• ovarian cancer
• targeted therapies

• Female
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/pathology
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/metabolism
• MRE11 Homologue Protein
• Humans
• Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
• Phthalazines/pharmacology
• Animals
• Mice
• Cell Line, Tumor
• Acid Anhydride Hydrolases
• Piperazines/pharmacology
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Cell Cycle Proteins/antagonists & inhibitors
• Cell Cycle Proteins/metabolism
• Cell Cycle Proteins/genetics
• Xenograft Model Antitumor Assays
• Drug Synergism
• DNA Breaks, Double-Stranded/drug effects
• Nuclear Proteins/metabolism
• Nuclear Proteins/genetics
• Nuclear Proteins/antagonists & inhibitors

• 81672582 National Natural Science Foundation of China (National Science Foundation of China)
• 31771521 National Natural Science Foundation of China (National Science Foundation of China)
• Top Talent of Innovative Research Team Government of Jiangsu Province (Jiangsu Province)
• Training Project for Young Backbone Teachers Jiangsu University (Advanced Talents Foundation of Jiangsu University)
• BE2016718 Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)

• Cell proliferation
• Hepatocellular carcinoma
• PDZK1
• PI3K/AKT
• miR-101-3p

• 2019GYB22 the Public Welfare Applied Research Project of Huzhou City
• LQ20H030006 Natural Science Foundation of Zhejiang Province
• 82000618 National Natural Science Foundation of China
• 2020380736 General project of Zhejiang Medicine and Health Science and Technology Department
• 2017AY33037 the Science and Technology Planning Project of Jiaxing City

• Behaviour
• Comportamiento
• Cáncer gástrico
• Gastric cancer
• PTEN

• Humans
• Stomach Neoplasms
• Tensins
• Cross-Sectional Studies
• Staining and Labeling
• PTEN Phosphohydrolase

• SEMA3B
• SEMA3B‐AS1
• colorectal carcinoma
• epigenetic regulation
• tumor angiogenesis

• National Natural Science Foundation of China

• metabolic disorders
• deubiquitylating enzymes

• Mice
• Animals
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/metabolism
• Liver/metabolism
• Liver Cirrhosis/metabolism
• Mice, Knockout
• Lipids
• Deubiquitinating Enzymes
• Diet, High-Fat/adverse effects
• Mice, Inbred C57BL
• Disease Models, Animal

• National Research Foundation of Korea (NRF)

• DNA damage response
• G2/M checkpoint
• NSCLC
• P53
• PTEN
• cell fate determination

• 2021/09070-8 São Paulo Research Foundation
• 2015/22308-2 São Paulo Research Foundation
• 2016-06014 Swedish Research Council
• 150960/2022-0 National Council for Scientific and Technological Development

• Cyclin-dependent kinases (CDKs)
• Cyclins
• cell cycle regulation
• cell signaling
• gastric cancer
• kinases
• molecular oncology

• Humans
• Cyclin-Dependent Kinases/metabolism
• Cyclins/genetics
• Cyclins/metabolism
• Stomach Neoplasms
• Cell Cycle
• Cell Division

• Gene regulation
• Notch1
• Ovarian cancer
• SETD1A
• Tumorigenesis

• DLX1
• HOTAIR
• Papillary thyroid cancer
• lncRNA

• Gastric cancer cell apoptosis
• Metformin
• MiR-365
• PTEN

• 3' Untranslated Regions
• AMP-Activated Protein Kinases/metabolism
• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Metformin/pharmacology
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/genetics
• MicroRNAs/metabolism
• PTEN Phosphohydrolase/genetics
• PTEN Phosphohydrolase/metabolism
• Phosphorylation
• Signal Transduction
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays
• Mice

Contrasting with zebrafish, retinal regeneration from Müller cells (MCs) is largely limited in mammals, where they undergo reactive gliosis that consist of a hypertrophic response and ultimately results in vision loss. Transforming growth factor β (TGFβ) is essential for wound healing, including both scar formation and regeneration. However, targeting TGFβ may affect other physiological mechanisms, owing its pleiotropic nature. The regulation of various cellular activities by TGFβ relies on its interaction with other pathways including Notch. Here, we explore the interplay of TGFβ with Notch and how this regulates MC response to injury in zebrafish and mice. Furthermore, we aimed to characterize potential similarities between murine and human MCs during chronic reactive gliosis.

