• STAT3
• anticancer
• chemotherapy.
• herbal medicine
• ischemic heart disease
• natural medicine

• Humans
• STAT3 Transcription Factor/antagonists & inhibitors
• STAT3 Transcription Factor/metabolism
• Neoplasms/drug therapy
• Animals
• Signal Transduction/drug effects
• Biological Products/therapeutic use
• Biological Products/pharmacology
• Patents as Topic
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology

• Biodegradable vascular scaffold
• Cardiovascular disease
• Everolimus
• Inflammation
• Magnesium hydroxide
• Re-endothelialization
• Restenosis

• Carcinogenesis
• Gastric Cancer
• IARC Classification
• Signaling Pathways
• Targeted Therapy

• Animals
• Humans
• Stomach Neoplasms/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• NF-kappa B/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Reactive Oxygen Species/metabolism
• Carcinogens
• Cell Transformation, Neoplastic/pathology
• Transforming Growth Factor beta

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mechanistic target of rapamycin complex 1 activity but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient.

• S-adenosylmethionine
• mTORC1
• methionine adenosyltransferase 2A
• methylation
• ribosome
• translation
• translation factor

• BKM120
• C-Myc
• Chronic myeloid leukemia
• Imatinib
• NF-κB
• PI3K Inhibition

• Gastric cancer
• PI3K/Akt/mTOR pathway
• PTEN
• Phosphatidylinositol-3-kinase

• Akt
• CPA4
• Cardiac hypertrophy
• PI3K
• mTOR

• 3-Phosphoinositide-Dependent Protein Kinases/metabolism
• Animals
• Carboxypeptidases A/metabolism
• Cardiomegaly/chemically induced
• Cardiomegaly/enzymology
• Cardiomegaly/genetics
• Cardiomegaly/pathology
• Case-Control Studies
• Cell Size
• Cells, Cultured
• Disease Models, Animal
• Humans
• Isoproterenol
• Male
• Mice, Inbred C57BL
• Myocytes, Cardiac/enzymology
• Myocytes, Cardiac/pathology
• Phosphatidylinositol 3-Kinase/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Rats, Sprague-Dawley
• Signal Transduction
• TOR Serine-Threonine Kinases/metabolism
• Up-Regulation

• AZ628
• BP-1-102
• RAF
• STAT3
• lung cancer harboring KRAS mutations

• Apoptosis
• Cancer
• Cycloastragenol
• Paclitaxel
• STAT3

• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Janus Kinase 1
• Janus Kinase 2/metabolism
• Paclitaxel/administration & dosage
• Paclitaxel/pharmacology
• Phosphorylation/drug effects
• Phytotherapy
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism
• Sapogenins/administration & dosage
• Sapogenins/pharmacology
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop original mouse models of patient-derived primary GC orthotopic xenografts (PDOX) allowing the development of distant metastases as preclinical models to study the anti-metastatic efficiency of drugs such as the phosphatidylinositol 3-kinase (PI3K) inhibitor Buparlisib (BKM120). Luciferase-encoding cells generated from primary GC were injected into the stomach wall of immunocompromised mice; gastric tumor and metastases development were followed by bioluminescence imaging. The anti-CSC properties of BKM120 were evaluated on the GC cells’ phenotype (CD44 expression) and tumorigenic properties in vitro and in vivo on BKM120-treated mice. After eight weeks, PDOX mice formed tumors in the stomach as well as distant metastases, that were enriched in CSC, in the liver, the lung, and the peritoneal cavity. BKM120 treatment significantly inhibited the CSC properties in vitro and reduced the number of distant metastases in mice. These new preclinical models offer the opportunity to study the anti-metastatic efficiency of new CSC-based therapeutic strategies.

