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Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling. Exploring new therapy target is urgent. The purpose of the present study is to investigate whether and how spliced x-box binding protein 1 (xbp1s), a key component of endoplasmic reticulum stress (ERS), contributes to the pathogenesis of PH. Forty male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), MCT+AAV-CTL (control), and MCT+AAV-xbp1s. The xbp1s protein levels were found to be elevated in lung tissues of the MCT group. Intratracheal injection of adeno-associated virus serotype 1 carrying xbp1s shRNA (AAV-xbp1s) to knock down the expression of xbp1s effectively ameliorated the MCT-induced elevation of right ventricular systolic pressure (RVSP), total pulmonary resistance (TPR), right ventricular hypertrophy and medial wall thickness of muscularized distal pulmonary arterioles. The abnormally increased positive staining rates of proliferating cell nuclear antigen (PCNA) and Ki67 and decreased positive staining rates of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) in pulmonary arterioles were also reversed in the MCT+AAV-xbp1s group. For mechanistic exploration, bioinformatics prediction of the protein network was performed on the STRING database, and further verification was performed by qRT-PCR, Western blots and co-immunoprecipitation (Co-IP). DNA damage-inducible transcript 3 (Ddit3) was identified as a downstream protein that interacted with xbp1s. Overexpression of Ddit3 restored the decreased proliferation, migration and cell viability caused by silencing of xbp1s. The protein level of Ddit3 was also highly consistent with xbp1s in the animal model. Taken together, our study demonstrated that xbp1s-Ddit3 may be a potential target to interfere with vascular remodeling in PH.

To date, mechanistic treatments targeting the initial cause of Parkinson's disease (PD) are limited due to the underlying biological cause(s) been unclear. Endosomes and their associated cellular homeostasis processes have emerged to have a significant role in the pathophysiology associated with PD. Several variants within retromer complex have been identified and characterised within familial PD patients. The retromer complex represents a key sorting platform within the endosomal system that regulates cargo sorting that maintains cellular homeostasis. In this review, we summarise the current understandings of how PD-associated retromer variants disrupt cellular trafficking and how the retromer complex can interact with other PD-associated genes to contribute to the disease progression.

Conventional approaches in drug development involve testing on 2D-cultured mammalian cells, followed by experiments in rodents. Although this is the common strategy, it has significant drawbacks: in 2D cell culture with human cells, the cultivation at normoxic conditions on a plastic or glass surface is an artificial situation that significantly changes energy metabolism, shape and intracellular signaling, which in turn directly affects drug response. On the other hand, rodents as the most frequently used animal models have evolutionarily separated from primates about 100 million years ago, with significant differences in physiology, which frequently leads to results not reproducible in humans. As an alternative, spheroid technology and micro-organoids have evolved in the last decade to provide 3D context for cells similar to native tissue. However, organoids used for drug testing are usually just in the 50–100 micrometers range and thereby too small to mimic micro-environmental tissue conditions such as limited nutrient and oxygen availability. An attractive alternative offers 3D bioprinting as this allows fabrication of human tissue equivalents from scratch with hollow structures for perfusion and strict spatiotemporal control over the deposition of cells and extracellular matrix proteins. Thereby, tissue surrogates with defined geometry are fabricated that offer unique opportunities in exploring cellular cross-talk, mechanobiology and morphogenesis. These tissue-equivalents are also very attractive tools in drug testing, as bioprinting enables standardized production, parallelization, and application-tailored design of human tissue, of human disease models and patient-specific tissue avatars. This review, therefore, summarizes recent advances in 3D bioprinting technology and its application for drug screening.

The Hippo pathway is a dynamic cellular signalling nexus that regulates differentiation and controls cell proliferation and death. If the Hippo pathway is not precisely regulated, the functionality of the upstream kinase module is impaired, which increases nuclear localisation and activity of the central effectors, the transcriptional co-regulators YAP and TAZ. Pathological YAP and TAZ hyperactivity consequently cause cancer, fibrosis and developmental defects. The Hippo pathway controls an array of fundamental cellular processes, including adhesion, migration, mitosis, polarity and secretion of a range of biologically active components. Recent studies highlight that spatio-temporal regulation of Hippo pathway components are central to precisely controlling its context-dependent dynamic activity. Several levels of feedback are integrated into the Hippo pathway, which is further synergized with interactors outside of the pathway that directly regulate specific Hippo pathway components. Likewise, Hippo core kinases also ‘moonlight’ by phosphorylating multiple substrates beyond the Hippo pathway and thereby integrates further flexibility and robustness in the cellular decision-making process. This topic is still in its infancy but promises to reveal new fundamental insights into the cellular regulation of this therapeutically important pathway. We here highlight recent advances emphasising feedback dynamics and multilevel regulation of the Hippo pathway with a focus on mitosis and cell migration, as well as discuss potential productive future research avenues that might reveal novel insights into the overall dynamics of the pathway.

Peripheral nerve injury can result in severe long-term disability and current clinical approaches for repairing large gaps rely on the nerve autograft. Engineered Neural Tissue (EngNT) has been developed to provide living aligned therapeutic cells in a stabilised collagen hydrogel, mimicking the key features of the autograft. This Perspective article will introduce the field and discuss the current stage of translation, highlighting the key opportunities for commercial and clinical development.

Cancer is initiated largely by specific cohorts of genetic aberrations, which are generated by mutagens and often mimic active growth factor receptors, or downstream effectors. Once initiated cells outgrow and attract blood vessels, a multi-step process, called metastasis, disseminates cancer cells primarily through vascular routes. The major steps of the metastatic cascade comprise intravasation into blood vessels, circulation as single or collectives of cells, and eventual colonization of distant organs. Herein, we consider metastasis as a multi-step process that seized principles and molecular players employed by physiological processes, such as tissue regeneration and migration of neural crest progenitors. Our discussion contrasts the irreversible nature of mutagenesis, which establishes primary tumors, and the reversible epigenetic processes (e.g. epithelial–mesenchymal transition) underlying the establishment of micro-metastases and secondary tumors. Interestingly, analyses of sequencing data from untreated metastases inferred depletion of putative driver mutations among metastases, in line with the pivotal role played by growth factors and epigenetic processes in metastasis. Conceivably, driver mutations may not confer the same advantage in the microenvironment of the primary tumor and of the colonization site, hence phenotypic plasticity rather than rigid cellular states hardwired by mutations becomes advantageous during metastasis. We review the latest reported examples of growth factors harnessed by the metastatic cascade, with the goal of identifying opportunities for anti-metastasis interventions. In summary, because the overwhelming majority of cancer-associated deaths are caused by metastatic disease, understanding the complexity of metastasis, especially the roles played by growth factors, is vital for preventing, diagnosing and treating metastasis.

