• branched polymers
• drug delivery
• enzyme-responsive nanomedicine
• gastric cancer
• synergistic therapy

• Humans
• Angiogenesis Inhibitors
• Cathepsin B
• Cell Line, Tumor
• Paclitaxel
• Phosphatidylinositol 3-Kinases
• Polymers
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-akt
• Stomach Neoplasms/drug therapy

• 2023NSFSC1592 Sichuan Province Science and Technology Support Program
• ZYJC21006 West China Hospital, Sichuan University
• ZYJC21013 Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System
• 32271445 National Natural Science Foundation of China
• 52073193 National Natural Science Foundation of China
• 82072688 National Natural Science Foundation of China
• 82202322 National Natural Science Foundation of China
• Sichuan Province Science and Technology Support Program
• West China Hospital, Sichuan University
• Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System
• National Natural Science Foundation of China

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in multiple cellular processes, including cell survival, proliferation, differentiation, metabolism and cytoskeletal reorganisation. The downstream effectors of this PI3K pathway are also essential for maintaining physiologic homeostasis, commonly dysregulated in most solid tumours. AKT is the key regulator in PI3K/AKT/mTOR signalling, interacting with multiple intracellular molecules. AKT activation subsequently leads to a number of potential downstream effects, and its aberrant activation results in the pathogenesis of cancer. Accordingly, as an attractive therapeutic target for cancer treatment, several AKT inhibitors are currently under development and in multiple stages of clinical trials for various types of malignancy, including gastric cancer (GC). Therefore, the authors review the significance of AKT and recent studies on AKT inhibitors in GC, focusing on the scientific background with the potential to improve treatment outcomes.

• AKT
• gastric cancer

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

• Biomarker
• Epstein-Barr virus
• Gastric cancer
• HER2
• Prognosis

The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for hereditary diffuse gastric cancer syndrome (HDGC). Using cell viability assays, we identified that breast (MCF10A) and gastric (NCI-N87) cells lacking CDH1 expression are more sensitive to allosteric AKT inhibitors than their CDH1-expressing isogenic counterparts. Apoptosis priming and total apoptosis assays in the isogenic MCF10A cells confirmed the enhanced sensitivity of E-cadherin-null cells to the AKT inhibitors. In addition, two of these inhibitors, ARQ-092 and MK2206, preferentially targeted mouse-derived gastric Cdh1^−/− organoids for growth arrest. AKT protein expression and activation (as measured by phosphorylation of serine 473) were differentially regulated in E-cadherin-null MCF10A and NCI-N87 cells, with downregulation in the normal breast cells, but upregulation in the gastric cancer cells. Bioinformatic analysis of the TCGA STAD dataset revealed that AKT3, but not AKT1 or AKT2, is upregulated in the majority of E-cadherin-deficient gastric cancers. In conclusion, allosteric AKT inhibitors represent a promising class of drugs for chemoprevention and chemotherapy of cancers with E-cadherin loss.

• AKT
• E-cadherin
• chemoprevention
• diffuse gastric cancer
• synthetic lethality

• Aged
• Animals
• Apoptosis/drug effects
• Cell Movement
• Cell Proliferation
• Disease Progression
• Disulfides/pharmacology
• Female
• Humans
• Imidazoles/pharmacology
• Lentivirus/metabolism
• Male
• Mice, Nude
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Metastasis
• PTEN Phosphohydrolase/metabolism
• Prognosis
• Proportional Hazards Models
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Thioredoxins/metabolism
• Up-Regulation/drug effects

