• epithelial–mesenchymal transition
• gastric cancer
• invasion
• mesenchymal–amoeboid transition
• metastasis
• non-coding RNAs
• targeted therapy
• tumor microenvironment

• No. 18H02883 KAKENHI (Grant-in-Aid for Scientific Research)

• CHIP
• Endometriosis
• Glycolysis
• HMGB1
• Protein modification
• Ubiquitination

• Animals
• Female
• Humans
• Mice
• Endometriosis/pathology
• Glycolysis
• HMGB1 Protein/metabolism
• Ubiquitination
• Ubiquitin-Protein Ligases/metabolism

• 81602301 National Natural Science Foundation of China
• 81972489 National Natural Science Foundation of China
• ZR2021MH235 Natural Science Foundation of Shandong Province
• J17KA254 Shandong province college science and technology plan project
• 2021wyfylcyj01 Clinical Research Center of Affiliated Hospital of Weifang Medical University

• CHIP
• Chaperones (HSC70/HSP70 & HSP90)
• Oncogene
• Therapy
• Tumor suppressor
• Ubiquitin proteasome system (UPS)

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) is an intracellular adapter protein with E3 ligase activity, which interacts with a plethora of other signaling proteins, including plasma membrane receptors, kinases, phosphatases, other E3 ligases, and deubiquitinases. TRAF2 is involved in various cancer-relevant cellular processes, such as the activation of transcription factors of the NFκB family, stimulation of mitogen-activated protein (MAP) kinase cascades, endoplasmic reticulum (ER) stress signaling, autophagy, and the control of cell death programs. In a context-dependent manner, TRAF2 promotes tumor development but it can also act as a tumor suppressor. Based on a general description, how TRAF2 in concert with TRAF2-interacting proteins and other TRAF proteins act at the molecular level is discussed for its importance for tumor development and its potential usefulness as a therapeutic target in cancer therapy.

Tumor necrosis factor (TNF) receptor associated factor-2 (TRAF2) has been originally identified as a protein interacting with TNF receptor 2 (TNFR2) but also binds to several other receptors of the TNF receptor superfamily (TNFRSF). TRAF2, often in concert with other members of the TRAF protein family, is involved in the activation of the classical NFκB pathway and the stimulation of various mitogen-activated protein (MAP) kinase cascades by TNFRSF receptors (TNFRs), but is also required to inhibit the alternative NFκB pathway. TRAF2 has also been implicated in endoplasmic reticulum (ER) stress signaling, the regulation of autophagy, and the control of cell death programs. TRAF2 fulfills its functions by acting as a scaffold, bringing together the E3 ligase cellular inhibitor of apoptosis-1 (cIAP1) and cIAP2 with their substrates and various regulatory proteins, e.g., deubiquitinases. Furthermore, TRAF2 can act as an E3 ligase by help of its N-terminal really interesting new gene (RING) domain. The finding that TRAF2 (but also several other members of the TRAF family) interacts with the latent membrane protein 1 (LMP1) oncogene of the Epstein–Barr virus (EBV) indicated early on that TRAF2 could play a role in the oncogenesis of B-cell malignancies and EBV-associated non-keratinizing nasopharyngeal carcinoma (NPC). TRAF2 can also act as an oncogene in solid tumors, e.g., in colon cancer by promoting Wnt/β-catenin signaling. Moreover, tumor cell-expressed TRAF2 has been identified as a major factor-limiting cancer cell killing by cytotoxic T-cells after immune checkpoint blockade. However, TRAF2 can also be context-dependent as a tumor suppressor, presumably by virtue of its inhibitory effect on the alternative NFκB pathway. For example, inactivating mutations of TRAF2 have been associated with tumor development, e.g., in multiple myeloma and mantle cell lymphoma. In this review, we summarize the various TRAF2-related signaling pathways and their relevance for the oncogenic and tumor suppressive activities of TRAF2. Particularly, we discuss currently emerging concepts to target TRAF2 for therapeutic purposes.