Adhesive structures between cells and with the surrounding matrix are essential for the development of multicellular organisms. In addition to providing mechanical integrity, they are key signalling centres providing feedback on the extracellular environment to the cell interior, and vice versa. During development, mitosis and repair, cell adhesions must undergo extensive remodelling. Post-translational modifications of proteins within these complexes serve as switches for activity. Tyrosine phosphorylation is an important modification in cell adhesion that is dynamically regulated by the protein tyrosine phosphatases (PTPs) and protein tyrosine kinases. Several PTPs are implicated in the assembly and maintenance of cell adhesions, however, their signalling functions remain poorly defined. The PTPs can act by directly dephosphorylating adhesive complex components or function as scaffolds. In this review, we will focus on human PTPs and discuss their individual roles in major adhesion complexes, as well as Hippo signalling. We have collated PTP interactome and cell adhesome datasets, which reveal extensive connections between PTPs and cell adhesions that are relatively unexplored. Finally, we reflect on the dysregulation of PTPs and cell adhesions in disease.

Living cells interpret a variety of signals in different contexts to elucidate functional responses. While the understanding of signalling molecules, their respective receptors and response at the gene transcription level have been relatively well-explored, how exactly does a single cell interpret a plethora of time-varying signals? Furthermore, how their subsequent responses at the single cell level manifest in the larger context of a developing tissue is unknown. At the same time, the biophysics and chemistry of how receptors are trafficked through the complex dynamic transport network between the plasma membrane–endosome–lysosome–Golgi–endoplasmic reticulum are much more well-studied. How the intracellular organisation of the cell and inter-organellar contacts aid in orchestrating trafficking, as well as signal interpretation and modulation by the cells are beginning to be uncovered. In this review, we highlight the significant developments that have strived to integrate endosomal trafficking, signal interpretation in the context of developmental biology and relevant open questions with a few chosen examples. Furthermore, we will discuss the imaging technologies that have been developed in the recent past that have the potential to tremendously accelerate knowledge gain in this direction while shedding light on some of the many challenges.

Epithelial–mesenchymal transition or EMT is an extremely dynamic process involved in conversion of epithelial cells into mesenchymal cells, stimulated by an ensemble of signaling pathways, leading to change in cellular morphology, suppression of epithelial characters and acquisition of properties such as enhanced cell motility and invasiveness, reduced cell death by apoptosis, resistance to chemotherapeutic drugs etc. Significantly, EMT has been found to play a crucial role during embryonic development, tissue fibrosis and would healing, as well as during cancer metastasis. Over the years, work from various laboratories have identified a rather large number of transcription factors (TFs) including the master regulators of EMT, with the ability to regulate the EMT process directly. In this review, we put together these EMT TFs and discussed their role in the process. We have also tried to focus on their mechanism of action, their interdependency, and the large regulatory network they form. Subsequently, it has become clear that the composition and structure of the transcriptional regulatory network behind EMT probably varies based upon various physiological and pathological contexts, or even in a cell/tissue type-dependent manner.

The endomembrane system of mammalian cells provides massive capacity for the segregation of biochemical reactions into discrete locations. The individual organelles of the endomembrane system also require the ability to precisely transport material between these compartments in order to maintain cell homeostasis; this process is termed membrane traffic. For several decades, researchers have been systematically identifying and dissecting the molecular machinery that governs membrane trafficking pathways, with the overwhelming majority of these studies being carried out in cultured cells growing as monolayers. In recent years, a number of methodological innovations have provided the opportunity for cultured cells to be grown as 3-dimensional (3D) assemblies, for example as spheroids and organoids. These structures have the potential to better replicate the cellular environment found in tissues and present an exciting new opportunity for the study of cell function. In this mini-review, we summarize the main methods used to generate 3D cell models and highlight emerging studies that have started to use these models to study basic cellular processes. We also describe a number of pieces of work that potentially provide the basis for adaptation for deeper study of how membrane traffic is coordinated in multicellular assemblies. Finally, we comment on some of the technological challenges that still need to be overcome if 3D cell biology is to become a mainstream tool toward deepening our understanding of the endomembrane system in mammalian cells.

Lung cancer remains the leading cause of cancer mortality because of its metastatic potential and high malignancy. The discovery of new applications for old drugs is a shortcut for cancer therapy. We recently investigated the antitumor effect of digoxin, a well-established drug for treating heart failure, against nonsmall cell lung cancer A549 and H1299 cells. Digoxin inhibited the proliferation and colony-forming ability of the two cell lines and arrested the cell cycle at the G0/G1 phase in A549 cells and the G2/M phase in H1299 cells. Mitochondria-mediated apoptosis was induced in A549 cells but not in H1299 cells after treatment with digoxin. Moreover, digoxin inhibited the migration, invasion, adhesion and epithelial–mesenchymal transition of A549 and H1299 cells. Autophagy was induced in both cell lines after treatment with digoxin, with an increase in autophagosome foci. In addition, digoxin inhibited the phosphorylation of Akt, mTOR and p70S6K, signaling molecules of the PI3K/Akt pathway that are known to be involved in tumor cell survival, proliferation, metastasis and autophagy. Our findings suggest that digoxin has the potential to be used for therapy for human nonsmall cell lung cancer, but further evidence is required.

Sauchinone, a lignan isolated from Saururus chinenesis, is known to exhibit anti-inflammatory and anti-oxidant effects. Recently, sauchinone has been reported to inhibit the growth of various cancer cells, but its effects on breast cancer cells remain poorly understood. In the present study, we investigated the effects of sauchinone on the growth of breast cancer cells along with the underlying molecular mechanisms. Our results show that sauchinone treatment markedly inhibited the proliferation, migration, and invasion of breast cancer cells. Sauchinone reduced the phosphorylation of Akt, ERK, and CREB increased by transforming growth factor-β (TGF-β). In particular, sauchinone treatment suppressed the expression of matrix metalloproteinase (MMP)-13 (MMP13) by regulating the Akt-CREB signaling pathway. Sauchinone was less effective in inhibiting cell migration in Mmp13-knockdown cells than in control cells, suggesting that MMP13 may be a novel target for sauchinone. Our study suggests that sauchinone inhibits the growth of breast cancer cells by attenuating the Akt-CREB-MMP13 pathway. In addition, the targeted inhibition of MMP13 by sauchinone represents a promising approach for the treatment of breast cancer.