Improvements in survival rates for pancreatic cancer have been slow and the morality rate continues to increase in patients. MicroRNA (miR)-448 is reported to be significantly downregulated in several types of cancer. In this study, Rab2B is target of miR-488 was confirmed by bioinformatics analysis and validated using a luciferase reporter assay. A total of 72 cases of pancreatic cancer in patients diagnosed at The First Affiliated Hospital, School of Medicine, Zhejiang University (Hangzhou, China) were enrolled, and cancer specimens and their adjacent normal tissues were collected for analysis. The expression levels of miR-448 and Rab2B in these tissues and in pancreatic cancer cell lines were quantified using reverse transcription-polymerase chain reaction analysis. miR-448 overexpression was achieved by cell transfection. Protein expression was assessed using western blot analysis. Cell viability, cell cycle and apoptosis were analyzed using CCK-8 assay and flow cytometry, respectively. The results revealed a negative correlation between miR-448 and Rab2B in the pancreatic tissues and cell lines. The results of bioinformatics analysis indicated that miR-448 directly targeted Rab2B. Aberrant miR-448 levels in PANC-1 cells downregulated the expression of Rab2B, and significantly decreased cell proliferation and promoted apoptosis of cancer cells. It was also found that miR-448 mimics resulted in G₀/G₁ cell cycle arrest and affected the expression of cell cycle regulators, including cyclin D1, p21 and p27. In addition, the miR-448 mimics led to inactivation of the Akt/Mammalian target of rapamycin signaling pathway. The miR-448 mimics induced apoptosis and activated the expression of caspase-3, caspase-9 and poly(ADP-ribose) polymerase. The results suggested that miR-448 was a negative regulator of Rab2B and promoted cell cycle arrest and apoptosis in pancreatic cancer.

• EBV infection
• gastric cancer
• gene expression profile
• gene mutation
• miRNA
• microsatellite
• molecular gastric cancer subtype
• preclinical models

• Animals
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Microsatellite Instability
• Mutation
• Signal Transduction
• Stomach Neoplasms/classification
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Transcriptome

• gastric cancer
• meta-analysis
• p-Akt
• prognosis
• survival

Gastric carcinoma is one of the most common malignancies in men, and microRNA plays a critical role in regulating the signaling networks of gastric carcinoma tumorigenesis and metastasis. We first report the functional characteristics of miR-221-3p in gastric carcinoma. Quantification in gastric carcinoma cell lines and tumor samples reveals significantly increasing miR-221-3p expression. Moreover, a high level of miR-221-3p is correlated with a poor prognosis for gastric carcinoma patients. Ectopic miR-221-3p expression significantly promotes gastric carcinoma cell proliferation, invasion, and sphere formation, while silencing miR-221-3p significantly inhibits these abilities in gastric carcinoma cells. Tests in vivo showed that miR-221-3p significantly promotes tumor growth in xenograft mouse models. In this study, we reveal that miR-221-3p targets PTEN mRNA and downregulates PTEN, which is the possible mechanism of miR-221-3p-induced oncogenic properties. Collectively, we reveal a critical role for miR-221-3p in gastric carcinoma development and progression.

• Akt
• HOXB7
• PTEN
• stomach cancer

Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance.

• Drug resistance
• Gastric cancer
• Chemotherapy

• Akt pathway
• MK-2206
• apoptosis
• caspase
• chemotherapy
• gastric cancer

Gastric cancer (GC) is the third leading cause of cancer mortality worldwide. Although surgical resection is a potentially curative approach for localized cases of GC, most cases of GC are diagnosed in an advanced, non-curable stage and the response to traditional chemotherapy is limited. Fortunately, recent advances in our understanding of the molecular mechanisms that mediate GC hold great promise for the development of more effective treatment strategies. In this review, an overview of the morphological classification, current treatment approaches, and molecular alterations that have been characterized for GC are provided. In particular, the most recent molecular classification of GC and alterations identified in relevant signaling pathways, including ErbB, VEGF, PI3K/AKT/mTOR, and HGF/MET signaling pathways, are described, as well as inhibitors of these pathways. An overview of the completed and active clinical trials related to these signaling pathways are also summarized. Finally, insights regarding emerging stem cell pathways are described, and may provide additional novel markers for the development of therapeutic agents against GC. The development of more effective agents and the identification of biomarkers that can be used for the diagnosis, prognosis, and individualized therapy for GC patients, have the potential to improve the efficacy, safety, and cost-effectiveness for GC treatments.