• BKM120
• CD44
• CSC
• PDOX
• PI3K
• dissemination
• gastric carcinoma
• metastases
• tumorsphere

• Clinical trials
• Gastrointestinal cancer
• PI3K pharmacological inhibitors

Gastric cancer is the third leading cause of cancer-associated deaths worldwide. Research into the underlying mechanisms of gastric cancer is essential for the development of novel therapeutic agents to improve the prognoses of patients with gastric cancer. Tanshinone IIA (Tan IIA) is the pure extract of Danshen root (Salvia miltiorrhiza) and has been report to inhibit the proliferation of gastric cancer cells; however, the intrinsic underlying mechanisms remain unclear. The aim of the present study was to investigate whether Tan IIA has a direct anti-cancer effect in gastric cancer cells and determine the underlying mechanisms responsible. The results revealed that Tan IIA effectively inhibits proliferation in three human gastric cancer cell lines (SNU-638, MKN1 and AGS) in a time- and dose-dependent manner. Furthermore, Tan IIA treatment induced an increase in apoptosis, B-cell lymphoma (Bcl-2)-associated protein X expression and cleaved caspase-3 levels, as well as a decrease in Bcl-2 expression. Treatment with Tan IIA inhibited Furthermore, treatment with Tan IIA significantly inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which may be responsible for the changes in apoptosis gene expression. However, overexpression of STAT3 significantly ameliorated the Tan IIA-induced suppression of cell growth and apoptosis. A nude mouse xenograft model was constructed and the results revealed that intraperitoneal Tan IIA treatment for 28 days significantly inhibited tumor growth and STAT3 activation. The results of the present study suggest that Tan IIA exerts potent anti-cancer activity in gastric cancer cells and this effect is mediated by the downregulation of STAT3 activation.

• Tanshinone IIA
• gastric cancer
• signal transducer and activator of transcription 3

• NVP-BKM120
• Opisthorchis viverrini
• cholangiocarcinoma
• phosphatidylinositol 3-kinase pathway

We generated myeloid specific sphingosine-1-phosphate receptor 1 (S1pr1) deficient mice by crossing mice that had myeloid specific expression of Cre recombinase (lyzM^Cre) with mice having the S1pr1 gene flanked by loxP recombination sites. We transplanted bone marrow from these mice and control lyzM^Cre mice with intact macrophage S1pr1 gene expression into low-density lipoprotein (LDL) receptor gene (Ldlr) deficient mice. The resulting chimeras were fed a high fat atherogenic diet for nine or twelve weeks and evaluated for atherosclerosis development in the aortic sinus. Selective S1pr1 deficiency in bone marrow-derived myeloid cells resulted in accelerated development of atherosclerosis, necrotic core formation and the appearance of apoptotic cells within atherosclerotic plaques of Ldlr knockout mice in response to a high fat diet. Examination of macrophages in culture revealed that the sphingosine-1-phosphate receptor 1 selective agonist, SEW2871 or high density lipoprotein (HDL), protected macrophages against apoptosis induced by endoplasmic reticulum (ER) stress or oxidized LDL, through activation of phosphatidylinositol-3-kinase/Akt signaling. Targeted S1pr1-deletion prevented Akt activation and protection against apoptosis by either SEW2871 or HDL. Our data suggests that sphingosine-1-phosphate receptor 1 in macrophages plays an important role in protecting them against apoptosis in vitro and in atherosclerotic plaques in vivo, and delays diet induced atherosclerosis development in Ldlr deficient mice.

• HDL
• apoptosis
• atherosclerosis
• macrophage
• mouse model
• sphingosine-1-phosphate receptor 1

• Animals
• Apoptosis/genetics
• Atherosclerosis/genetics
• Atherosclerosis/metabolism
• Atherosclerosis/pathology
• Atherosclerosis/therapy
• Diet, High-Fat/adverse effects
• Endoplasmic Reticulum Stress/drug effects
• Endoplasmic Reticulum Stress/genetics
• Humans
• Lipoproteins, HDL/metabolism
• Lipoproteins, LDL/genetics
• Lipoproteins, LDL/metabolism
• Macrophages/metabolism
• Macrophages/pathology
• Mice
• Mice, Knockout
• Myeloid Cells/drug effects
• Myeloid Cells/metabolism
• Myeloid Cells/pathology
• Oxadiazoles/administration & dosage
• Proto-Oncogene Proteins c-akt/genetics
• Receptors, LDL/genetics
• Receptors, Lysosphingolipid/genetics
• Signal Transduction/genetics
• Sphingosine-1-Phosphate Receptors
• Thiophenes/administration & dosage

