• EGFR
• MCL-1
• NSCLC
• cIAP-2
• miRNAs

• Humans
• MicroRNAs/genetics
• Myeloid Cell Leukemia Sequence 1 Protein/genetics
• Myeloid Cell Leukemia Sequence 1 Protein/metabolism
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Female
• Male
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Middle Aged
• Mutation
• Gene Expression Regulation, Neoplastic
• Apoptosis
• Aged
• HEK293 Cells
• Adult
• Baculoviral IAP Repeat-Containing 3 Protein/genetics
• Baculoviral IAP Repeat-Containing 3 Protein/metabolism

• Humans
• Lymphoma, Large-Cell, Anaplastic/drug therapy
• Lymphoma, Large-Cell, Anaplastic/therapy
• Lymphoma, Large-Cell, Anaplastic/pathology
• Child
• Hematopoietic Stem Cell Transplantation
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use

• Chloroquine
• Glycolysis inhibition
• Hydroquinone exposure
• Leukemia
• MCL1 downregulation

• Humans
• Myeloid Cell Leukemia Sequence 1 Protein/genetics
• Hydroquinones/pharmacology
• Chloroquine/pharmacology
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
• K562 Cells
• Apoptosis
• MicroRNAs/metabolism
• Glycolysis

• ALCL
• ALK
• DNA-demethylating agents
• alectinib
• synergistic efficacy

• JP17H06956 and JP20K07593 Japan Society for the Promotion of Science KAKENHI
• NA Fukuoka Foundation for Sound Health Cancer Research Fund
• NA OHARA Pharmaceutical Co

• Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6)
• Lung adenocarcinoma
• Tumor microenvironment
• miR-29a
• pH low insertion peptide (pHLIP)

• Humans
• Animals
• Mice
• Carcinoma, Non-Small-Cell Lung
• Cisplatin/pharmacology
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Cell Adhesion Molecules/genetics
• Adenocarcinoma of Lung/drug therapy
• Adenocarcinoma of Lung/genetics
• Disease Models, Animal
• Tumor Microenvironment
• Antigens, CD/genetics
• GPI-Linked Proteins

• 2020R1A5A2017476 National Research Foundation of Korea

• MicroRNAs
• T-cell malignancies
• diagnosis
• lymphomas
• metabolism
• prognosis

We recently reported that miR-146a is differentially expressed in ALK+ and ALK− anaplastic large cell lymphoma (ALCL). In this study, the downstream targets of miR-146a in ALK+ ALCL were investigated by transcriptome analysis, identifying CD147 as potential target gene. Because CD147 is differentially expressed in ALK+ ALCL versus ALK− ALCL and normal T cells, this gene emerged as a strong candidate for the pathogenesis of this tumor. Here we demonstrate that CD147 is a direct target of miR-146 and contributes to the survival and proliferation of ALK+ ALCL cells in vitro and to the engraftment and tumor growth in vivo in an ALK+ ALCL-xenotransplant mouse model. CD147 knockdown in ALK+ ALCL cells resulted in loss of monocarboxylate transporter 1 (MCT1) expression, reduced glucose consumption and tumor growth retardation, as demonstrated by [¹⁸F]FDG-PET/MRI analysis. Investigation of metabolism in vitro and in vivo supported these findings, revealing reduced aerobic glycolysis and increased basal respiration in CD147 knockdown. In conclusion, our findings indicate that CD147 is of vital importance for ALK+ ALCL to maintain the high energy demand of rapid cell proliferation, promoting lactate export, and tumor growth. Furthermore, CD147 has the potential to serve as a novel therapeutic target in ALK+ ALCL, and warrants further investigation.