The pathogenesis of diabetic nephropathy (DN) has not been fully elucidated. MicroRNAs (miRNAs) play an important role in the onset and development of DN renal fibrosis. Thus, the present study aimed to investigate the effect of miR-92d-3p on the progression of DN renal fibrosis. We used qRT-PCR to detect the expression levels of miR-92d-3p in the kidneys of patients with DN. Then, after transfecting lentiviruses containing miR-92d-3p into the kidneys of a DN mouse model and HK-2 cell line, we used qRT-PCR to detect the expression levels of miR-92d-3p, C3, HMGB1, TGF-β1, α-SMA, E-cadherin, and Col I. The expression levels of interleukin (IL) 1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) in the HK-2 cells were detected through enzyme-linked immunosorbent assay (ELISA), and Western blotting and immunofluorescence were used in detecting the expression levels of fibronectin, α-SMA, E-cadherin, and vimentin. Results showed that the expression levels of miR-92d-3p in the kidney tissues of patients with DN and DN animal model mice decreased, and C3 stimulated HK-2 cells to produce inflammatory cytokines. The C3/HMGB1/TGF-β1 pathway was activated, and epithelial-to-interstitial transition (EMT) was induced in the HK-2 cells after human recombinant C3 and TGF-β1 protein were added. miR-92d-3p inhibited inflammatory factor production by C3 in the HK-2 cells and the activation of the C3/HMGB1/TGF-β1 pathway and EMT by C3 and TGF-β1. miR-92d-3p suppressed the progression of DN renal fibrosis by inhibiting the activation of the C3/HMGB1/TGF-β1 pathway and EMT.

Background: The decreased level of miR-192-5p has been reported in several kinds of cancers, including bladder, colon, ovarian, and non-small cell lung cancer. However, the expression and function of miR-192-5p in papillary thyroid carcinoma/cancer (PTC) remains unknown. Objective: The present study aimed to explore the function and underlying mechanism of miR-192-5p in PTC development. Methods: PTC tissues and relative normal controls from PTC patients were collected. qRT-PCR analysis was performed to measure miR-192-5p and SH3RF3 mRNA level in PTC tissues and cell lines. CCK-8 method and FCM assay were used to test cell proliferation and apoptosis in TPC-1 cells, respectively. The abilities of cell migration and invasion were detected by wound healing and transwell assays, respectively. The protein expression was evaluated by Western blot. The interaction between miR-192-5p and Src homology 3 (SH3) domain containing ring finger 3 (SH3RF3) were confirmed by dual-luciferase reporter assay. Results: MiR-192-5p level was obviously decreased in PTC tissues and cell lines. Overexpression of miR-192-5p suppressed proliferation, migration, invasion, and EMT process, while induced apoptosis in TPC-1 cells. In addition, miR-192-5p negatively modulated SH3RF3 expression by binding to its 3′-untranslated region (3′UTR). Silencing SH3RF3 inhibited the migration, invasion, and EMT of TPC-1 cells. In the meantime, matrine, an alkaloid extracted from herb, exerted its anti-cancer effects in PTC cells dependent on increase in miR-192-5p expression and decrease in SH3RF3 expression. Conclusion: We firstly declared that miR-192-5p played a tumor suppressive role in PTC via targeting SH3RF3. Moreover, matrine exerted its anti-cancer effects in PTC via regulating miR-192-5p/SH3RF3 pathway.

Directed cell migration is critical for embryogenesis and organ development, wound healing and the immune response. Microtubules are dynamic polymers that control directional migration through a number of coordinated processes: microtubules are the tracks for long-distance intracellular transport, crucial for delivery of new membrane components and signalling molecules to the leading edge of a migrating cell and the recycling of adhesion receptors. Microtubules act as force generators and compressive elements to support sustained cell protrusions. The assembly and disassembly of microtubules is coupled to Rho GTPase signalling, thereby controlling actin polymerisation, myosin-driven contractility and the turnover of cellular adhesions locally. Cross-talk of actin and microtubule dynamics is mediated through a number of common binding proteins and regulators. Furthermore, cortical microtubule capture sites are physically linked to focal adhesions, facilitating the delivery of secretory vesicles and efficient cross-talk. Here we summarise the diverse functions of microtubules during cell migration, aiming to show how they contribute to the spatially and temporally coordinated sequence of events that permit efficient, directional and persistent migration.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, metastasis accounts for most of the cases. Angiogenesis plays an important role in cancer metastasis, but how tumor cells affect the function of endothelial cells by dictating their microRNA (miRNA) expression remains largely unknown. Differentially expressed miRNAs (DEMs) were identified through dataset downloaded from the Gene Expression Omnibus (GEO) database and analyzed by GEO2R. We then used online tools to obtain potential targets of candidate miRNAs and functional enrichment analysis, as well as the protein-protein interaction (PPI). Finally, the function of miR-302c-3p was validated through in vitro assay. In the current study, we found that HCC cells altered miRNA expression profiles of human umbilical vein endothelial cells (HUVECs) and miR-302c-3p was the most down-regulated miRNA in HUVECs when they were co-cultured with HCC-LM3 cells. Functional enrichment analysis of the candidate targets revealed that these genes were involved in epigenetic regulation of gene expression, in particular, cytosine methylation. In addition, PPI network demonstrated distinct roles of genes targeted by miR-302c-3p. Importantly, inhibition of angiogenesis, migration and permeability by the most down-regulated miR-302c-3p in HUVECs was confirmed in vitro. These findings brought us novel insight into the regulation of angiogenesis by HCC cells and provided potential targets for the development of therapeutic strategies.

Background: WT161, as a selective HDAC6 inhibitor, has been shown to play anti-tumor effects on several kinds of cancers. The aim of the present study is to explore the roles of WT161 in osteosarcoma and its underlying mechanisms. Methods: The anti-proliferative effect of WT161 on osteosarcoma cells was examined using MTT assay and colony formation assay. Cell apoptosis was analyzed using flow cytometer. The synergistic effect was evaluated by isobologram analysis using CompuSyn software. The osteosarcoma xenograft models were established to evaluate the anti-proliferative effect of WT161 in vivo. Results: WT161 suppressed the cell growth and induced apoptosis of osteosarcoma cells in a dose- and time-dependent manner. Mechanistically, we found that WT161 treatment obviously increased the protein level of PTEN and decreased the phosphorylation level of protein kinase-B (AKT). More importantly, WT161 showed synergistic inhibition with 5-FU on osteosarcoma cells in vitro and in vivo. Conclusions: These results indicate that WT161 inhibits the growth of osteosarcoma through PTEN and has a synergistic efficiency with 5-FU.

Calpain-1 and calpain-2 are highly structurally similar isoforms of calpain. The calpains, a family of intracellular cysteine proteases, cleave their substrates at specific sites, thus modifying their properties such as function or activity. These isoforms have long been considered to function in a redundant or complementary manner, as they are both ubiquitously expressed and activated in a Ca2+- dependent manner. However, studies using isoform-specific knockout and knockdown strategies revealed that each calpain species carries out specific functions in vivo. To understand the mechanisms that differentiate calpain-1 and calpain-2, we focused on the efficiency and longevity of each calpain species after activation. Using an in vitro proteolysis assay of troponin T in combination with mass spectrometry, we revealed distinctive aspects of each isoform. Proteolysis mediated by calpain-1 was more sustained, lasting as long as several hours, whereas proteolysis mediated by calpain-2 was quickly blunted. Calpain-1 and calpain-2 also differed from each other in their patterns of autolysis. Calpain-2-specific autolysis sites in its PC1 domain are not cleaved by calpain-1, but calpain-2 cuts calpain-1 at the corresponding position. Moreover, at least in vitro, calpain-1 and calpain-2 do not perform substrate proteolysis in a synergistic manner. On the contrary, calpain-1 activity is suppressed in the presence of calpain-2, possibly because it is cleaved by the latter protein. These results suggest that calpain-2 functions as a down-regulation of calpain-1, a mechanism that may be applicable to other calpain species as well.