Focal damage to photoreceptors was induced with a 532 nm diode laser in TgBAC (gfap:gfap-GFP) zebrafish (ZF) and B6-Tg (Rlbp1-GFP) mice. Transcriptomics, immunofluorescence, and flow cytometry were employed for a comparative analysis of MC response to laser-induced injury between ZF and mouse. The laser-induced injury was paired with pharmacological treatments to inhibit either Notch (DAPT) or TGFβ (Pirfenidone) or TGFβ/Notch interplay (SIS3). To determine if the murine laser-induced injury model translates to the human system, we compared the ensuing MC response to human donors with early retinal degeneration.

Investigations into injury-induced changes in murine MCs revealed TGFβ/Notch interplay during reactive gliosis. We found that TGFβ1/2 and Notch1/2 interact via Smad3 to reprogram murine MCs towards an epithelial lineage and ultimately to form a glial scar. Similar to what we observed in mice, we confirmed the epithelial phenotype of human Müller cells during gliotic response.

The study indicates a pivotal role for TGFβ/Notch interplay in tuning MC stemness during injury response and provides novel insights into the remodeling mechanism during retinal degenerative diseases.

The online version contains supplementary material available at 10.1186/s13024-021-00482-z.

• Laser injury
• Müller cells
• Notch pathway
• Retinal degeneration
• Retinal regeneration
• Smad3
• TGFβ signaling
• Vertebrates

• Esophageal adenocarcinoma
• Integrator
• NACK
• Notch signaling
• SGK223
• Transcriptional activation
• Tumorigenesis

Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human CDH1 gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. After proteolysis, the extracellular fragment of the full-length E-cadhein is released into the extracellular environment and the blood, which is called soluble E-cadherin (sE-cadherin). sE-cadherin promots invasion and metastasis as a paracrine/autocrine signaling molecule in the progression of various types of cancer including gastric cancer. This review mainly summarizes the dysregulation of E-cadherin and the regulatory roles in the progression, invasion, metastasis, and drug-resistance, as well as its clinical applications in diagnosis, prognosis, and therapeutics of gastric cancer.

• CDH1
• EMT
• e-cadherin
• gastric cancer
• precision therapy

Background: Mitochondrial fission regulator 2 (MTFR2) which can promote mitochondrial fission, has recently been reported to be involved in tumorigenesis. However, little is known about its expression levels and function in gastric cancer (GC). This study aims to clarify the role of MTFR2 in GC.

Methods:We firstly determined the expression level and prognostic value of MTFR2 in GC by integrated bioinformatics (Oncomine, GEPIA, Kaplan-Meier Plotter database) and experimental approaches (RT-qPCR, western blot, immunohistochemistry). After constructing stable down-regulated GC cells, the biological functions of MTFR2 in vitro and in vivo were studied through cell clone formation, wound healing, transwell and tumor formation experiments.To understand the reason for the high expression of MTFR2 in GC, copy number alternation, promoter methylation and mutation of MTFR2 were detected by UALCAN and cBioPortal. TargetScanHuman and PROMO databases were also used to explore the miRNAs and transcription factors of MTFR2, and the regulatory network was visualized by Cytoscape. LinkedOmics was used to detect the co-expression profile, and then these co-expressed genes were used for gene oncology function and pathway enrichment analysis to deepen the understanding of MTFR2 mechanism. The protein interaction network of MTFR2 was constructed by the GeneMANIA platform. Docking study of the binding mode was conducted by H DOCK webserver, and PYMOL is used for visualization, and analysis. TIMER database was used to explore the correlation between MTFR2 expression level and immune cells infiltration and gene markers of tumor infiltrating immune cells.