The antiapoptotic B cell lymphoma-2 (Bcl-2) family members are apical regulators of the intrinsic pathway of apoptosis that orchestrate mitochondrial outer membrane permeabilization (MOMP) through interactions with their proapoptotic counterparts. Overexpression of antiapoptotic Bcl-2 family proteins has been linked to therapy resistance and poor prognosis in diverse cancers. Among the antiapoptotic Bcl-2 family members, predominant overexpression of the prosurvival myeloid cell leukemia-1 (Mcl-1) has been reported in a myriad of hematological malignancies and solid tumors, contributing to therapy resistance and poor outcomes, thus making it a potential druggable target. The unique structure of Mcl-1 and its complex regulatory mechanism makes it an adaptive prosurvival switch that ensures tumor cell survival despite therapeutic intervention. This review focusses on diverse mechanisms adopted by tumor cells to maintain sustained elevated levels of Mcl-1 and how high Mcl-1 levels contribute to resistance in conventional as well as targeted therapies. Moreover, recent developments in the Mcl-1-targeted therapeutics and the underlying challenges and considerations in designing novel Mcl-1 inhibitors are also discussed.

Anaplastic large cell lymphoma is a rare type of disease that occurs throughout the world and has four subtypes. A summary and comparison of these subtypes can assist with advancing our knowledge of the mechanism and treatment of ALCL, which is helpful in making progress in this field.

Anaplastic large cell lymphoma (ALCL) is an uncommon type of non-Hodgkin’s lymphoma (NHL), as well as one of the subtypes of T cell lymphoma, accounting for 1 to 3% of non-Hodgkin’s lymphomas and around 15% of T cell lymphomas. In 2016, the World Health Organization (WHO) classified anaplastic large cell lymphoma into four categories: ALK-positive ALCL (ALK+ALCL), ALK-negative ALCL (ALK−ALCL), primary cutaneous ALCL (pcALCL), and breast-implant-associated ALCL (BIA-ALCL), respectively. Clinical symptoms, gene changes, prognoses, and therapy differ among the four types. Large lymphoid cells with copious cytoplasm and pleomorphic characteristics with horseshoe-shaped or reniform nuclei, for example, are found in both ALK+ and ALK−ALCL. However, their epidemiology and pathogenetic origins are distinct. BIA-ALCL is currently recognized as a new provisional entity, which is a noninvasive disease with favorable results. In this review, we focus on molecular pathogenesis and management of anaplastic large cell lymphoma.

• ALK (anaplastic lymphoma kinase)
• anaplastic large cell lymphoma (ALCL)
• breast-implant-associated ALCL
• management
• pathogenesis

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase expressed at early stages of normal development and in various cancers including ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), in which it is the main therapeutic target. ALK tyrosine kinase inhibitors (ALK TKIs) have greatly improved the prognosis of ALK+ALCL patients, but the emergence of drug resistance is inevitable and limits the applicability of these drugs. Although various mechanisms of resistance have been elucidated, the problem persists and there have been relatively few relevant clinical studies. This review describes research progress on ALK+ ALCL including the application and development of new therapies, especially in relation to drug resistance. We also propose potential treatment strategies based on current knowledge to inform the design of future clinical trials.

• ALCL
• ALK
• ALK-TKI
• drug resistance
• lymphoma
• therapy

• anaplastic large cell lymphoma
• cytokine
• oncogenesis
• signaling pathways

• National Science and Technology Development Agency
• Faculty of Science, Kasetsart University
• Office of National Higher Education Science Research and Innovation policy council
• National Nanotechnology Center

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase associated with Anaplastic Large Cell lymphoma (ALCL) through oncogenic translocations mainly NPM-ALK. Chemotherapy is effective in ALK(+) ALCL patients and induces remission rates of approximately 80%. The remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. Different classes of ALK tyrosine kinase inhibitors (TKI) are available but used exclusively for EML4-ALK (+) lung cancers. The significant toxicities of most ALK inhibitors explain the delay in their use in pediatric ALCL patients. Some ALCL patients do not respond to the first generation TKI or develop an acquired resistance. Combination therapy with ALK inhibitors in ALCL is the current challenge.

Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is the current challenge.

