL1 were mutually exclusive and collectively found in zero of 20 benign thyroid tumors, 3.22% (n = 1 of 31) of papillary thyroid cancers, 31.70% (n = 13 of 41) of FTCs, and 33.33% (n = 10 of 30) of ATCs. A rate of 20.83% (n = 5 of 24) of tumors carrying RASAL1 mutation or methylation at high levels (>50%) vs 44.16% (n = 34 of 77) of tumors carrying no RASAL1 mutation or methylation at low levels (< 50%) harbored any of the classical mutations (two-sided P = .02, Fisher exact test) in RAS, BRAF, PTEN, and PIK3CA genes in the MAPK and PI3K pathways, revealing a largely mutually exclusive relationship.
CONCLUSIONS: We identified RASAL1 as a major tumor suppressor gene that is frequently inactivated by hypermethylation and mutations, providing a new alternative genetic background for thyroid cancer, particularly FTC and ATC.

Related: Signal Transduction Thyroid Cancer RASAL1

Haffner MC, Mosbruger T, Esopi DM, et al.
Tracking the clonal origin of lethal prostate cancer.
J Clin Invest. 2013; 123(11):4918-22 [PubMed] Article available free on PMC after 06/11/2014 Related Publications
Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.

Related: Prostate Cancer

Tesio M, Oser GM, Baccelli I, et al.
Pten loss in the bone marrow leads to G-CSF-mediated HSC mobilization.
J Exp Med. 2013; 210(11):2337-49 [PubMed] Article available free on PMC after 21/04/2014 Related Publications
The phosphatase and tumor suppressor PTEN inhibits the phosphoinositol-3-kinase (PI3K) signaling pathway and plays a key role in cell growth, proliferation, survival, and migration. Pten conditional deletion using MxCre or Scl-CreER(T) leads to splenomegaly and leukemia formation, which occurs after the relocation of normal hematopoietic stem cells (HSCs) from the bone marrow to the spleen. Unexpectedly, dormant HSCs in the bone marrow do not enter the cell cycle upon Pten loss, they do not lose self-renewal activity, and they are not exhausted. Instead, Pten deficiency causes an up-regulation of the PI3K pathway in myeloid cells, but not in HSCs. Strikingly, myeloid cells secrete high levels of G-CSF upon Pten loss, leading to the mobilization of HSCs from the bone marrow and accumulation in the spleen. After deletion of Pten in mice lacking G-CSF, the splenomegaly, myeloproliferative disease, and splenic HSC accumulation are rescued. Our data show that although PTEN has little if any role in normal HSCs, it is essential to prevent overt G-CSF production by myeloid and stromal cells which otherwise causes HSCs to relocate to the spleen followed by lethal leukemia initiation.

Related: Cytokines AKT1

Rosti RO, Sadek AA, Vaux KK, Gleeson JG
The genetic landscape of autism spectrum disorders.
Dev Med Child Neurol. 2014; 56(1):12-8 [PubMed] Related Publications
Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that show impaired communication and socialization, restricted interests, and stereotypical behavioral patterns. Recent advances in molecular medicine and high throughput screenings, such as array comparative genomic hybridization (CGH) and exome and whole genome sequencing, have revealed both novel insights and new questions about the nature of this spectrum of disorders. What has emerged is a better understanding about the genetic architecture of various genetic subtypes of ASD and correlations of genetic mutations with specific autism subtypes. Based on this new information, we outline a strategy for advancing diagnosis, prognosis, and counseling for patients and families.

Related: Chromosome 22 CGH

Shames DS, Wistuba II
The evolving genomic classification of lung cancer.
J Pathol. 2014; 232(2):121-33 [PubMed] Related Publications
EGFR gene mutations and ALK gene fusions are well-characterized molecular targets in NSCLC. Activating alterations in a variety of potential oncogenic driver genes have also been identified in NSCLC, including ROS1, RET, MET, HER2, and BRAF. Together with EGFR and ALK, these mutations account for ∼20% of NSCLCs. The identification of these oncogenic drivers has led to the design of rationally targeted therapies that have produced superior clinical outcomes in tumours harbouring these mutations. Many patients, however, have de novo or acquired resistance to these therapies. In addition, most NSCLCs are genetically complex tumours harbouring multiple potential activating events. For these patients, disease subsets are likely to be defined by combination strategies involving a number of targeted agents. These targets include FGFR1, PTEN, MET, MEK, PD-1/PD-L1, and NaPi2b. In light of the myriad new biomarkers and targeted agents, multiplex testing strategies will be invaluable in identifying the appropriate patients for each therapy and enabling targeted agents to be channelled to the patients most likely to gain benefit. The challenge now is how best to interpret the results of these genomic tests, in the context of other clinical data, to optimize treatment choices in NSCLC.