Results: We demonstrated that MTFR2 was up-regulated in GC, and its overexpression led to poorer prognosis. MTFR2 downregulation inhibited the proliferation, migration, and invasion of GC cells in vitro and in vivo. By bioinformatics analysis, we identified the possible factors in MTFR2 overexpression. Moreover, function and pathway enrichment analyses found that MTFR2 was involved in chromosome segregation, catalytic activity, cell cycle, and ribonucleic acid transport. A MTFR2-protein interaction network revealed a potential direct protein interaction between MTFR2 and protein kinase adenosine-monophosphate-activated catalytic subunit alpha 1 (PRKAA1), and their potential binding site was predicted in a molecular docking model. In addition, we also found that MTFR2 may be correlated with immune infiltration in GC.

Conclusions: Our study has effectively revealed the expression, prognostic value, potential functional networks, protein interactions and immune infiltration of MTFR2 in GC. Altogether, our data identify the possible underlying mechanisms of MTFR2 and suggest that MTFR2 may be a prognostic biomarker and therapeutic target in GC.

• Gastric cancer
• Immune.
• MTFR2
• Mitochondria
• Prognosis
• Proliferation

The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.

• Notch signaling pathway
• angiogenesis
• epithelial-mesenchymal transition (EMT)
• gain and loss of function mutations (GOF and LOF)
• metastasis
• oncogenic mutations
• personalized cancer medicine
• tumor microenvironment (TME)
• tumor progression
• tumor suppressor gene

• Furin/Notch1 intracellular domain (NICD)/phosphate and tension homology (PTEN) pathway
• Metastasis
• Nasopharyngeal carcinoma
• Placenta-specific protein 1
• Proliferation

• gastric cancer
• tumour biomarkers

Prostate cancer is the most frequently diagnosed cancer in men. Despite the importance of radical radiotherapy for the management of this disease, recurrence remains a challenge. PTEN is a tumour suppressor that is frequently inactivated in advanced prostate cancer and has been associated with relapse following radiotherapy. The present study shows that the role of PTEN in response to ionizing radiation is complex. Furthermore, it demonstrates that in the absence of PTEN, an increased response to combined treatment using radiotherapy and the ATM inhibitor KU-60019 can be observed. Our findings provide a strong rationale for evaluating loss of PTEN in prostate cancer as a therapeutic target for ATM inhibitor in combination with radiotherapy in the clinical setting.

Radical radiotherapy, often in combination with hormone ablation, is a safe and effective treatment option for localised or locally-advanced prostate cancer. However, up to 30% of patients with locally advanced PCa will go on to develop biochemical failure, within 5 years, following initial radiotherapy. Improving radiotherapy response is clinically important since patients exhibiting biochemical failure develop castrate-resistant metastatic disease for which there is no curative therapy and median survival is 8–18 months. The aim of this research was to determine if loss of PTEN (highly prevalent in advanced prostate cancer) is a novel therapeutic target in the treatment of advanced prostate cancer. Previous work has demonstrated PTEN-deficient cells are sensitised to inhibitors of ATM, a key regulator in the response to DSBs. Here, we have shown the role of PTEN in cellular response to IR was both complex and context-dependent. Secondly, we have confirmed ATM inhibition in PTEN-depleted cell models, enhances ionising radiation-induced cell killing with minimal toxicity to normal prostate RWPE-1 cells. Furthermore, combined treatment significantly inhibited PTEN-deficient tumour growth compared to PTEN-expressing counterparts, with minimal toxicity observed. We have further shown PTEN loss is accompanied by increased endogenous levels of ROS and DNA damage. Taken together, these findings provide pre-clinical data for future clinical evaluation of ATM inhibitors as a neoadjuvant/adjuvant in combination with radiation therapy in prostate cancer patients harbouring PTEN mutations.

• ATM
• DNA damage
• PTEN
• ROS
• ionising radiation
• prostate cancer

Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, but its exact pathogenesis has not been fully elucidated. ETS homologous factor (EHF) is an important member of the ETS family and contributes to the pathogenesis of multiple malignant tumors. To date, whether EHF participates in the development of GC via the c-Met signaling pathway remains unclear.

To investigate the role and mechanism of EHF in the occurrence and development of GC.