• anaplastic large cell lymphoma
• anaplastic lymphoma kinase
• chemotherapy
• drug resistance
• lymphoma
• target therapy
• tyrosine kinase

• Epigenetic drugs
• Epigenetics
• Pathogenesis
• Peripheral T-cell lymphoma
• Therapy progressions

Immunotherapy, designed to exploit the functions of the host immune system against tumors, has shown considerable potential against several malignancies. However, the utility of immunotherapy is heavily limited due to the low response rate and various side effects in the clinical setting. Immune escape of tumor cells may be a critical reason for such low response rates. Noncoding RNAs (ncRNAs) have been identified as key regulatory factors in tumors and the immune system. Consequently, ncRNAs show promise as targets to improve the efficacy of immunotherapy in tumors. However, the relationship between ncRNAs and tumor immune escape (TIE) has not yet been comprehensively summarized. In this review, we provide a detailed account of the current knowledge on ncRNAs associated with TIE and their potential roles in tumor growth and survival mechanisms. This review bridges the gap between ncRNAs and TIE and broadens our understanding of their relationship, providing new insights and strategies to improve immunotherapy response rates by specifically targeting the ncRNAs involved in TIE.

• Argonaute
• Drosha
• RNAi
• biogenesis
• disease pathogenesis
• microRNA
• super-enhancer
• synthetic biology

• Animals
• Argonaute Proteins/metabolism
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Messenger/metabolism
• Synthetic Biology

• NA Osamu Hayaishi Memorial Scholarship for Study Abroad

• Hepatocellular carcinoma
• Mutant ACTB mRNA 3′-UTR
• miR-1
• miR-29a

Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that regulate gene expression in eukaryotes. Recently, exosomes from cardiomyocytes (CMs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including circRNA. However, the functions of exosomal circRNAs are not clear. The present research is aimed at determining whether circHIPK3 released from hypoxia-pretreated CMs is transferred into cardiac microvascular endothelial cells (CMVECs) by exosomes and becomes functionally active in the CMVECs under oxidative stress conditions.

Quantitative polymerase chain reactions were conducted to detect the expression pattern of circHIPK3 in CMVECs under oxidative stress. Annexin V-FITC/propidium iodide (PI) staining assays, TUNEL assays, ROS assays, and Western blot analysis were conducted to detect the role of exosomal circHIPK3 in CMVEC function in vitro. Luciferase activity assays and RNA immunoprecipitation studies were conducted in vitro to reveal the mechanism of circHIPK3-mediated CMVEC function.

circHIPK3 expression was significantly upregulated in hypoxic exosomes (HPC-exos) compared with normoxic exosomes (Nor-exos). Moreover, HPC-exos induced stronger antioxidant effects than Nor-exos. The silencing or overexpression of circHIPK3 changed CMVEC survival under oxidative conditions in vitro. Furthermore, circHIPK3 silencing in HPC-exos abrogated the protective effects of HPC-exos in CMVECs, as shown by increased levels of apoptosis, ROS, MDA, and proapoptotic proteins. circHIPK3 acted as an endogenous miR-29a sponge to sequester and inhibit miR-29a activity, which led to increased IGF-1 expression. The ectopic expression of miR-29a mimicked the effect of circHIPK3 silencing in CMVECs in vitro.

circHIPK3 in HPC-exos plays a role in CMVECs under oxidative conditions through miR-29a-mediated IGF-1 expression, leading to a decrease in oxidative stress-induced CMVECs dysfunction. These data suggest that the exosomal circRNA in CMs is a potential target to control CMVECs dysfunction under oxidative conditions.

Acute myeloid leukemia (AML) is a set of Myeloproliferative neoplasms that are identified by excessive growth of myeloid blasts and production of abnormal blood cells. AML is the most common type of acute leukemia that occurs in adults. In addition, AML progresses rapidly and is considered a fatal disease. Thus, there is an urgent need to find new targets for molecularly designed therapies. In This study, we evaluated the circulatory levels of microRNA-29a-3p (miR-29a-3p) and miR-92a-3p beside exploring the expression pattern of their target gene myeloid cell leukemia sequence1 (MCL1) to investigate the role of these molecules in AML pathophysiology and to assess their ability to diagnose AML patients.

40 adult AML patients along with 20 healthy subjects were enrolled in this study. Plasma were separated from venous blood samples, collected on EDTA, of all individuals were used to assess circulating miRNAs’ levels. In the meantime, total RNA was extracted from isolated leukocytes and was used to quantify target mRNA transcript levels.