The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, but while PRK1 is relatively well-characterized, the entire PRK family remains understudied. Here, we provide a holistic overview of the structure and function of PRKs and describe the molecular events that govern activation and autoregulation of catalytic activity, including phosphorylation, protein interactions and lipid binding. We begin with a structural description of the regulatory and catalytic domains, which facilitates the understanding of their regulation in molecular detail. We then examine their diverse physiological roles in cytoskeletal reorganization, cell adhesion, chromatin remodelling, androgen receptor signalling, cell cycle regulation, the immune response, glucose metabolism and development, highlighting isoform redundancy but also isoform specificity. Finally, we consider the involvement of PRKs in pathologies, including cancer, heart disease and bacterial infections. The abundance of PRK-driven pathologies suggests that these enzymes will be good therapeutic targets and we briefly report some of the progress to date.

Objective: Long non-coding RNAs (lncRNAs) recently have been identified as influential indicators in a variety of malignancies. The aim of the present study was to identify a functional lncRNA LINC00488 and its effects on thyroid cancer in the view of cell proliferation and apoptosis. Methods: In order to evaluate the effects of LINC00488 on the cellular process of thyroid cancer, we performed a series of in vitro experiments, including cell counting kit-8 (CCK-8) assay, EdU (5-ethynyl-2′-deoxyuridine) assay, flow cytometry, transwell chamber assay, Western blot and RT-qPCR. The target gene of LINC00488 was then identified by bioinformatics analysis (DIANA and TargetScan). Finally, a series of rescue experiments was conducted to validate the effect of LINC00488 and its target genes on proliferation, migration, invasion and apoptosis of thyroid cancer. Results: Our findings revealed that LINC00488 was highly expressed in thyroid cancer cell lines (BCPAP, BHP5-16, TPC-1 and CGTH-W3) and promoted the proliferation, migration and invasion, while inhibited the apoptosis of thyroid cancer cells (BCPAP and TPC-1). The results of bioinformatics analysis and dual luciferase reporter gene assay showed that LINC00488 could directly bind to miR-376a-3p and down-regulated the expression level of miR-376a-3p. In addition, Paraoxonase-2 (PON2) was a target gene of miR-376a-3p and negatively regulated by miR-376a-3p. Rescue experiment indicated that LINC00488 might enhance PON2 expression by sponging miR-376a-3p in thyroid cancer. Conclusion: Taken together, our study revealed that lncRNA LINC00488 acted as an oncogenic gene in the progression of thyroid cancer via regulating miR-376a-3p/PON2 axis, which indicated that LINC00488-miR-376a-3p-PON2 axis could serve as novel biomarkers or potential targets for the treatment of thyroid cancer.

Transparency represents the functional phenotype of eye lens. A number of defined steps including quiescence, proliferation, migration and cell differentiation culminates in cell elongation and organelle degradation, allowing the light to reach the retina. HOPS (Hepatocyte Odd Protein Shuttling)/TMUB1 (Trans Membrane Ubiquitin-like containing protein 1) is a nucleo-cytoplasmic shuttling protein, highly expressed both in vivo and in vitro proliferating systems, bearing a ubiquitin-like domain. The present study shows HOPS expression during the phases of lens cell proliferation and fiber differentiation, and its localisation in lens compartments. In lens, HOPS localises mainly in the nucleus of central epithelial cells. During mitosis, HOPS/TMUB1 shuttles to the cytoplasm and returns to the nucleus at the end of mitosis. The differentiating cells share distinct HOPS/TMUB1 localisation in transitional zone depending on the differentiation phases. HOPS/TMUB1 is observed in lens cortex and nucleus. Here, it is attached to fibers, having a structural function with crystallin proteins, probably acting in the ubiquitin–proteasome system.

Background: Both meta-analyses and systematic reviews were used to assess the relationship between purinergic receptor P2X ligand-gated ion channel 7 (P2RX7) rs3751143 polymorphism and the risk of cancer. Materials and methods: The data used in this research were collected from Google Scholar, Web of Science, CNKI, and Wan Fang Data databases. The final retrieval ended on 22 February 2019. The strength of correlation was assessed using odds ratios and 95% confidence intervals. Based on the heterogeneity test results, fixed-effect (Mantel–Haenszel) or random-effects (DerSimonian–Laird) models were selected to summarise the collective effects. Results: Eight separate studies containing 1462 cancer cases and 3037 controls were enrolled. Overall, there was no significant association between P2RX7 rs3751143 polymorphism and the risk of cancer in the allelic, homozygous, heterozygous, dominant, or recessive models. Conclusions: Our meta-analysis indicates that there is no significant association between P2RX7 rs3751143 polymorphism and the risk of cancer in the allelic, homozygous, heterozygous, dominant, and recessive models.

Triple-negative breast cancer (TNBC) is the most malignant and fatal subtype of breast cancer, which has characterized by negativity expression of ER, PR, and HER2. Metastasis is the main factor affecting the prognosis of TNBC, and the process of metastasis is related to abnormal activation of epithelial–mesenchymal transition (EMT). Recent studies have shown that long non-coding RNA (LncRNA) plays an important role in regulating the metastasis and invasion of TNBC. Therefore, based on the metastasis-related EMT signaling pathway, great efforts have confirmed that LncRNA is involved in the molecular mechanism of TNBC metastasis, which will provide new strategies to improve the treatment and prognosis of TNBC. In this review, we summarized many signal pathways related to EMT involved in the transfer process. The advances from the most recent studies of lncRNAs in the EMT-related signal pathways of TNBC metastasis. We also discussed the clinical research, application, and challenges of LncRNA in TNBC.