The expression of EHF mRNA in GC tissues and cell lines was measured by quantitative PCR. Western blotting was performed to determine the protein expression of EHF, c-Met, and its downstream signal molecules. The EHF expression in GC tissues was further detected by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNA (siRNA) against EHF was transfected into GC cells. The cell proliferation of GC cells was determined by Cell Counting Kit-8 and colony formation assays. Flow cytometry was performed following Annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. Cell migration and invasion were assessed by transwell assays.

The data showed that EHF was upregulated in GC tissues and cell lines in which increased expression of c-Met was also observed. Silencing of EHF by siRNA reduced the proliferation of GC cells. Inhibition of EHF induced significant apoptosis and cell cycle arrest in GC cells. Cell migration and invasion were significantly inhibited. EHF silencing led to c-Met downregulation and further blocked the Ras/c-Raf/extracellular signal-related kinase 1/2 (Erk1/2) pathway. Additionally, phosphatase and tensin homolog was upregulated and glycogen synthase kinase 3 beta was deactivated. Moreover, inactivation of signal transducer and activator of transcription 3 was detected following EHF inhibition, leading to inhibition of the epithelial-to-mesenchymal transition (EMT).

These results suggest that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway. Therefore, EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.

• Gastric cancer
• ETS homologous factor
• c-Met
• Antineoplastic target
• Signaling pathway

• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Invasiveness
• Stomach Neoplasms/genetics

Objective: Anaplastic thyroid cancer/ATC is a highly aggressive malignancy with extremely poor prognosis. Resveratrol/Res promotes re-differentiation of cancer cells and exerts inhibitory effects on ATC cells. Sodium/iodide symporter/NIS and phosphate and tension homology deleted on chromsome ten/PTEN levels are positively correlated with the grade of thyroid cancer differentiation, while the impact of Res on them remain unknown.

Materials and Methods: The patterns of NIS and PTEN expression and intracellular distribution in THJ-16T and THJ-21T ATC and Nthy-ori 3-1 normal thyroid cells and their relevance with Res-caused ATC suppression were investigated via multiple experimental methods. E-cadherin was cited as a re-differentiation biomarker of ATC cells.

Results: MTT and EdU cell proliferation assays showed distinct growth suppression in ATC cells after Res treatment. TUNEL staining revealed extensive apoptosis of Res-treated THJ-16T and THJ-21T rather than Nthy-ori 3-1 cells. Western blotting, immunocytochemical/ICC and double-labeled immunofluorescent/IF staining showed increased PTEN levels accompanied with distinct NIS and PTEN nuclear co-translocation in Res-treated THJ-16T and THJ-21T cells. E-cadherin but not NIS appeared on the outer membrane.

Conclusion: PTEN upregulation and the concurrent NIS and PTEN nuclear translocation in Res-suppressed ATC cells may indicate the better therapeutic outcome and would be a group of beneficial prognostic factors of ATCs.

• NIS
• PTEN
• anaplastic thyroid cancer
• intracellular distribution
• resveratrol

• 3T3-L1 preadipocytes
• Adipose browning
• Notch signaling pathway
• Obesity
• γ-secretase inhibitor

• 3T3-L1 Cells
• Adipocytes/drug effects
• Adipogenesis/drug effects
• Adipose Tissue, Beige/drug effects
• Amyloid Precursor Protein Secretases/antagonists & inhibitors
• Animals
• Anti-Obesity Agents/chemistry
• Anti-Obesity Agents/pharmacology
• Apoptosis/drug effects
• Cell Proliferation
• Cell Survival/drug effects
• Dose-Response Relationship, Drug
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/pharmacology
• Lipid Droplets/chemistry
• Mice
• Organelle Biogenesis
• Receptors, Notch/antagonists & inhibitors

• R01 CA212609 NCI NIH HHS
• R43 DK115277 NIDDK NIH HHS
• R43DK115277 NIDDK NIH HHS
• R01CA212609 NCI NIH HHS

• PI3K/Akt
• gastric cancer
• growth
• metastasis
• phosphatase and tensin homolog (PTEN)