Our data revealed that the circulating levels of miR-29a-3p and miR-92a-3p exhibited significant reduction in 90% and 100% of AML patients, respectively, when compared to the control group (p<0.001). On the other hand, the transcript level of the target gene of these miRNAs, MCL1, showed a sharp increase in 77.5% (p<0.001) of AML patients, along with a negative correlation with its regulatory miRNAs, miR-29a-3p and miR-92a-3p.

Our data validates the negative regulatory role of miR-29a-3p and miR-92a-3p to the expression levels of MCL1 in peripheral blood and indicates that these miRNAs can be used as non-invasive diagnostic markers. Furthermore, our study highlights the therapeutic potential of miR-29a-3p and miR-92a-3p to target and downregulate a very important gene (MCL1), which is highly implicated in the pathogenesis of AML.

• AML
• MCL1
• RNA
• miRNAs
• qPCR

• JAK/STAT
• STAT3
• T cell lymphoma
• lymphomagenesis

• Apoptosis
• Cancer
• Endoplasmic reticulum stress
• MicroRNAs
• Necroptosis

• Antagomirs/genetics
• Antagomirs/metabolism
• Antagomirs/therapeutic use
• Antineoplastic Agents/metabolism
• Antineoplastic Agents/therapeutic use
• Apoptosis/genetics
• Endoplasmic Reticulum Stress/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• MicroRNAs/agonists
• MicroRNAs/antagonists & inhibitors
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Myeloid Cell Leukemia Sequence 1 Protein/genetics
• Myeloid Cell Leukemia Sequence 1 Protein/metabolism
• Necroptosis/genetics
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• Oligoribonucleotides/genetics
• Oligoribonucleotides/metabolism
• Oligoribonucleotides/therapeutic use
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Signal Transduction
• TNF-Related Apoptosis-Inducing Ligand/genetics
• TNF-Related Apoptosis-Inducing Ligand/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• fas Receptor/genetics
• fas Receptor/metabolism

• Apoptosis
• Autism
• BCL2
• CASP8
• hsa-29c-3p

Non-coding RNAs (ncRNAs) are essential regulators of gene expression. In recent years, it has become more and more evident that the different classes of ncRNAs, such as micro RNAs, long non-coding RNAs and circular RNAs are organized in tightly controlled networks. It has been suggested that deregulation of these networks can lead to disease. Several studies show a contribution of these so-called competing-endogenous RNA networks in various cancer entities. In this review, we highlight the involvement of ncRNA networks in anaplastic-large cell lymphoma (ALCL), a T-cell neoplasia. A majority of ALCL cases harbor the molecular hallmark of this disease, a fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin (NPM, NPM1) gene leading to a permanently active kinase that promotes the malignant phenotype. We have focused especially on ncRNAs that are regulated by the NPM-ALK fusion gene and illustrate how their deregulation contributes to the pathogenesis of ALCL. Lastly, we summarize the findings and point out potential therapeutic implications.

• anaplastic large cell lymphoma
• anaplastic lymphoma kinase
• biomarkers
• circRNA
• competing endogenous RNA
• drug resistance
• lncRNA
• lymphoma
• microRNA
• non-coding RNA

• Expression profile analysis
• Ovarian development
• Small Tail Han Sheep
• miRNAs

Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness.

microRNA expression profiles from 197 glioblastomas were analyzed to identify the candidate miRNAs that are correlated to glioblastoma aggressiveness. The candidate miRNA, miR-29a, was further studied in vitro and in vivo.

Members of the miR-29 subfamily display increased expression in the two glioblastoma subclasses with the worst prognoses (astrocytic and neural). We observed that miR-29a is among the microRNAs that are most positively-correlated with PTEN copy number in glioblastoma, and that miR-29a promotes glioblastoma growth and invasion in part by targeting PTEN. In PTEN-deficient glioblastoma cells, however, miR-29a nevertheless activates AKT by downregulating the metastasis suppressor, EphB3. In addition, miR-29a robustly promotes invasion in PTEN-deficient glioblastoma cells by repressing translation of the Sox4 transcription factor, and this upregulates the invasion-promoting protein, HIC5. Indeed, we identified Sox4 as the most anti-correlated predicted target of miR-29a in glioblastoma. Importantly, inhibition of endogenous miR-29a decreases glioblastoma growth and invasion in vitro and in vivo, and increased miR-29a expression in glioblastoma specimens correlates with decreased patient survival.