• B-cell lymphoma
• TNF receptor associated factor 2 (TRAF2)
• apoptosis
• autophagy
• cellular inhibitor of apoptosis 1/2 (cIAP1/2)
• necroptosis
• nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NFκB)
• tumor necrosis factor (TNF)

• RNA sequencing
• STUB1
• acute kidney injury
• cisplatin
• network-based expression analysis

• E3s
• p53
• tumor

• 201807090113 China Scholarship Council
• 813599 European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement

The carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, participates in many cellular processes such as protein degradation, trafficking, autophagy, apoptosis, and multiple signaling transductions. The mutant of CHIP (p.T246M) causes the spinocerebellar autosomal recessive 16 (SCAR16), a neurodegenerative disease characterized by spinocerebellar atrophy. Previous studies have shown that Wnt signaling and activity-regulated cytoskeleton-associated protein (Arc) play important roles in neurodegenerative diseases. However, the mechanisms by which CHIP regulates Wnt signaling and the stability of Arc that may affect SCAR16 are still unclear. We show that overexpression of CHIP promoted the activation of Wnt signaling, and enhanced the interaction between LEF1 and β-catenin through heightening the K63-linked polyubiquitin chains attached to LEF1, while the knockdown of CHIP had the opposite effect. Moreover, we verified that Wnt signaling was inhibited in the rat models of SCAR16 induced by the CHIP (p.T246M) mutant. CHIP also accelerated the degradation of Arc and regulated the interaction between Arc and GSK3β by heightening the K48- or K63-linked polyubiquitin chains, which further potentiated the interaction between GSK3β and β-catenin. Our data identify that CHIP is an undescribed regulator of Wnt signaling and Arc stability which may be related to the occurrence of SCAR16.

• Cisplatin resistance
• E3 ligase
• Gastric cancer
• Oncoprotein
• Tumor suppressor

Neurodegenerative disorders and cancer may appear unrelated illnesses. Yet, epidemiologic studies indicate an inverse correlation between their respective incidences for specific cancers. Possibly explaining these findings, increasing evidence indicates that common molecular pathways are involved, often in opposite manner, in the pathogenesis of both disease families. Genetic mutations in the MAPT gene encoding for TAU protein cause an inherited form of frontotemporal dementia, a neurodegenerative disorder, but also increase the risk of developing cancer. Assigning TAU at the interface between cancer and neurodegenerative disorders, two major aging-linked disease families, offers a possible clue for the epidemiological observation inversely correlating these human illnesses. In addition, the expression level of TAU is recognized as a prognostic marker for cancer, as well as a modifier of cancer resistance to chemotherapy. Because of its microtubule-binding properties, TAU may interfere with the mechanism of action of taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network and impair cell division. Indeed, a low TAU expression is associated to a better response to taxanes. Although TAU main binding partners are microtubules, TAU is able to relocate to subcellular sites devoid of microtubules and is also able to bind to cancer-linked proteins, suggesting a role of TAU in modulating microtubule-independent cellular pathways associated to oncogenesis. This concept is strengthened by experimental evidence linking TAU to P53 signaling, DNA stability and protection, processes that protect against cancer. This review aims at collecting literature data supporting the association between TAU and cancer. We will first summarize the evidence linking neurodegenerative disorders and cancer, then published data supporting a role of TAU as a modifier of the efficacy of chemotherapies and of the oncogenic process. We will finish by addressing from a mechanistic point of view the role of TAU in de-regulating critical cancer pathways, including the interaction of TAU with cancer-associated proteins.

• DNA protection
• TAU protein
• cancer
• neurodegeneration
• tauopathies

To date, >650 E3 ubiquitin ligases have been described in humans, including >600 really interesting new genes (RINGs), 28 homologous to E6-associated protein C-terminus (HECTs) and several RING-in-between-RINGs. They are considered key regulators and therapeutic targets of many types of human cancers, including gastric cancer (GC). Among them, some RING and HECT E3 ligases are closely related to the proliferation, infiltration and prognosis of GC. During the past few years, abnormal expressions and functions of many E3 ligases have been identified in GC. However, the functional roles of E3 ligases in GC have not been fully elucidated. The present article focuses on the functional roles of E3 ligases related to the proteasome in GC. In this comprehensive review, the latest research progress on E3 ligases involved in GC and elaborate their structure, classification, functional roles and therapeutic value in GC was summarized. Finally, 30 E3 ligases that serve essential roles in regulating the development of GC were described. Some of these ligases may serve as oncogenes or tumor suppressors in GC, whereas the pathological mechanism of others needs further study; for example, constitutive photomorphogenic 1. In conclusion, the present review demonstrated that E3 ligases are crucial tumor regulatory factors and potential therapeutic targets in GC. Therefore, more studies should focus on the therapeutic targeting of E3 ligases in GC.