• cancer stem cells
• chemotherapy
• gastric cancer
• molecular classification
• signaling pathway

• Gastric mucosa
• Imaging mass spectrometry
• Phosphatidylcholine
• Sphingomyelin
• iMScope

• AGS, MKN28 and MKN45 cell lines
• Gastric cancer
• PI3K/AKT/mTOR pathway

• cancer biomarker detection
• phosphoprotein preservation
• preanalytical tissue processing
• time of flight
• ultrasound imaging

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

Helicobacter pylori (H. pylori) infection is strongly associated with the development of gastric diseases but also with several extragastric diseases. The clinical outcomes caused by H. pylori infection are considered to be associated with a complex combination of host susceptibility, environmental factors and bacterial isolates. Infections involving H. pylori strains that possess the virulence factor CagA have a worse clinical outcome than those involving CagA-negative strains. It is remarkable that CagA-positive H. pylori increase the risk for gastric cancer over the risk associated with H. pylori infection alone. CagA behaves as a bacterial oncoprotein playing a key role in H. pylori-induced gastric cancer. Activation of oncogenic signaling pathways and inactivation of tumor suppressor pathways are two crucial events in the development of gastric cancer. CagA shows the ability to affect the expression or function of vital protein in oncogenic or tumor suppressor signaling pathways via several molecular mechanisms, such as direct binding or interaction, phosphorylation of vital signaling proteins and methylation of tumor suppressor genes. As a result, CagA continuously dysregulates of these signaling pathways and promotes tumorigenesis. Recent research has enriched our understanding of how CagA effects on these signaling pathways. This review summarizes the results of the most relevant studies, discusses the complex molecular mechanism involved and attempts to delineate the entire signaling pathway.

• Gastric cancer
• Prognosis
• Rictor
• pAktSer473
• pS6

• microRNA
• next-generation sequencing
• pathway enrichment analysis
• prostate cancer

• Aged
• Aged, 80 and over
• China
• Computational Biology
• Gene Expression Profiling
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• MicroRNAs/genetics
• Middle Aged
• Prostatic Neoplasms/genetics
• Real-Time Polymerase Chain Reaction

• Breast Neoplasms/enzymology
• Disease-Free Survival
• Female
• Humans
• Phosphorylation
• Proto-Oncogene Proteins c-akt/metabolism
• Publication Bias
• Regression Analysis

• H. pylori
• Protein synthesis
• S6 ribosomal protein
• eIF4
• mTOR

• Adaptor Proteins, Signal Transducing/metabolism
• Adult
• Aged
• Aged, 80 and over
• Blotting, Western
• Cell Cycle Proteins
• Cell Line, Tumor
• Elongation Factor 2 Kinase/metabolism
• Enzyme Activation
• Eukaryotic Initiation Factor-4E/metabolism
• Helicobacter Infections/genetics
• Helicobacter Infections/metabolism
• Helicobacter Infections/microbiology
• Helicobacter pylori/physiology
• Host-Pathogen Interactions
• Humans
• Middle Aged
• Phosphatidylinositol 3-Kinase/metabolism
• Phosphoproteins/metabolism
• Phosphorylation
• Protein Biosynthesis
• Proto-Oncogene Proteins c-akt/metabolism
• Receptor, IGF Type 1/genetics
• Receptor, IGF Type 1/metabolism
• Ribosomal Protein S6 Kinases/metabolism
• Signal Transduction
• TOR Serine-Threonine Kinases/metabolism
• Young Adult

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.