• gastric cancer
• germline mutation
• molecular subtyping
• somatic mutaiton
• targeted sequencing

BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.

Buparlisib/BKM120 is in phase 3 clinical trials as a phosphoinositide 3-kinase (PI3K) inhibitor. Here, Bohnacker et al. combine chemical biology and structural biology approaches to segregate BKM120's biological actions, and suggest that it causes mitotic arrest predominantly by binding microtubules and disrupting their dynamics.

• GIST
• HDAC
• HSP90
• MAPK
• PI3K
• accessory pathway
• tyrosine kinase inhibitors

• ERK pathway
• Ras
• ST2/IL1RL1
• STAT3
• promoter

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent.

Metastatic colorectal cancer (CRC) patients with v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to monoclonal antibody that targets the epidermal growth factor receptor such as cetuximab. BKM120 targets phosphatidylinositide‐3‐kinase (PIK3CA), but it is unknown whether BKM120 can reverse cetuximab resistance in KRAS mutant CRC. Human CRC cell lines with KRAS mutations (DLD‐1, HCT116, and LoVo) were used to test the effect of cetuximab, BKM120, and cetuximab plus BKM120 on cell proliferation in vitro and in vivo. BKM120 reduced cell proliferation in a concentration‐dependent manner in the LoVo (PI3KCA wild type) as well as the HCT116 and DLD1 cells (that carry a PI3KCA mutation). BKM120 only inhibited ERK phosphorylation in LoVo cells (PIK3CA wild type), but not in DLD1 or HCT116 cells at a concentration of 1 μmol/L. Treatment with cetuximab and BKM120 significantly reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone (P = 0.034). BKM120 may overcome cetuximab resistance in colon cancer cells with KRAS mutation.

• BKM120
• KRAS
• PIK3CA
• colon cancer
• combination therapy

Frequent activation of phosphatidylinositol-3 kinases (PI3K)/Akt/mTOR signaling pathway in gastric cancer (GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3CA gene or loss of function of PTEN, a tumor suppressor protein, to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis, hence, there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development, further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein, we review the common dysregulation of PI3K/Akt/mTOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/mTOR pathway inhibition.

• Epidemiology
• Gastric cancer
• PI3K/Akt/mTOR pathway
• Predictive biomarkers
• Targeted therapy

• Animals
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma/drug therapy
• Carcinoma/enzymology
• Carcinoma/genetics
• Carcinoma/pathology
• Drug Discovery/methods
• Humans
• Molecular Targeted Therapy
• Phosphatidylinositol 3-Kinase/genetics
• Phosphatidylinositol 3-Kinase/metabolism
• Phosphoinositide-3 Kinase Inhibitors
• Precision Medicine
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-akt/antagonists & inhibitors
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/enzymology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/metabolism
• Treatment Outcome