• E3 ligases
• gastric cancer
• signaling pathways
• targeted therapy
• ubiquitin

• CHIP
• IKKβ
• Invasion
• Proliferation
• Triple-negative breast cancer

• Cell Cycle
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Neoplasm Invasiveness
• Signal Transduction
• Triple Negative Breast Neoplasms/metabolism
• Triple Negative Breast Neoplasms/pathology
• Ubiquitin-Protein Ligases/metabolism

• 81400154 the National Natural Science Foundation of China
• QNRC2016725 the Project of invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Youth Talent
• SS201875 Suzhou Natural Science Foundation
• LCZX201813 Special Technical Project of Diagnosis and Treatment of Key Clinical Diseases of Suzhou
• SYSD2016112 Guiding Projects of Suzhou Science and Technology Plan

CHIP is an E3 ubiquitin ligase that plays contrast roles in diverse human malignancies, depending on its targets. To date, the mechanisms underlying the function of CHIP in gastric cancer remains unclear. Here, we aim to further clarify the effects of CHIP on the development and progression of gastric cancer and explore its potential target.

Stably transfected CHIP-shRNA and TRAF2-shRNA AGS gastric cancer cell lines were established using Lipofectamine 2000. Cell growth was measured by an xCelligence real-time monitoring system and colony formation assay. Cell proliferation was detected using CCK-8, Ki-67, or CFSE assays. Apoptosis was detected by TUNEL assay or Annexin V/PI-staining followed by flow cytometric analysis. Cell cycle distribution was detected by PI-staining followed by flow cytometric analysis. Cell migration and invasion abilities were measured by a real-time xCelligence system, Transwell insert, and scratch assays. The expression of cell cycle-related proteins, apoptosis-related proteins, AKT, ERK, NF-κB signaling subunits, MMP2, MMP9, and Integrin β-1 were detected by Western blotting analysis. NF-κB DNA-binding capability was quantified using an ELISA-based NF-κB activity assay. Gastric cancer tissue microarray was analyzed to investigate the expression of both CHIP and TRAF2, and their clinical significance.

The CHIP-silencing in the AGS cells was oncogenic evidenced by the appearance of capable of anchorage-independent growth. The CHIP-silencing significantly enhanced the AGS cell proliferation capability likely due to the induced phosphorylation of ERK. The CHIP-silencing significantly inhibited apoptosis due to increased expression of Bcl-2. The CHIP-silencing promoted the AGS cell migration and invasion abilities, likely by regulating the expression of Integrin β-1. TRAF2 expression was markedly decreased in the CHIP-overexpressing cells at protein level, but not at mRNA level. The TRAF2-silencing markedly inhibited the proliferation ability of the AGS cells, the defected cell proliferation and enhanced apoptosis were involved in. The TRAF2-silencing also attenuated the cell migration and invasion capacities of the AGS cells. Furthermore, the expression of CHIP was downregulated while the expression of TRAF2 was upregulated in gastric cancer tissues. TRAF2 expression is independent prognostic factors of gastric cancer. The expression of CHIP and TRAF2 was negatively correlated in the gastric cancer tissue. Lower CHIP or higher TRAF2 was significantly linked to shorter overall survival in gastric cancer patients.

TRAF2 influenced diverse aspects of cellular behavior of gastric cancer cells, including cell growth, migration, and invasion, which was in contrast to the functions of CHIP. TRAF2 could be considered as an independent prognostic factor in gastric cancer patients. It is possible that TRAF2 was a substrate of CHIP and CHIP regulated the TRAF2/NF-κB axis, which modulated diverse cellular behaviors in the AGS gastric cancer cells.

The online version of this article (10.1186/s12935-019-0832-z) contains supplementary material, which is available to authorized users.