• NA Ministry of Education - Singapore
• NMRC/OFIRG/0020/2016 National Medical Research Council

• Barrett’s Esophagus
• Carcinogenesis
• Esophageal Adenocarcinoma
• Goblet Cells

• Adenocarcinoma/diagnosis
• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Aged
• Animals
• Barrett Esophagus/diagnosis
• Barrett Esophagus/genetics
• Barrett Esophagus/pathology
• Biopsy
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Cell Differentiation/genetics
• Cross-Sectional Studies
• Disease Models, Animal
• Disease Progression
• Esophageal Mucosa/cytology
• Esophageal Mucosa/diagnostic imaging
• Esophageal Mucosa/pathology
• Esophageal Neoplasms/diagnosis
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/pathology
• Esophagoscopy
• Female
• Gastric Mucosa/cytology
• Gastric Mucosa/pathology
• Goblet Cells/pathology
• Humans
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• NF-kappa B/metabolism
• Prospective Studies
• RNA, Messenger/analysis
• RNA, Messenger/metabolism
• Receptors, Notch/genetics
• Receptors, Notch/metabolism
• Signal Transduction

• P01 CA098101 NCI NIH HHS
• P30 CA013696 NCI NIH HHS
• R01 CA208711 NCI NIH HHS
• U54 CA163004 NCI NIH HHS

• Apoptosis
• Cancer therapy
• Cell cycle arrest
• Nuclear medicine
• Selective radionuclide therapy
• β-radiating radionuclides

• G1/S transition
• PTEN
• miR-301a
• proliferation
• renal cell carcinoma

Hypoxia-exposed lung cancer-released exosomal microRNA-23a (miR-23a) has been shown to enhance angiogenesis as well as vascular permeability, contributing to the close correlation between exosomal miR-23a and tumorigenesis. The current study aimed to investigate whether gastric cancer (GC) cell-derived exosomal miR-23a could induce angiogenesis and to elucidate the potential mechanisms associated with the process. Differentially expressed miRNAs in GC were initially screened from the Gene Expression Omnibus database. Target genes were selected following miRNA-mRNA prediction and subsequently verified by dual luciferase reporter assay. RT-qPCR was conducted to detect miR-23a and PTEN expression in GC tissues, cells and exosomes. Human umbilical venous endothelial cells (HUVECs) were co-cultured with GC cell-derived exosomes to assess the angiogenesis mediated by exosomes in vitro. Additionally, PTEN was overexpressed in HUVECs to analyze the mechanism by which miR-23a regulates angiogenesis. miR-23a was highly expressed in GC tissues and cells and GC cell-derived exosomes. Angiogenesis was promoted by the co-culture of HUVECs and GC cells-derived exosomes, as evidenced by the increased expression of VEGF but decreased expression of TSP-1. PTEN was targeted by miR-23a and was lowly expressed in GC tissues. In a co-culture system, miR-23a carried by GC cells-derived exosomes promoted angiogenesis via the repression of PTEN. Collectively, GC cell-derived exosomal miR-23a could promote angiogenesis and provide blood supply for growth of GC cells. This study contributes to advancement of miRNA-targeted therapeutics.

• AKT pathway
• PTEN
• angiogenesis
• exosome
• gastric cancer
• microRNA-23a

• apoptosis
• gastric cancer
• molecular mechanism
• notch signaling pathway
• penicilazaphilone C

• A-kinase anchor protein 5 (AKAP5)
• Stomach neoplasms
• adenocarcinoma
• survival analysis

• Down syndrome
• XIST
• dosage compensation
• gene therapy
• human pluripotent stem cells
• neural differentiation
• notch signaling
• scRNA-seq
• single-cell

• Hu-antigen R
• carcinoma
• gastric cancer
• microRNA-145

• Notch
• endometriosis
• interferon-induced transmembrane protein 1
• leukemia inhibitory factor receptor
• podocalyxin-like
• sex-determining region Y (SRY)- box 2
• stem cells
• therapy