Related: Lung Cancer

Song Y, Zhang Q, Kutlu B, et al.
Evolutionary etiology of high-grade astrocytomas.
Proc Natl Acad Sci U S A. 2013; 110(44):17933-8 [PubMed] Article available free on PMC after 21/04/2014 Related Publications
Glioblastoma (GBM), the most common brain malignancy, remains fatal with no effective treatment. Analyses of common aberrations in GBM suggest major regulatory pathways associated with disease etiology. However, 90% of GBMs are diagnosed at an advanced stage (primary GBMs), providing no access to early disease stages for assessing disease progression events. As such, both understanding of disease mechanisms and the development of biomarkers and therapeutics for effective disease management are limited. Here, we describe an adult-inducible astrocyte-specific system in genetically engineered mice that queries causation in disease evolution of regulatory networks perturbed in human GBM. Events yielding disease, both engineered and spontaneous, indicate ordered grade-specific perturbations that yield high-grade astrocytomas (anaplastic astrocytomas and GBMs). Impaired retinoblastoma protein RB tumor suppression yields grade II histopathology. Additional activation of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) network drives progression to grade III disease, and further inactivation of phosphatase and tensin homolog (PTEN) yields GBM. Spontaneous missense mutation of tumor suppressor Trp53 arises subsequent to KRAS activation, but before grade III progression. The stochastic appearance of mutations identical to those observed in humans, particularly the same spectrum of p53 amino acid changes, supports the validity of engineered lesions and the ensuing interpretations of etiology. Absence of isocitrate dehydrogenase 1 (IDH1) mutation, asymptomatic low grade disease, and rapid emergence of GBM combined with a mesenchymal transcriptome signature reflect characteristics of primary GBM and provide insight into causal relationships.

Related: TP53

Vizeacoumar FJ, Arnold R, Vizeacoumar FS, et al.
A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities.
Mol Syst Biol. 2013; 9:696 [PubMed] Article available free on PMC after 21/04/2014 Related Publications
Improved efforts are necessary to define the functional product of cancer mutations currently being revealed through large-scale sequencing efforts. Using genome-scale pooled shRNA screening technology, we mapped negative genetic interactions across a set of isogenic cancer cell lines and confirmed hundreds of these interactions in orthogonal co-culture competition assays to generate a high-confidence genetic interaction network of differentially essential or differential essentiality (DiE) genes. The network uncovered examples of conserved genetic interactions, densely connected functional modules derived from comparative genomics with model systems data, functions for uncharacterized genes in the human genome and targetable vulnerabilities. Finally, we demonstrate a general applicability of DiE gene signatures in determining genetic dependencies of other non-isogenic cancer cell lines. For example, the PTEN(-/-) DiE genes reveal a signature that can preferentially classify PTEN-dependent genotypes across a series of non-isogenic cell lines derived from the breast, pancreas and ovarian cancers. Our reference network suggests that many cancer vulnerabilities remain to be discovered through systematic derivation of a network of differentially essential genes in an isogenic cancer cell model.

Related: Breast Cancer Ovarian Cancer Cancer of the Pancreas Pancreatic Cancer

Li Y, Li L, Guan Y, et al.
MiR-92b regulates the cell growth, cisplatin chemosensitivity of A549 non small cell lung cancer cell line and target PTEN.
Biochem Biophys Res Commun. 2013; 440(4):604-10 [PubMed] Related Publications
MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance of human cancer. Fewer studies were explored the roles of miR-92b on human lung cancer cell growth and resistance to cisplatin (CDDP). In this paper, we utilized real-time PCR to verify miR-92b was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues compared to matched adjacent normal tissues. In vitro assay demonstrated that knock-down of miR-92b inhabits cell growth and sensitized the A549/CDDP cells to CDDP. Furthermore, we found miR-92b could directly target PTEN, a unique tumor suppressor gene, which was downregulated in lung cancer tissues compared to the matched adjacent normal tissues. These data indicate that the miR-92b play an oncogene roles by regulates cell growth, cisplatin chemosensitivity phenotype, and could serve as a novel potential maker for NSCLC therapy.

Related: Apoptosis Non-Small Cell Lung Cancer Cisplatin Lung Cancer

Shukla S, Pia Patric IR, Thinagararjan S, et al.
A DNA methylation prognostic signature of glioblastoma: identification of NPTX2-PTEN-NF-κB nexus.
Cancer Res. 2013; 73(22):6563-73 [PubMed] Related Publications
Glioblastoma (GBM) is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n = 44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in GBM patients. A risk-score derived from methylation signature predicted survival in univariate analysis in our and The Cancer Genome Atlas (TCGA) cohort. Multivariate analysis identified methylation risk score as an independent survival predictor in TCGA cohort. Methylation risk score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NF-κB pathway association with high-risk group. NF-κB inhibition reversed glioma chemoresistance, and RNA interference studies identified interleukin-6 and intercellular adhesion molecule-1 as key NF-κB targets in imparting chemoresistance. Promoter hypermethylation of neuronal pentraxin II (NPTX2), a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts, which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth, and rendered glioma cells chemosensitive. Furthermore, NPTX2 repressed NF-κB activity by inhibiting AKT through a p53-PTEN-dependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NF-κB-activated high-risk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Prosurvival NF-κB pathway activation characterized high-risk patients with poor prognosis, indicating it to be a therapeutic target.

Related: Signal Transduction


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