• CHIP
• Cellular behaviors
• Gastric cancer
• Prognostic factor
• TRAF2

• CHIP E3 ligase
• UBXN2A
• colorectal cancer
• mortalin-2
• mouse
• veratridine

• metastases
• non-small-cell lung cancer
• proteasome caspase-like activity
• proteasome chymotrypsin-like activity
• total proteasome pool

• CHIP
• aggregating mutant
• autophagy
• p53
• ubiquitination

• CHIP
• NF-κB
• RHBDF2
• TACE
• Ubc13
• Uev1A

• breast cancer
• chymotrypsin-related and caspase-like activity of proteasome
• lung cancer
• metastasis
• total activity of calpains

The aim of the present study was to investigate the effect of purified Omphalia lapidescens protein (pPeOp) extracted by polyvinylpyrrolidone from the fungus Omphalia lapidescens Schroet on the proliferation and cell cycle progression of MC-4 human gastric tumor cells. Using polyvinylpyrrolidone, pPeOp was extracted from O. lapidescens Schroet. MC-4 cells were cultured with 30, 60 or 90 µg/ml pPeOp, with 5-fluorouracil used as a positive control. Survival rates of treated cells were significantly decreased compared with those of the untreated control group in a dose-dependent manner. Using flow cytometric analysis, cells treated with pPeOp were demonstrated to arrest in S phase and exhibit abnormal G0/G1 and G2/M phase cell cycle distribution. In addition, a wound healing assay demonstrated that pPeOp significantly inhibited the migration of MC-4 cells. The mRNA and protein expression levels of cyclin D1/cyclin-dependent kinase (CDK) 4, cyclin B/CDK1, cyclin A/CDK2, matrix metalloproteinase (MMP)-2 and MMP-9 were determined using reverse transcription-quantitative polymerase chain reaction analysis and western blotting. The mRNA expression level of CDK4 and cyclin A was significantly increased compared with the untreated control; however, cyclin D1, CDK1, CDK2, cyclin B, MMP-2, and MMP-9 exhibited a significantly decreased mRNA expression level, indicating that there is a negative association between concentration and cyclin D1 expression levels. The expression of the cycle arrest-associated proteins and migration-associated proteins examined were similar to the observed mRNA expression levels. In conclusion, pPeOp was identified to inhibit migration of and cause S phase cell cycle arrest in MC-4 cells.

• Omphalia lapidescens proteins
• cell cycle
• gastric cancer
• migration

• CHIP
• Cardiomyocytes
• High glucose
• NF-κB
• ROS

• Animals
• Diabetic Cardiomyopathies/genetics
• Diabetic Cardiomyopathies/metabolism
• Diabetic Cardiomyopathies/pathology
• Gene Expression Regulation
• Glucose/toxicity
• Heart Injuries/chemically induced
• Heart Injuries/genetics
• Heart Injuries/physiopathology
• Humans
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• Neoplasm Proteins/genetics
• Nucleocytoplasmic Transport Proteins/genetics
• Oxidative Stress/genetics
• Proto-Oncogene Proteins c-bcl-2/biosynthesis
• Proto-Oncogene Proteins c-bcl-2/genetics
• Rats
• Reactive Oxygen Species/metabolism
• Ubiquitin-Protein Ligases/genetics
• bcl-2-Associated X Protein/biosynthesis
• bcl-2-Associated X Protein/genetics
• p38 Mitogen-Activated Protein Kinases/genetics

Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin-associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI-encoded products form a type 4 secretion system (T4SS), a pilus-like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF-κB, but CagA and VacA are dispensable for direct NF-κB activation. NF-κB-driven gene products include cytokines/chemokines, growth factors, anti-apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF-κB promote gastric carcinogenesis. Since it has been shown that chemotherapy-caused cellular stress could elicit activation of the survival factor NF-κB, which leads to acquisition of chemoresistance, the NF-κB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF-κB activation in gastric mucosa in order to understand the role of NF-κB in gastric carcinogenesis.

• Helicobacter pylori
• NF‐κB
• Type 4 secretion system
• VacA toxin
• chemoresistance
• gastric cancer
• inflammation
• tumor microenvironment

• Animals
• Humans
• Infections/complications
• Infections/metabolism
• Inflammation Mediators/metabolism
• NF-kappa B/metabolism
• Polymorphism, Genetic
• Stomach Neoplasms/etiology
• Stomach Neoplasms/metabolism
• Tumor Suppressor Proteins/metabolism

The ubiquitin proteasome system (UPS) is important for the degradation of proteins in eukaryotic cells. It is involved in nearly every cellular process and plays an important role in maintaining body homeostasis. An increasing body of evidence has linked alterations in the UPS to gastrointestinal malignancies, including esophageal, gastric and colorectal cancers. Here, we summarize the current literature detailing the involvement of the UPS in gastrointestinal cancer, highlighting its role in tumor occurrence and development, providing information for therapeutic targets research and anti-gastrointestinal tumor drug design.

• Ubiquitin proteasome system
• Gastrointestinal cancer