• PI3K
• PTEN
• phosphatase
• regulation

• Apoptosis
• Autophagy
• Ginsenoside Rg5
• Human gastric cancer
• MAPK
• ROS

Transient receptor potential vanilloid type 4 (TRPV4) is a Ca²⁺-permeable cation channel that is known to be an osmosensor and thermosensor. Currently, limited evidence shows that TRPV4 plays opposite roles in either promoting or inhibiting cancer development in different cancer types. Furthermore, the precise biological functions and the underlying mechanisms of TRPV4 in carcinogenesis are still poorly understood. In this study, we demonstrated that TRPV4 is upregulated in colon cancer and associated with poor prognosis. Contrary to the reported cell death-promoting activity of TRPV4 in certain cancer cells, TRPV4 positively regulates cell survival in human colon cancer in vitro and in vivo. Inhibition of TRPV4 affects the cell cycle progression from the G1 to S phase through modulating the protein expression of D-type cyclins. Apoptosis and autophagy induced by TRPV4 silencing attenuate cell survival and potentiate the anticancer efficacy of chemotherapeutics against colon cancer cells. In addition, PTEN is activated by inhibition of TRPV4 as indicated by the dephosphorylation and increased nuclear localization. Knockdown of PTEN significantly abrogates TRPV4 silencing induced growth inhibition and recovers the capability of clonogenicity, as well as reduced apoptosis in colon cancer cells. Thus, PTEN regulates the antigrowth effects induced by TRPV4 inhibition through both phosphatase-dependent and independent mechanisms. In conclusion, inhibition of TRPV4 suppresses colon cancer development via activation of PTEN pathway. This finding suggests that downregulation of TPRV4 expression or activity would conceivably constitute a novel approach for the treatment of human colon cancer.

Gastric cancer (GC) is one of a most threatening cancer globally. Rhotekin (RTKN), a Rho effector, has been reported to be upregulated in GC tissues. This study aimed to investigate the underlying regulatory roles of RTKN in the biological behavior of GC.

Real-time PCR and Western blotting were carried out to detect the mRNA and protein expression, respectively. Cell Counting Kit-8 and xenograft nude mice model were used to evaluate cell proliferation. Flow cytometry analysis was performed to assess cell cycle distribution and cell apoptosis.

RTKN had high expression level in GC compared with normal tissues. RTKN expression strongly associated with tumor size, TNM stage, lymphnode metastasis and the poor prognosis of patients with GC. Downregulation of RTKN significantly repressed GC cell proliferation, but increased cell population in G1/S phase and induced cell apoptosis. Moreover, the RTKN expression level was related to the p53 signaling pathway and histone deacetylase (HDAC) Class I pathway. RTKN knockdown caused a notable increment in the acetylation level of p53 (Lys382), and the expression of p53-target genes (p21, Bax, and PUMA), as well as a reduction in the expression of a potential deacetylase for p53, HDAC1. Notably, downregulation of HDAC1 had similar effects as RTKN knockdown, and RTKN overexpression could hardly abrogate the effects of HDAC1 knockdown on GC cells.

RTKN could work as an oncogene via regulating HDAC1/p53 and may become a promising treatment strategy for GC.

• HDAC1/p53
• RTKN
• gastric cancer
• invasion
• proliferation

Vinpocetine, a phosphodiesterase (PDE) type-1 inhibitor, increases cAMP and cGMP levels and is currently used for the management of cerebrovascular disorders, such as stroke, cerebral hemorrhage, and cognitive dysfunctions. In this study, we first determined that vinpocetine effectively suppressed adipogenesis and lipid accumulation. However, we questioned which molecular mechanism is involved because the role of PDE in adipogenesis is still controversial. Vinpocetine decreased adipogenic cell signaling, including the phosphorylation of ERK, AKT, JAK2, and STAT3, and adipokine secretion, including IL-6, IL-10, and IFN-α. Interestingly, vinpocetine increased the phosphorylation of HSL, suggesting the induction of the lipolysis pathway. Moreover, vinpocetine increased UCP1 expression via increasing cAMP and PKA phosphorylation. The administration of vinpocetine with a normal-chow diet (NFD) or a high-fat diet (HFD) in mice attenuated body weight gain in mice fed both the NFD and HFD. These effects were larger in the HFD-fed mice, without a difference in food intake. Vinpocetine drastically decreased fat weight and adipocyte cell sizes in gonadal and inguinal white adipose tissues and in the liver in both diet groups. Serum triacylglycerol levels and fasting blood glucose levels were reduced by vinpocetine treatment. This study suggested that vinpocetine prevents adipocyte differentiation through the inhibition of adipogenesis-associated cell signaling in the early stages of adipogenesis. Moreover, upregulating cAMP levels leads to an increase in lipolysis and UCP1 expression and then inhibits lipid accumulation. Therefore, we suggest that vinpocetine could be an effective agent for treating obesity, as well as improving cognition and cardiovascular function in older individuals.