Interleukin-8 (IL-8) promotes cell homing and angiogenesis, but its effects on activating human bone marrow mesenchymal stem cells (BMSCs) and promoting angiogenesis are unclear. We used bioinformatics to predict these processes. In vitro, BMSCs were stimulated in a high-glucose (HG) environment with 50 or 100 μg/ml IL-8 was used as the IL-8 group. A total of 5 μmol/l Triciribine was added to the two IL-8 groups as the Akt inhibitor group. Cultured human umbilical vein endothelial cells (HUVECs) were cultured in BMSCs conditioned medium (CM). The changes in proliferation, apoptosis, migration ability and levels of VEGF and IL-6 in HUVECs were observed in each group. Seventy processes and 26 pathways were involved in vascular development, through which IL-8 affected BMSCs. Compared with the HG control group, HUVEC proliferation absorbance value (A value), Gap closure rate, and Transwell cell migration rate in the IL-8 50 and IL-8 100 CM groups were significantly increased (P

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. Neovascularization is closely related to the malignancy of tumors. We constructed a signature of angiogenesis-related long noncoding RNA (lncRNA) to predict the prognosis of patients with HCC. The lncRNA expression matrix of 424 HCC patients was downloaded from The Cancer Genome Atlas (TCGA). First, gene set enrichment analysis (GSEA) was used to distinguish the differentially expressed genes of the angiogenesis genes in liver cancer and adjacent tissues. Next, a signature of angiogenesis-related lncRNAs was constructed using univariate and multivariate analyses, and receiver operating characteristic (ROC) curves were used to assess the accuracy. The signature and relevant clinical information were used to construct the nomogram. A 5-lncRNA signature was highly correlated with overall survival (OS) in HCC patients and performed well in evaluations using the C-index, areas under the curve, and calibration curves. In summary, the 5-lncRNA model can serve as an accurate signature to predict the prognosis of patients with liver cancer, but its mechanism of action must be further elucidated by experiments.

Chemokine (C-X-C motif) ligand 5 is an important regulator of tumor progression in many cancers, and could serve as potential serum cancer biomarker. Our initial analysis identified CXCL5 as a cancer-related gene highly expressed in PC. Patients with PC exhibited markedly higher preoperative serum CXCL5 levels compared with that in healthy individuals (P

Background: Total saponins from Rubus parvifolius L. (TSRP) are the main bioactive fractions responsible for the anti-tumor activities. The work was aimed to evaluate the anti-tumor effect of TSRP in malignant melanoma (MM) in vitro and in vivo. Methods and results: Anti-melanoma cell proliferation, invasion and migration effect of TSRP were detected in human MM A375 cells under the indicated time and dosages. In vivo anti-tumor effect of TSRP was measured in A375 xenograft immunodeficient nude mice. Sixty A375 xenografts were randomly divided into five groups: Vehicle, cyclophosphamide (CTX, 20 mg/kg), TSRP (25 mg/kg), TSRP (50 mg/kg) and TSRP (100 mg/kg) groups for 14 days’ treatment. In addition, the melanoma metastasis in lung in vivo of TSRP was detected in A375 tail vein injection mice, and the histopathalogical analysis of the lung metastasis was detected by Hematoxylin–Eosin (H&E) staining. TSRP significantly inhibited the cell proliferation, invasion and migration of A375 in vitro at the indicated time and dosages. TSRP treatment effectively blocked the tumor growth in immunodeficient nude mice. In addition, TSRP also significantly inhibited the lung metastasis of melanoma. Conclusion: The present study indicated that the TSRP has a remarkable anti-MM effect, which mainly through the inhibition of the cell invasion, migration and tumor metastasis.

Microglia are the resident immune cells of the central nervous system and are important for immune processes. Besides their classical roles in pathological conditions, these cells also dynamically interact with neurons and influence their structure and function in physiological conditions. Recent evidence revealed their role in healthy brain homeostasis, including the regulation of neurogenesis, cell survival, and synapse maturation and elimination, especially in the developing brain. In this review, we summarize the current state of knowledge on microglia in brain development, with a focus on their neuroprotective function. We will also discuss how microglial dysfunction may lead to the impairment of brain function, thereby contributing to disease development.

PTMs and microtubule-associated proteins (MAPs) are known to regulate microtubule dynamicity in somatic cells. Reported literature on modulation of α-tubulin acetyl transferase (αTAT1) and histone deacetylase 6 (HDAC6) in animal models and cell lines illustrate disparity in correlating tubulin acetylation status with stability of MT. Our earlier studies showed reduced acetyl tubulin in sperm of asthenozoospermic individuals. Our studies on rat sperm showed that on inhibition of HDAC6 activity, although tubulin acetylation increased, sperm motility was reduced. Studies were therefore undertaken to investigate the influence of tubulin acetylation/deacetylation on MT dynamicity in sperm flagella using rat and human sperm. Our data on rat sperm revealed that HDAC6 specific inhibitor Tubastatin A (T) inhibited sperm motility and neutralized the depolymerizing and motility debilitating effect of Nocodazole. The effect on polymerization was further confirmed in vitro using pure MT and recHDAC6. Also polymerized axoneme was less in sperm of asthenozoosperm compared to normozoosperm. Deacetylase activity was reduced in sperm lysates and axonemes exposed to T and N+T but not in axonemes of sperm treated similarly suggesting that HDAC6 is associated with sperm axonemes or MT. Deacetylase activity was less in asthenozoosperm. Intriguingly, the expression of MDP3 physiologically known to bind to HDAC6 and inhibit its deacetylase activity remained unchanged. However, expression of acetyl α-tubulin, HDAC6 and microtubule stabilizing protein SAXO1 was less in asthenozoosperm. These observations suggest that MAPs and threshold levels of MT acetylation/deacetylation are important for MT dynamicity in sperm and may play a role in regulating sperm motility.

The cellular cytoskeleton self-organizes by specific monomer-monomer interactions resulting in the polymerization of filaments. While we have long thought about the role of polymerization in cytoskeleton formation, we have only begun to consider the role of condensation in cytoskeletal organization. In this review, we highlight how the interplay between polymerization and condensation leads to the formation of the cytoskeleton.

Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of nasal mucosa provoking T helper cell (Th) 17 response. Chlorogenic acid (CGA), one of the most abundant polyphenol compounds in various agricultural products, possesses antiviral, anti-inflammatory, and antibacterial properties. However, the effect of CGA on AR is unclear. Thus, our study explored the effect of CGA in modulating AR-related symptoms and immunoreaction, especially Th17 response. AR mice were induced by ovalbumin (OVA) administration and further treated with CGA or dexamethasone (Dex). The frequencies of rubbing and sneezing of AR mice were recorded. Histopathological analysis of nasal mucosa was conducted by Hematoxylin–Eosin and Periodic acid–Schiff stainings. The serum and nasal mucosa levels of OVA-immunoglobulin (Ig)E, interferon (IFN)-γ, retinoic acid-associated nuclear orphan receptor (ROR)-γt, and interleukin (IL)-17A were measured by enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), or Western blot. The ratio of CD4+IL-17+Th17 cells to CD4+ T cells in peripheral blood of AR mice was assessed by flow cytometer. CGA diminished the frequencies of rubbing and sneezing of AR mice in a concentration-dependent manner. CGA attenuated histopathological abnormalities and decreased goblet cell number in nasal mucosa of AR mice. CGA decreased the serum levels of OVA-IgE, ROR-γt, and IL-17A, while increasing the serum level of IFN-γ in AR mice. Meanwhile, CGA decreased the ratio of CD4+IL-17+Th17 cells to CD4+T cells in peripheral blood and the mRNA and protein levels of IL-17A and ROR-γt in AR mice. CGA ameliorated AR-related symptoms in mice by regulating Th17 cells, which could be a candidate for the treatment of AR.