Taken together, these data identify miR-29a as a master regulator of glioblastoma growth and invasion.

The online version of this article (10.1186/s13046-019-1026-1) contains supplementary material, which is available to authorized users.

• Glioblastoma
• Invasion
• PTEN
• Sox4
• miR-29a

Although lymphoma is a very heterogeneous group of biologically complex malignancies, tumor cells across all B cell lymphoma subtypes share a set of underlying traits that promote the development and sustain malignant B cells. One of these traits, the ability to evade apoptosis, is essential for lymphoma development. Alterations in the Bcl-2 family of proteins, the key regulators of apoptosis, is a hallmark of B cell lymphoma. Significant efforts have been made over the last 30 years to advance knowledge of the biology, molecular mechanisms, and therapeutic potential of targeting Bcl-2 family members. In this review, we will highlight the complexities of the Bcl-2 family, including our recent discovery of overexpression of the anti-apoptotic Bcl-2 family member Bcl-w in lymphomas, and describe recent advances in the field that include the development of inhibitors of anti-apoptotic Bcl-2 family members for the treatment of B cell lymphomas and their performance in clinical trials.

• B cell lymphoma
• BCL-2
• BCL-W
• BH-3 mimetic
• CLL
• apoptosis
• navitoclax
• venetoclax

For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors.

• cancer
• children
• leukemia
• lymphoma
• miRNA
• review

• Biomarkers, Tumor/genetics
• Child
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Hematologic Neoplasms/genetics
• Humans
• MicroRNAs/genetics
• Prognosis

• MiRNA therapeutics
• MicroRNA
• MicroRNA regulation
• Oncogene addiction
• Tumour initiation
• Tumour progression

• Disease Progression
• Humans
• MicroRNAs/genetics
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/therapy
• Oncogenes

• 19995 Cancer Research UK
• 20465 Cancer Research UK
• C5759/A20971 Cancer Research UK
• C5759/A20465 Cancer Research UK

Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed.

• ALK (anaplastic lymphoma kinase)
• anaplastic large cell lymphoma (ALCL)
• breast implant-associated ALCL
• lymphoma
• morphology

Systemic anaplastic large-cell lymphoma (ALCL) is a childhood T cell neoplasm defined by the presence or absence of translocations that lead to the ectopic expression of anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Polychemotherapy involving doxorubicin is the standard first-line treatment but for the 25 to 35% of patients who relapse and develop resistance the prognosis remains poor. We studied the potential role of the microRNA miR-125b in the development of resistance to doxorubicin in NPM-ALK(+) ALCL. Our results show that miR-125b expression is repressed in NPM-ALK(+) cell lines and patient samples through hypermethylation of its promoter. NPM-ALK activity, in cooperation with DNA topoisomerase II (Topo II) and DNA methyltransferase 1 (DNMT1), is responsible for miR-125b repression through DNA hypermethylation. MiR-125b repression was reversed by the inhibition of DNMTs with decitabine or the inhibition of DNA topoisomerase II with either doxorubicin or etoposide. In NPM-ALK(+) cell lines, doxorubicin treatment led to an increase in miR-125b levels by inhibiting the binding of DNMT1 to the MIR125B1 promoter and downregulating the pro-apoptotic miR-125b target BAK1. Reversal of miR-125b silencing, increased miR-125b levels and reduced BAK1 expression also led to a lower efficacy of doxorubicin, suggestive of a pharmacoresistance mechanism. In line with this, miR-125b repression and increased BAK1 expression correlated with early relapse in human NPM-ALK(+) ALCL primary biopsies. Collectively our findings suggest that miR-125b could be used to predict therapeutic outcome in NPM-ALK(+) ALCL.