• JAK2
• Methylation
• SHP1
• STAT3

The pharmacokinetics (PK) and safety of single‐dose buparlisib (30 mg) were assessed in subjects with mild to severe hepatic impairment (n = 6 each) relative to healthy controls (n = 13). Blood samples were collected until 336 hours postdose and evaluated by liquid chromatography tandem mass spectrometry. PK parameters (including area under the curve [AUC_∞] and C_max) were derived using noncompartmental analysis. Buparlisib was rapidly absorbed in all groups (median T_max 1.0–1.3 h). Buparlisib exposure (AUC_∞) was moderately increased in subjects with mild (geometric mean ratio [GMR] 1.16; 90%CI 0.81, 1.65), moderate (GMR 1.14; 90%CI 0.80, 1.63), or severe (GMR 1.20; 90%CI 0.84, 1.72) hepatic impairment, relative to healthy controls. Apparent oral clearance was similar across groups. Due to a higher unbound fraction in the severe group (0.21) than all other groups (0.17), subjects with severe hepatic impairment had greater exposure to unbound buparlisib (GMR relative to healthy controls: AUC_∞ 1.52; 90%CI 1.09, 2.13; C_max 1.83; 90%CI 1.42, 2.36). The results indicate that a buparlisib dose adjustment may not be necessary for patients with mild to moderate hepatic impairment. The safety and therapeutic indices should be considered before determining if a dose adjustment is appropriate for patients with severe hepatic impairment.

• PI3K inhibitor
• buparlisib
• hepatic impairment
• pharmacokinetics

Tumor control of hepatocellular carcinoma by radiotherapy remains unsatisfactory. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a critical role in inhibiting cancer cell death. Elevated PI3K/Akt activity is associated with increased cellular resistance to irradiation. Our aim was to determine whether the inhibition of PI3K/Akt activity by a PI3K inhibitor, BKM120, contributes to the increased sensitivity of liver cancer cells to irradiation. The hepatocellular carcinoma cell lines (Huh7 and BNL) were used to evaluate the in vitro synergism between BKM120 and irradiation. Balb/c mice bearing ectopic BNL xenografts were treated with BKM120 and/or radiotherapy to assess the in vivo response. BKM120 increased cell killing by radiation, increased the expression of apoptotic markers, and suppressed the repair of radiation-induced DNA double-strand breaks. BKM120 pretreatment inhibited radiation-induced Akt phosphorylation and enhanced the tumor-suppressive effect and radiation-induced tumor cell apoptosis in ectopic xenografts. Inhibition of mTOR phosphorylation by rapamycin enhanced the radiosensitivity of BKM120-treated hepatocellular carcinoma cells. The synergism between BKM120 and irradiation likely inhibits the activation of Akt by radiation, leading to increased cell apoptosis and suppression of DNA-double-strand breaks repair in hepatocellular carcinoma cells. These data suggest that the BKM120/radiation combination may be a strategy worthy of clinical trials.

• HDAC
• Histone deacetylase inhibitor
• Psammaplin A
• Structure–activity relationship

• Cell apoptosis
• H9C2 cardiomyocytes
• Hypoxia–reoxygenation
• Ischemia–reperfusion
• MicroRNA-30b
• Ras–PI3K–Akt

Pancreatic cancer is the only major cancer with very low survival rates (1%). It is the fourth leading cause of cancer-related death. Hyperactivated growth hormone receptor (GHR) levels have been shown to increase the risk of cancer in general and this pathway is a master regulator of key cellular functions like proliferation, apoptosis, differentiation, metastasis, etc. However, to date there is no available data on how GHR promotes pancreatic cancer pathogenesis. Here, we used an RNA interference approach targeted to GHR to determine whether targeting GHR is an effective method for controlling pancreatic cancer growth and metastasis. For this, we used an in vitro model system consisting of HPAC and PANC-1 pancreatic cancer cells lines. GHR is upregulated in both of these cell lines and silencing GHR significantly reduced cell proliferation and viability. Inhibition of GHR also reduced the metastatic potential of pancreatic cancer cells, which was aided through decreased colony-forming ability and reduced invasiveness. Flow cytometric and western blot analyses revealed the induction of apoptosis in GHR silenced cells. GHR silencing affected phosphatidylinositol 3 kinase/AKT, mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase, Janus kinase/signal transducers and activators of transcription and mammalian target of rapamycin signaling, as well as, epithelial to mesenchymal transition. Interestingly, silencing GHR also suppressed the expression of insulin receptor-β and cyclo-oxygenease-2. Altogether, GHR silencing controls the growth and metastasis of pancreatic cancer and reveals its importance in pancreatic cancer pathogenesis.