The present study was aimed at investigating the detailed functions of atorvastatin, a lipid-lowering agent, in the pathogenesis of coronary slow flow (CSF), a clinical disease characterized by delayed angiographic coronary opacity without obstructive coronary disease. In the present study, we successfully identified isolated endothelial progenitor cells (EPCs) from the peripheral blood of patients with CSF. Their vascular endothelial growth factor-A (VEGFA) protein levels were determined using immunoblotting analyses. We determined cell viability using MTT assays, cell migration capacity using Transwell assays, and the angiogenic capacity using a tube formation assay. The target association between miR-221 and VEGFA was validated with a luciferase reporter assay. Atorvastatin treatment increased EPC VEGFA protein levels, proliferation, migration, and angiogenesis. miR-221 expression was down-regulated after atorvastatin treatment; miR-221 overexpression exerted an opposing effect to atorvastatin treatment on VEGFA protein, EPC proliferation, migration, and angiogenesis. The protective effects of atorvastatin treatment on VEGFA protein and EPCs could be significantly suppressed by miR-221 overexpression. miR-221 directly bound the VEGFA 3′UTR to inhibit its expression. In conclusion, atorvastatin improves the cell proliferation, migration, and angiogenesis of EPCs via the miR-221/VEGFA axis. Thus, atorvastatin could be a potent agent against CSF, pending further in vivo and clinical investigations.

Scribble is a critical cell polarity regulator that has been shown to work as either an oncogene or tumor suppressor in a context dependent manner, and also impacts cell migration, tissue architecture and immunity. Mutations in Scribble lead to neural tube defects in mice and humans, which has been attributed to a loss of interaction with the planar cell polarity regulator Vangl2. We show that the Scribble PDZ domains 1, 2 and 3 are able to interact with the C-terminal PDZ binding motif of Vangl2 and have now determined crystal structures of these Scribble PDZ domains bound to the Vangl2 peptide. Mapping of mammalian neural tube defect mutations reveal that mutations located distal to the canonical PDZ domain ligand binding groove can not only ablate binding to Vangl2 but also disrupt binding to multiple other signaling regulators. Our findings suggest that PDZ-associated neural tube defect mutations in Scribble may not simply act in a Vangl2 dependent manner but as broad-spectrum loss of function mutants by disrupting the global Scribble-mediated interaction network.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that can be a useful source of cells for the treatment of many diseases, including neurologic diseases. The curative effect of MSCs relies mostly on cell’s capacity of migration, proliferation and differentiation. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles on regulating various cell behaviors. Here, we report that miRNA-124 (miR124) and miRNA-21-5p (miR21-5p) display different regulatory roles on migration, proliferation and neuron differentiation of MSCs. MiR124 was shown greatly promoting MSCs migration and neuronal differentiation. MiR21-5p could significantly enhance the proliferation and neuronal differentiation ability of MSCs. MiR124 and miR21-5p synergistically promote differentiation of MSCs into neurons. Collectively, miR124 and miR21-5p can functionally regulate cell migration, proliferation and neuronal differentiation of MSCs. Therefore, miR124 and miR21-5p may be promising tools to improve transplantation efficiency for neural injury.

As a negative immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain containing molecule-3 (Tim-3) has been found to serve a crucial role in immune escape and tumour progression. Previous studies have reported that Tim-3 is important to endothelial cells and it has also been demonstrated to be involved in numerous types of human diseases, including melanoma, lymphoma, rickettsial infection and atherosclerosis; however, its exact mechanism of action remains largely unknown. In the present study, Tim-3 was overexpressed in vascular endothelial human lung microvascular endothelial cells (HMVECs) and human umbilical vein endothelial cells (HUVECs), and in vitro assays were used to determine that Tim-3 promoted cell proliferation, migration, invasion and tube formation through activating cyclin D1 (CCND1), Ras homolog gene family member A and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2). Additionally, Tim-3 decreased tight junction (TJ) formation and the transepithelial resistance (TER) of endothelial cells by decreasing the expression levels of TJ protein 2, Occludin and claudin 1 (CLND1). In conclusion, these findings suggested that Tim-3 may exert a positive role in angiogenesis and a negative role in TJ formation in vascular endothelial cells, which may provide novel strategies for the treatment of Tim-3-associated diseases.

The phosphatidylinositol 3-kinase (PI3K) pathway is a critical regulator of many cellular processes including cell survival, growth, proliferation and motility. Not surprisingly therefore, the PI3K pathway is one of the most frequently mutated pathways in human cancers. In addition to their canonical role as part of the PI3K holoenzyme, the class IA PI3K regulatory subunits undertake critical functions independent of PI3K. The PI3K regulatory subunits exist in excess over the p110 catalytic subunits and therefore free in the cell. p110-independent p85 is unstable and exists in a monomer-dimer equilibrium. Two conformations of dimeric p85 have been reported that are mediated by N-terminal and C-terminal protein domain interactions, respectively. The role of p110-independent p85 is under investigation and it has been found to perform critical adaptor functions, sequestering or influencing compartmentalisation of key signalling proteins. Free p85 has roles in glucose homeostasis, cellular stress pathways, receptor trafficking and cell migration. As a regulator of fundamental pathways, the amount of p110-independent p85 in the cell is critical. Factors that influence the monomer-dimer equilibrium of p110-independent p85 offer additional control over this system, disruption to which likely results in disease. Here we review the current knowledge of the structure and functions of p110-independent class IA PI3K regulatory subunits.

Transforming growth factor-β1 (TGF-β1) is involved in human cancer development and progression. Nonetheless, the role of TGF-β1 as regards peritoneal metastasis of gastric cancer has not been completely characterized. In the present study, we investigated the exact role of TGF-β1 on peritoneal metastasis of gastric cancer. The results indicated that human peritoneal mesothelial cells (HPMCs) exposed to TGF-β1 or serum-free conditional medium (SF-CM) of SGC7901 that produced a large amount of TGF-β1 became exfoliated, apoptosis and exhibited signs of injury, and the tumor-mesothelial cell adhesion significantly increased. Connective tissue growth factor (CTGF) expression was also increased when HPMCs were exposed to TGF-β1 or SF-CM of SGC7901. However, these effects were significantly decreased when HPMCs were exposed to SF-CM of SGC7901-TGFβS, a TGF-β1 knockdown stable cell line. Animal studies revealed that nude mice injected with SGC7901-TGFβS cells featured a smaller number of peritoneal seeding nodules and lower expression of CTGF in ascites than the control cell lines. These findings suggest that TGF-β1 promotes peritoneal metastasis of gastric cancer and induces CTGF expression. Therefore, blockage of TGF-β1 or TGF-β1 signaling pathway might prevent and treat peritoneal metastasis of gastric cancer.