• DNA topoisomerase II
• DNMT1
• chemoresistance
• doxorubicin
• miR-125b

• biomarkers
• cancer
• metastases
• miR-29a
• microRNA
• proliferation

Anti-apoptotic B cell lymphoma 2 (BCL2) family members (BCL2, MCL1, BCLxL, BCLW, and BFL1) are key players in the regulation of intrinsic apoptosis. Dysregulation of these proteins not only impairs normal development, but also contributes to tumor progression and resistance to various anti-cancer therapies. Therefore, cells maintain strict control over the expression of anti-apoptotic BCL2 family members using multiple mechanisms. Over the past two decades, the importance of post-transcriptional regulation of mRNA in controlling gene expression and its impact on normal homeostasis and disease have begun to be appreciated. In this review, we discuss the RNA binding proteins (RBPs) and microRNAs (miRNAs) that mediate post-transcriptional regulation of the anti-apoptotic BCL2 family members. We describe their roles and impact on alternative splicing, mRNA turnover, and mRNA subcellular localization. We also point out the importance of future studies in characterizing the crosstalk between RBPs and miRNAs in regulating anti-apoptotic BCL2 family member expression and ultimately apoptosis.

• RNA binding proteins
• alternative splicing
• anti-apoptotic BCL2 subfamily
• apoptosis
• mRNA stability
• mRNA subcellular localization
• microRNA
• post-transcriptional regulation

• anaplastic lymphoma kinase
• ceritinib
• crizotinib
• neuroblastoma
• non-small-cell lung cancer
• tyrosine kinase inhibitor

Anaplastic large cell lymphomas (ALCL) are mainly characterized by harboring the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The ALK inhibitor, crizotinib specifically induced apoptosis in Ba/F3 cells expressing NPM-ALK by inhibiting the activation of NPM-ALK and its downstream molecule, signal transducer and activator of transcription factor 3 (STAT3). We found that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although α-tocopherol suppressed the inhibitory effects of crizotinib on the signaling axis including NPM-ALK and STAT3, it had no influence on the intake of crizotinib into cells. Crizotinib also directly inhibited the kinase activity of NPM-ALK; however, this inhibitory effect was not altered by the co-treatment with α-tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with α-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of α-tocopherol attenuated the anti-tumor activity of crizotinib against NPM-ALK-provoked tumorigenesis in vivo. Furthermore, the α-tocopherol-induced inhibition of crizotinib-caused apoptosis was also observed in NPM-ALK-positive cells derived from ALCL patients, namely, SUDHL-1 and Ki-JK. Collectively, these results not only revealed the novel mechanism underlying crizotinib-induced apoptosis in NPM-ALK-positive cells, but also suggest that the anti-tumor effects of crizotinib are attenuated when it is taken in combination with vitamin E.

• Animals
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Line
• Cell Line, Transformed
• Cell Line, Tumor
• Cell Nucleus/drug effects
• Cell Nucleus/metabolism
• Crizotinib
• Female
• Humans
• Lymphoma, Large-Cell, Anaplastic/metabolism
• Mice, Nude
• Phosphorylation/drug effects
• Protein-Tyrosine Kinases/metabolism
• Pyrazoles/pharmacology
• Pyridines/pharmacology
• Reactive Oxygen Species/metabolism
• Subcellular Fractions/metabolism
• alpha-Tocopherol/pharmacology

• Ministry of Education, Culture, Sports, Science and Technology
• NOVARTIS Foundation (Japan) for the promotion of Science

The discovery of microRNA (miRNA) has provided new and powerful tools for studying the mechanism, diagnosis and treatment of human cancers. The down-regulation of tumor suppressive miRNA by hypermethylation of CpG island (CpG is shorthand for 5′-C-phosphate-G-3′, that is, cytosine and guanine separated by only one phosphate) is emerging as a common hallmark of cancer and appears to be involved in drug resistance. This review discusses the role of miRNA and DNA methylation in drug resistance mechanisms and highlights their potential as anti-cancer therapies in Anaplastic Lymphoma Kinase (ALK)-positive lymphomas. These are a sub-type of non-Hodgkin’s lymphomas that predominantly affect children and young adults and are characterized by the expression of the nucleophosmin (NPM)/ALK chimeric oncoprotein. Dysregulation of miRNA expression and regulation has been shown to affect several signaling pathways in ALK carcinogenesis and control tumor growth, both in cell lines and mouse models. These data suggest that the modulation of DNA methylation and/or the expression of these miRNA could serve as new biomarkers and have potential therapeutic applications for ALK-positive malignancies.