A compound extracted from the periwinkle plant can limit the over-production of fat cells and may be a useful agent for treating obesity. Being overweight is the result of changes in the size and number of fat cells, or adipocytes, in the body. Scientists are searching for molecules that can limit the growth and replication of adipocytes, but many anti-obesity agents found to date have unpleasant side-effects. Kyung-Hee Chun at Yonsei University in Seoul, South Korea and co-workers examined the effects of 502 naturally occuring compounds on adipocyte differentiation in cell culture. One compound called vincamine, which is safely used to treat vascular diseases in the brain, decreased cell signaling pathways involved in adipocyte generation in mice and also lowered fasting blood glucose levels.

MIIP is associated with cancer progression in various cancers. However, its expression pattern, and associated molecular mechanisms in gastric cancer (GC) progression are still mysterious. We aimed to explore the role of MIIP in proliferation and invasion of GC.

MIIP expression was evaluated in human GC tissues and cell lines. Public clinical database of GC patients was used to probe the correlation between MIIP expression and prognosis of patients. The effects of forced MIIP expression on GC cells were determined by MTT, cell cycle distribution, colony formation, wound-healing and Transwell assays in vitro, as well as in vivo growth of subcutaneous tumor xenografts and metastasis of xenografted tumors to the lungs in mice. The expressions of GC progression-associated genes, including HOTAIR, MALAT1, HDAC6, AC-tubulin, and cyclin D1, were assessed by Western blotting or qRT-PCR.

Both GC tissues and GC cell lines had lower MIIP expression. Higher level of MIIP in GC tissues predicts better survival in patients. Ectopic expression of MIIP in GC cell lines BGC823 and HGC27 induced G₀/G₁ cell cycle arrest and inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as the growth of GC xenografts and metastasis of tumors in vivo. Furthermore, overexpression of MIIP suppressed mRNA expressions of HOTAIR and MALAT1, decreased protein expression of HDAC6 and cyclin D1, and elevated AC-tubulin protein expression.

MIIP is a suppressor for GC progression and is a potential therapeutic target for treating GC.

• MIIP
• gastric cancer
• invasion
• metastasis
• migration
• proliferation

Breast cancer is the second most common malignancy, worldwide. Treatment decisions are based on tumor stage, histological subtype, and receptor expression and include combinations of surgery, radiotherapy, and systemic treatment. These, together with earlier diagnosis, have resulted in increased survival. However, initial treatment efficacy cannot be guaranteed upfront, and these treatments may come with (long-term) serious adverse effects, negatively affecting a patient's quality of life. Gene expression-based tests can accurately estimate the risk of recurrence in early stage breast cancers. Disease recurrence correlates with treatment resistance, creating a major need to resensitize tumors to treatment. Notch signaling is frequently deregulated in cancer and is involved in treatment resistance. Preclinical research has already identified many combinatory therapeutic options where Notch involvement enhances the effectiveness of radiotherapy, chemotherapy or targeted therapies for breast cancer. However, the benefit of targeting Notch has remained clinically inconclusive. In this review, we summarize the current knowledge on targeting the Notch pathway to enhance current treatments for breast cancer and to combat treatment resistance. Furthermore, we propose mechanisms to further exploit Notch-based therapeutics in the treatment of breast cancer.

• Notch
• breast cancer
• personalized precision treatment
• resensitisation
• treatment resistance