Glioma is the most prevalent solid tumor in the central nervous system (CNS). Recently, it has been indicated that long non-coding RNAs (lncRNAs) substantially adjust the development of a variety of human cancers. In the present study, it was found and verified via microarray analysis that lncRNA PSMA3-AS1 exhibited a high expression in glioma tissues and cell lines. Then CCK-8, 5-Ethynyl-2′-deoxyuridine (EdU) staining, plate clone assay, Transwell assay, Western blotting and nude mouse model were adopted to verify PSMA3-AS1’s effects on glioma. Knockdown of PSMA3-AS1 inhibited the migration, proliferation and invasion of glioma cells in vivo and in vitro. Besides, PSMA3-AS1 bound to miR-302a-3p directly reduced the expression of miR-302a-3p, thus functioning as an endogenous sponge confirmed by luciferase reporter assay and bioinformatics analysis. PSMA3-AS1 knockdown remarkably enhanced the role of miR-302a-3p overexpression in cell behaviors in glioma. Moreover, these assays also confirmed that RAB22A was a target of miR-302a-3p. In this research, therefore, the PSMA3-AS1/miR-302a-3p/RAB22A pathway regulatory axis may be revealed in the pathogenesis of glioma, and PSMA3-AS1 can be used as an underlying target for the treatment and prognosis of glioma.

Background: Long non-coding RNAs (lncRNAs) are increasingly being regarded as regulators of glioma development. Notably, some studies report that GNG12-AS1 plays important functions and molecular mechanism in breast cancer, but there are no existing studies in glioma. Objective: To analyze the biological functions and potential mechanisms of GNG12-AS1 in glioma. Methods: We detected the expression of GNG12-AS1 in glioma tissues through analyzing TCGA data as well as our clinical samples. We then evaluated cell proliferation through MTT assay and colony formation and cell migration by transwell assay, wound healing assay and single cell tracking assay. After, we analyzed the effects of the AKT/GSK-3β/β-catenin through Western blotting and utilized the β-catenin agonist SKL2001 for the rescue experiment. Results: GNG12-AS1 was highly expressed in glioma tissues. The silence of GNG12-AS1 inhibited the proliferation, migration and epithelial–mesenchymal transition of glioma cells, and reduced the activity of the AKT/GSK-3β/β-catenin pathway. Notably, SKL2001 could reverse cell migration as well as β-catenin expression in glioma cells with lower GNG12-AS1 expression. Conclusions: GNG12-AS1 regulates proliferation and migration of glioma cells through the AKT/GSK-3β/β-catenin signaling and can perhaps be a new target for the treatment of glioma.

KRAB domain-associated protein 1 (KAP1) is highly expressed in atherosclerotic plaques. Here, we studied the role of KAP1 in atherosclerosis development using a cell model of endothelial dysfunction induced by oxidative low-density lipoprotein (OxLDL). The phosphorylation and protein levels of KAP1 were similar between OxLDL-treated and non-treated endothelial cells (ECs). KAP1 depletion significantly inhibited the production of OxLDL-enhanced reactive oxygen species and the expression of adhesion molecules in ECs. Treatment with OxLDL promoted the proliferation and migration of ECs, which was also confirmed by the elevated levels of the proliferative markers c-Myc and PCNA, as well as the migratory marker MMP-9. However, these effects were also abrogated by KAP1 depletion. Moreover, the depletion of KAP1 in OxLDL-treated ECs resulted in decreases in the LOX-1 level and increases in eNOS expression. Generally, the data suggest that strategies targeting KAP1 depletion might be particularly useful for the prevention or treatment of atherosclerosis.

Merkel cell carcinoma (MCC) is an aggressive skin cancer with high rates of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases. MCPyV-induced tumourigenesis is largely dependent on the expression of the small tumour antigen (ST). Recent findings implicate MCPyV ST expression in the highly metastatic nature of MCC by promoting cell motility and migration, through differential expression of cellular proteins that lead to microtubule destabilisation, filopodium formation and breakdown of cell–cell junctions. However, the molecular mechanisms which dysregulate these cellular processes are yet to be fully elucidated. Here, we demonstrate that MCPyV ST expression activates p38 MAPK signalling to drive cell migration and motility. Notably, MCPyV ST-mediated p38 MAPK signalling occurs through MKK4, as opposed to the canonical MKK3/6 signalling pathway. In addition, our results indicate that an interaction between MCPyV ST and the cellular phospatase subunit PP4C is essential for its effect on p38 MAPK signalling. These results provide novel opportunities for the treatment of metastatic MCC given the intense interest in p38 MAPK inhibitors as therapeutic agents.

The extracellular matrix (ECM) is a complex network of macromolecules surrounding cells providing structural support and stability to tissues. The understanding of the ECM and the diverse roles it plays in development, homoeostasis and injury have greatly advanced in the last three decades. The ECM is crucial for maintaining tissue homoeostasis but also many pathological conditions arise from aberrant matrix remodelling during ageing. Ageing is characterised as functional decline of tissue over time ultimately leading to tissue dysfunction, and is a risk factor in many diseases including cardiovascular disease, diabetes, cancer, dementia, glaucoma, chronic obstructive pulmonary disease (COPD) and fibrosis. ECM changes are recognised as a major driver of aberrant cell responses. Mesenchymal cells in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. It was recently postulated that cellular senescence contributes to the pathogenesis of chronic fibrotic diseases in the heart, kidney, liver and lung. Senescent cells negatively impact tissue regeneration while creating a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP) favouring disease progression. In this review, we explore and summarise the current knowledge around how aberrant ECM potentially influences the senescent phenotype in chronic fibrotic diseases. Lastly, we will explore the possibility for interventions in the ECM–senescence regulatory pathways for therapeutic potential in chronic fibrotic diseases.

Background: The present study investigated the effects of microvascular endothelial cells (MECs) on the chemotaxis, adhesion and proliferation of bone marrow hematopoietic stem cells (HSCs) ex vivo. Methods and Results: MECs were collected from the lung tissue of C57BL/6 mice, and HSCs were isolated with immunomagnetic beads from bone marrow of GFP mice. MECs and HSCs were co-cultured with or without having direct cell–cell contact in Transwell device for the measurement of chemotaxis and adhesion of MECs to HSCs. Experimental results indicate that the penetration rate of HSCs from the Transwell upper chamber to lower chamber in ‘co-culture’ group was significantly higher than that of ‘HSC single culture’ group. Also, the HSCs in co-culture group were all adherent at 24 h, and the co-culture group with direct cell–cell contact had highest proliferation rate. The HSC number was positively correlated with vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) levels in supernatants of the culture. Conclusions: Our study reports that MECs enhance the chemotaxis, adhesion and proliferation of HSCs, which might be related to cytokines SDF-1 and VEGF secreted by MECs, and thus MECs enhance the HSC proliferation through cell–cell contact. The present study revealed the effect of MECs on HSCs, and provided a basis and direction for effective expansion of HSCs ex vivo.