CDDP [cisplatin or cis-diamminedichloroplatinum(II)] and CDDP-based combination chemotherapy have been confirmed effective against gastric cancer. However, CDDP efficiency is limited because of development of drug resistance. In this study, we found that PAK4 (p21-activated kinase 4) expression and activity were elevated in gastric cancer cells with acquired CDDP resistance (AGS/CDDP and MKN-45/CDDP) compared with their parental cells. Inhibition of PAK4 or knockdown of PAK4 expression by specific siRNA (small interfering RNA)-sensitized CDDP-resistant cells to CDDP and overcome CDDP resistance. Combination treatment of LY294002 [the inhibitor of PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B or PKB) pathway] or PD98509 {the inhibitor of MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] pathway} with PF-3758309 (the PAK4 inhibitor) resulted in increased CDDP efficacy compared with LY294002 or PD98509 alone. However, after the concomitant treatment of LY294002 and PD98509, PF-3758309 administration exerted no additional enhancement of CDDP cytotoxicity in CDDP-resistant cells. Inhibition of PAK4 by PF-3758309 could significantly suppress MEK/ERK and PI3K/Akt signalling in CDDP-resistant cells. Furthermore, inhibition of PI3K/Akt pathway while not MEK/ERK pathway could inhibit PAK4 activity in these cells. The in vivo results were similar with those of in vitro. In conclusion, these results indicate that PAK4 confers CDDP resistance via the activation of MEK/ERK and PI3K/Akt pathways. PAK4 and PI3K/Akt pathways can reciprocally activate each other. Therefore, PAK4 may be a potential target for overcoming CDDP resistance in gastric cancer.

• MEK/ERK
• PI3K/Akt
• cisplatin (CDDP)
• gastric cancer
• p21-activated kinase 4 (PAK4)

MicroRNAs play key roles in tumor proliferation and invasion. Here we show distinct expression of miR-222-3p between ERα-positive and ERα-negative endometrial carcinoma (EC) cell lines and primary tumors, and investigation of its relationship with ERα and other clinical parameters. In vitro, the function of miR-222-3p was examined in RL95-2 and AN3CA cell lines. MiR-222-3p expression was negatively correlated with ERα. Over-expressed miR-222-3p in RL95-2 cells promoted cell proliferation, enhanced invasiveness and induced a G1 to S phase shift in cell cycle. Furthermore, the miR-222-3p inhibitor decreased the activity of AN3CA cells to proliferate and invade. In vivo, down-regulated miR-222-3p of AN3CA cells inhibited EC tumor growth in a mouse xenograft model. Additionally, miR-222-3p increased raloxifene resistance through suppressing ERα expression in EC cells. In conclusion, miR-222-3p plays a significant role in the regulation of ERα expression and could be potential targets for restoring ERα expression and responding to antiestrogen therapy in a subset of ECs.

• Adult
• Animals
• Cell Line, Tumor
• Endometrial Neoplasms/metabolism
• Endometrial Neoplasms/pathology
• Estrogen Receptor alpha/biosynthesis
• Estrogen Receptor alpha/genetics
• Female
• G1 Phase
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Mice
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Proteins/biosynthesis
• Neoplasm Proteins/genetics
• RNA, Neoplasm/biosynthesis
• RNA, Neoplasm/genetics
• S Phase

• Adult
• Aged
• Carcinoma, Renal Cell/genetics
• Carcinoma, Renal Cell/mortality
• Carcinoma, Renal Cell/pathology
• Female
• Humans
• Kidney Neoplasms/genetics
• Kidney Neoplasms/mortality
• Kidney Neoplasms/pathology
• Male
• MicroRNAs/blood
• Middle Aged
• Neoplasm Staging
• Prognosis
• Proportional Hazards Models