• ALK
• DNA methylation
• biomarkers
• epigenetics
• lymphomas
• microRNA (miRNA)
• novel treatments

MicroRNAs exist widely in viruses, plants and animals. As endogenous small non-coding RNAs, miRNAs regulate a variety of biological processes. Tissue miRNA expression studies have discovered numerous functions for miRNAs in various tissues of chicken, but the regulation of miRNAs in chicken pituitary and hypothalamic development related to high and low egg-laying performance has remained unclear.

In this study, using high-throughput sequencing technology, we sequenced two tissues (pituitary and hypothalamus) in 3 high- and 3 low-rate egg production Luhua chickens at the age of 300 days. By comparing low- and high-rate egg production chickens, 46 known miRNAs and 27 novel miRNAs were identified as differentially expressed (P < 0.05). Six differentially expressed known miRNAs, which are expressed in both tissues, were used in RT-qPCR validation and SNP detection. Among them, seven SNPs in two miRNA precursors (gga-miR-1684a and gga-miR-1434) were found that might enhance or reduce the production of the mature miRNAs. In addition, 124 and 30 reciprocally expressed miRNA-target pairs were identified by RNA-seq in pituitary and hypothalamic tissues, respectively and randomly selected candidate miRNA and miRNA-target pairs were validated by RT-qPCR in Jiuyuan black fowl. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation illustrated that a large number of egg laying-related pathways were enriched in the high-rate egg production chickens, including ovarian steroidogenesis and steroid hormone biosynthesis.

These differentially expressed miRNAs and their predicted target genes, especially identified reciprocally expressed miRNA-target pairs, advance the study of miRNA function and egg production associated miRNA identification. The analysis of the miRNA-related SNPs and their effects provided insights into the effects of SNPs on miRNA biogenesis and function. The data generated in this study will further our understanding of miRNA regulation mechanisms in the chicken egg-laying process.

The online version of this article (doi:10.1186/s12864-017-3644-3) contains supplementary material, which is available to authorized users.

• Egg-laying
• Luhua chicken
• Reproduction regulation
• SNPs
• qRT-PCR

• PBMC
• apoptosis
• lncRNA
• p53
• paracrine
• radiation

• Apoptosis/genetics
• Apoptosis/radiation effects
• Cell Cycle Checkpoints/genetics
• Cell Cycle Checkpoints/radiation effects
• Dose-Response Relationship, Radiation
• Gene Expression Regulation/radiation effects
• Humans
• Leukocytes, Mononuclear/metabolism
• Leukocytes, Mononuclear/radiation effects
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Models, Biological
• Principal Component Analysis
• RNA, Long Noncoding/blood
• RNA, Long Noncoding/genetics
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Radiation, Ionizing
• Real-Time Polymerase Chain Reaction
• Time Factors
• Tumor Suppressor Protein p53/metabolism

• ALK
• ALK inhibitors
• ALK rearrangements
• acquired resistance to ALK inhibitors
• targeted therapy

• Anaplastic Lymphoma Kinase
• Antineoplastic Agents/therapeutic use
• Clinical Trials as Topic/methods
• Genetic Variation/genetics
• Humans
• Neoplasms/diagnosis
• Neoplasms/drug therapy
• Neoplasms/genetics
• Receptor Protein-Tyrosine Kinases/genetics

An increasing amount of evidence indicates that microRNAs (miRNAs) are closely related to many important biological processes and play a significant role in various human diseases.

• Myc
• apoptosis
• miRNA-29a
• myeloma

• anaplastic lymphoma kinase
• cancer
• inhibitor
• resistance
• therapy
• tyrosine kinase

• B cell lymphomas
• Peripheral T cell lymphomas (PTCLs)
• T cell lymphoma