• cip2a
• pp2a
• c-myc
• cancers
• prognosis
• biomarkers

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Apoptosis/genetics
• Autoantigens/genetics
• Autoantigens/metabolism
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Models, Genetic
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Binding
• Protein Phosphatase 2/antagonists & inhibitors
• Protein Phosphatase 2/genetics
• Protein Phosphatase 2/metabolism

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key signaling pathways induced by various receptor-tyrosine kinases. Accumulating evidence shows that this pathway is an important promoter of cell growth, metabolism, survival, metastasis, and resistance to chemotherapy. Genetic alterations in the PI3K/Akt/mTOR pathway in gastric carcinoma have often been demonstrated. Many kinds of molecular targeting therapies are currently undergoing clinical testing in patients with solid tumors. However, with the exception of the ErbB2-targeting antibody, targeting agents, including PI3K/Akt/mTOR inhibitors, have not been approved for treatment of patients with gastric carcinoma. This review summarizes the current knowledge on PI3K/Akt/mTOR signaling in the pathogenesis of gastric carcinoma and the possible therapeutic targets for gastric carcinoma. Improved knowledge of the PI3K/Akt/mTOR pathway in gastric carcinoma will be useful in understanding the mechanisms of tumor development and for identifying ideal targets of anticancer therapy for gastric carcinoma.

Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.

• BKM120
• Japanese patients
• buparlisib

The discovery of microRNAs (miRNAs) provides a new and powerful tool for studying the mechanism, diagnosis and treatment of human cancers. Currently, the methylation epigenetic silencing of miRNAs with tumor suppressor features by CpG island hypermethylation is emerging as a common hallmark of different tumors. Here we showed that miR-433 and miR-127 were significantly down-regulated in gastric cancer (GC) tissues compared with the adjacent normal regions in 86 paired samples. Moreover, the lower level of miR-433 and miR-127 was associated with pM or pTNM stage in clinical gastric cancer patients. The restored expression of miR-433 and miR-127 in GC cells upon 5-Aza-CdR and TSA treatment suggested the loss of miR-433 and miR-127 was at least partly regulated by epigenetic modification in GC. Furthermore, the ectopic expression of miR-433 and miR-127 in gastric cancer cell lines HGC-27 inhibits cell proliferation, cell cycle progression, cell migration and invasion by directly interacting with the mRNA encoding oncogenic factors KRAS and MAPK4 respectively. Taken together, our results showed that miR-433 and miR-127 might act as tumor suppressors in GC, and it may provide novel diagnostic and therapeutic options for human GC clinical operation in the near future.

• Akt
• Cancer Biology
• Cancer Therapy
• DNA-PK
• PP2A
• Rapamycin
• mTOR

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism
• Animals
• Antibiotics, Antineoplastic/pharmacology
• Cell Line, Tumor
• Cell Nucleus/drug effects
• Cell Nucleus/enzymology
• Cell Proliferation/drug effects
• Chromones/pharmacology
• Cytoplasm/drug effects
• Cytoplasm/enzymology
• DNA-Activated Protein Kinase/antagonists & inhibitors
• DNA-Activated Protein Kinase/metabolism
• Drug Synergism
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Nude
• Morpholines/pharmacology
• Multiprotein Complexes
• Okadaic Acid/pharmacology
• Phosphorylation
• Protein Phosphatase 2/antagonists & inhibitors
• Protein Phosphatase 2/metabolism
• Protein Processing, Post-Translational/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• RNA, Small Interfering/genetics
• Regulatory-Associated Protein of mTOR
• Sirolimus/pharmacology
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/metabolism
• Xenograft Model Antitumor Assays

• K23 CA164015 NCI NIH HHS
• P01 CA116676 NCI NIH HHS
• R01 CA118450 NCI NIH HHS
• R01 CA160522 NCI NIH HHS