• MK-2206
• carboplatinum
• gastric cancer
• paclitaxel

Krukenberg tumor originated from stomach in female patients is common in clinical practice, but it is still uncertain whether surgical resection of ovarian metastases could improve the outcome. Some studies suggested that a certain group of patients could benefit from the resection of ovarian metastases. However, conclusions were different between studies and there was no data to illustrate if certain molecular markers were associated with patients’ survival. In this study, we analyzed the effects of resection of ovarian metastases, and investigated prognostic factors in 133 patients with ovarian metastases originated from stomach. Furthermore, we examined the expression of some cancer stem cells (CSCs) markers or related molecules in 64 ovarian metastases specimens and analyzed the correlation between these molecules and patients’ survival. We found that the median overall survival (mOS) of all 133 patients was 16 months, and “gastrectomy” and “without ascites” were two independent prognostic factors associated with longer survival. The mOS of the patients with gastrectomy was longer than that of patients had not undergone gastrectomy (19 vs. 9 months, p = 0.048). Patients without ascites survived longer than those with ascites (mOS: 21 vs. 13 months, p = 0.008). We also found that Sox2, CD44 or CD133 positive expression in ovarian metastases were risk factors correlated with poor survival, and Sox2 expression was an independent prognostic indicator. These results suggested that ovarian metastasectomy might help to prolong the survivor of some patients with Krukenberg tumor originated from stomach. Patients without ascites, and with resected or resectable primary gastric cancer lesion could get benefit from and be potential candidate for surgical treatment. The expression of Sox2 might serve as a prognostic indicator for predicting patients’ survival and be helpful for selecting patients in future.

• HaCaT cells
• MicroRNA-141
• PTEN
• UVB
• apoptosis

• Animals
• Cell Proliferation
• Cell Survival
• Cell Transformation, Neoplastic
• Cytokine Receptor gp130/physiology
• Gastric Mucosa/metabolism
• Gastric Mucosa/pathology
• Humans
• Inflammation/complications
• Male
• Mice
• Mice, Inbred C57BL
• STAT3 Transcription Factor/physiology
• Stomach Neoplasms/etiology
• Toll-Like Receptor 2/physiology
• Up-Regulation

• 08-0644 Worldwide Cancer Research
• Cancer Research UK

Gastric cancer is a malignant disease that arises from the gastric epithelium. A potential biomarker for gastric cancer is the protein annexin A4 (ANXA4), an intracellular Ca²⁺ sensor. ANXA4 is primarily found in epithelial cells, and is known to be involved in various biological processes, including apoptosis, cell cycling and anticoagulation. In respect to cancer, ANXA4-overexpression has been observed in cancers of various origins, including gastric tumors associated with Helicobacter pylori infection. H. pylori induces ANXA4 expression and intracellular [Ca²⁺]_i elevation, and is an important risk factor for carcinogenesis that results in gastric cancer. Despite this correlation, the role of ANXA4 in the progression of gastric tumors remains unclear. In this study, we have investigated whether ANXA4 can mediate the rate of cell growth and whether ANXA4 downstream signals are involved in tumorigenesis. After observing the rate of cell growth in real-time, we determined that ANXA4 promotes cell proliferation. The transcription gene profile of ANXA4-overexpressing cells was measured and analyzed by human exon arrays. From this transcriptional gene data, we show that overexpression of ANXA4 regulates genes that are known to be related to cancer, for example the activation of hyaluronan mediated motility receptor (RHAMM), AKT, and cyclin-dependent kinase 1 (CDK1) as well as the suppression of p21. The regulation of these genes further induces cancer cell proliferation. We also found Ca²⁺ could regulate the transmission of downstream signals by ANXA4. We suggest that ANXA4 triggers a signaling cascade, leading to increased epithelial cell proliferation, ultimately promoting carcinogenesis. These results might therefore provide a new insight for gastric cancer therapy, specifically through the modification of ANXA4 activity.

• Annexin A4/metabolism
• Biomarkers, Tumor/metabolism
• Calcium/metabolism
• Cell Proliferation
• Enzyme Activation
• Exons
• Helicobacter pylori/isolation & purification
• Humans
• Signal Transduction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/pathology

• age
• ethnicity
• gastric cancer
• gender
• survival

• P30 CA014089 NCI NIH HHS

MicroRNAs (miRNAs) can function as either oncogenes or tumor suppressor genes via regulation of cell proliferation and/or apoptosis. MiR-221 and miR-222 were discovered to induce cell growth and cell cycle progression via direct targeting of p27 and p57 in various human malignancies. However, the roles of miR-221 and miR-222 have not been reported in human gastric cancer. In this study, we examined the impact of miR-221 and miR-222 on human gastric cancer cells, and identified target genes for miR-221 and miR-222 that might mediate their biology.

The human gastric cancer cell line SGC7901 was transfected with AS-miR-221/222 or transduced with pMSCV-miR-221/222 to knockdown or restore expression of miR-221 and miR-222, respectively. The effects of miR-221 and miR-222 were then assessed by cell viability, cell cycle analysis, apoptosis, transwell, and clonogenic assay. Potential target genes were identified by Western blot and luciferase reporter assay.

Upregulation of miR-221 and miR-222 induced the malignant phenotype of SGC7901 cells, whereas knockdown of miR-221 and miR-222 reversed this phenotype via induction of PTEN expression. In addition, knockdonwn of miR-221 and miR-222 inhibited cell growth and invasion and increased the radiosensitivity of SGC7901 cells. Notably, the seed sequence of miR-221 and miR-222 matched the 3'UTR of PTEN, and introducing a PTEN cDNA without the 3'UTR into SGC7901 cells abrogated the miR-221 and miR-222-induced malignant phenotype. PTEN-3'UTR luciferase reporter assay confirmed PTEN as a direct target of miR-221 and miR-222.

These results demonstrate that miR-221 and miR-222 regulate radiosensitivity, and cell growth and invasion of SGC7901 cells, possibly via direct modulation of PTEN expression. Our study suggests that inhibition of miR-221 and miR-222 might form a novel therapeutic strategy for human gastric cancer.

• 14-3-3 Proteins/genetics
• 3' Untranslated Regions
• Acetylation
• Apoptosis/genetics
• Cell Line, Tumor
• Cell Survival/genetics
• DNA Methylation
• Down-Regulation
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Histones/genetics
• Histones/metabolism
• Humans
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Oncogene Protein v-akt/metabolism
• Protein Serine-Threonine Kinases/genetics
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• RNA, Small Interfering/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Transfection

AIM: To investigate the effects of macrophage migration inhibitory factor (MIF) on proliferation of human gastric cancer MGC-803 cells and expression of cyclin D1 and p27^Kip1 in them, and further determine whether the effects are related to the PI3K/Akt signal transduction pathway.

METHODS: Gastric cancer MGC-803 cells were cultured and then treated with 50 μg/L recombinant human MIF (rhMIF) with and without a PI3K inhibitor, LY294002 (25 μmol/L). MTT assay was used to detect the proliferation of MGC-803 cells. Cell cycle was detected by flow cytometry. Expression of cyclin D1 and p27^Kip1 mRNA was by reverse transcription-polymerase chain reaction. Protein expression of phosphorylated Akt (p-Akt), Akt, cyclin D1 and p27^Kip1 was examined by immunocytochemistry and Western blotting.

RESULTS: rhMIF significantly stimulated the proliferation of MGC-803 cells and cell cycle progression from G1 phase to S phase in a concentration- and time-dependent manner. After the MGC-803 cells were treated with rhMIF for 24 h, the expression of cyclin D1 was significantly up-regulated compared with the cells not treated with rhMIF at both mRNA and protein levels (0.97 ± 0.02 vs 0.74 ± 0.01, P = 0.002; 0.98 ± 0.05 vs 0.69 ± 0.04, P = 0.003). The p27^Kip1 was down-regulated but only statistically significant at the protein level. rhMIF significantly increased the expression of p-Akt, which reached the peak at 30 min, but did not affect the expression of Akt. However, LY294002 inhibited all the effects of rhMIF.

CONCLUSION: Macrophage MIF increases the proliferation of gastric cancer cells, induces the expression of cyclin D1 at the transcriptional level and inhibits the expression of p27^Kip1 at the post-transcriptional level via the PI3K/Akt pathway.

• Macrophage migration inhibitory factor
• Gastric cancer
• Proliferation
• Cell cycle
• Cyclin D1
• p27^Kip1
• PI3K/Akt