Increasing evidence shows that circular RNAs (circRNAs) play a regulatory role in cancer. In the present study, we aimed to investigate the characteristics and effects of hsa_circ_0026134 in hepatocellular carcinoma (HCC). We investigated hsa_circ_0026134 expression in 20 pairs of clinical tissues from HCC patients; expression of hsa_circ_0026134 in different cell lines; effect of hsa_circ_0026134 on proliferation and invasion of HCC cell lines; and the regulatory mechanisms and interactions among hsa_circ_0026134, miR-127-5p, tripartite motif-containing protein 25 (TRIM25) and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). hsa_circ_0026134 expression was increased in HCC samples and cell lines. Down-regulation of hsa_circ_0026134 attenuated HCC cell proliferation and metastatic properties. Micro (mi)RNA (miR)-127-5p was sponged by hsa_circ_0026134. Rescue experiments indicated that inhibition of miR-127-5p expression promoted cell proliferation and invasion even after hsa_circ_0026134 silencing. TRIM25 and IGF2BP3 were targets of miR-127-5p. Overexpression of TRIM25 or IGF2BP3 promoted cell proliferation and invasion in cells overexpressing miR-127-5p. Down-regulation of hsa_circ_0026134 suppressed TRIM25- and IGF2BP3-mediated HCC cell proliferation and invasion via promotion of miR-127-5p expression, which have been confirmed by luciferase reporter assay. The present study provides a new treatment target for HCC.

Glioma is the most common malignant tumor in the human central nervous system. Although heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) was previously presumed to be a tumor-promoting gene, the relationship between hnRNPA2/B1 and glioma is unclear. Targeting hnRNPA2/B1 interference in glioma cells can significantly inhibit proliferation and increase apoptosis of human glioma cells in vitro. In a tumor xenograft model, knockdown of hnRNPA2/B1 suppressed tumor growth in glioma cells in vivo. In terms of a mechanism, the knockdown of hnRNPA2/B1 led to inactivation of the AKT and STAT3 signaling pathways, which ultimately reduced the expression of B-cell lymphoma-2 (Bcl-2), CyclinD1 and proliferating cell nuclear antigen (PCNA). Collectively, these data suggest that the inhibition of hnRNPA2/B1 can reduce the growth of gliomas through STAT3 and AKT signaling pathways, and this inhibition is expected to be a therapeutic target for gliomas.

Objective: Non-small cell lung cancer (NSCLC) continues to top the list of cancer mortalities worldwide. Early diagnosis and therapeutic interventions targeting NSCLC is becoming the world’s significant challenge. Circular RNAs (circRNAs) are emerging as a group of potential cancer biomarkers. Materials and methods: Quantitative real-time PCR (qRT-PCR) was employed to examine the expression of circ_0072309 in NSCLC tissues and cell lines. Cell counting kit 8 (CCK-8), wound healing and Transwell assays were used to analyze cell proliferation, migration and invasion in A549 and H1299 cells. The relationship between circ_0072309 and miR-580-3 was analyzed by Luciferase reporter and RNA pull down assays. Results: We screened circ_0072309 from Gene Expression Omnibus and found that circ_0072309 was lowly expressed in NSCLC tissues and cell lines. The transfection of circ_0072309-overexpressing vector significantly suppressed the cell proliferation, migration and invasion in A549 and H1299 cells. We predicted that miR-580-3p is a target of circ_0072309 by using publicly available bioinformatic algorithms Circinteractome tool and confirmed that circ_0072309 directly bound to miR-580-3p. Furthermore, the addition of miR-580-3p mitigated the blockage of cell proliferation, migration and invasion induced by circ_0072309. Conclusions: These data showed that circ_0072309 inhibits the progression of NSCLC progression via blocking the expression of miR-580-3p. These findings revealed the anti-tumor role of circ_0072309 during the development of NSCLC and provided a novel diagnostic biomarker and potential therapy for NSCLC.

The present study aims to investigate the relationship between miR-19b-3p and esophageal cancer (ESCA), and to detect the effects of miR-19b-3p transferred by exosomes on the phenotype of EC9706 cells. The expression of miR-19b-3p was detected by starBase analysis and real-time quantitative PCR (RT-qPCR). The target genes of miR-19b-3p were predicted by TargetScan and further verified by luciferase analysis. The mRNA and protein expression levels of PTEN and EMT-related genes were detected by RT-qPCR and Western blotting. The effects of miR-19b-3p transferred by exosomes and its target genes on the apoptosis, migration and invasion of EC9706 cells were studied by establishing a co-culture model of donor cells. The expression of miR-19b-3p in ESCA plasma, cells and exosomes was significantly up-regulated. miR-19b-3p transferred by exosomes could significantly reduce EC9706 cells apoptosis rate, promote cell migration and invasion, and could target the inhibition of PTEN expression. PTEN overexpression promoted apoptosis, inhibited cell migration and invasion, down-regulated the expression of MMP-2 and vimentin, and up-regulated E-cadherin expression; however, these effects could be partially reversed by miR-19b-3p. In summary, our results reveal that miR-19b-3p transferred by exosomes can target PTEN to regulate ESCA biological functions in the receptor EC9706 cells.

Metastasis is the main cause of cancer-associated deaths, yet this complex process is still not well understood. Many studies have shown that acetate is involved in cancer metastasis, but the molecular mechanisms remain to be elucidated. In the present study, we first measured the effect of acetate on zinc finger transcriptional repressor SNAI1 and acetyl-CoA synthetase 2 (ACSS2) under glucose limitation in renal cell carcinoma cell lines, 786-O and ACHN. Then, RNA interference and overexpression of ACSS2 were used to detect the role of acetate on SNAI1 expression and cell migration. Finally, chromatin immunoprecipitation assay (ChIP) was used to investigate the regulatory mechanism of acetate on SNAI1 expression. The results showed that acetate increased the expressions of SNAI1 and ACSS2 under glucose limitation. ACSS2 knockdown significantly decreased acetate-induced SNAI1 expression and cell migration, whereas overexpression of ACSS2 increased SNAI1 level and histone H3K27 acetylation (H3K27ac). ChIP results revealed that acetate increased H3K27ac levels in regulatory region of SNAI1, but did not increase ACSS2-binding ability. Our study identified a novel inducer, acetate, which can promote SNAI1 expression by ACSS2-mediated histone acetylation in partly. This finding has important implication in treatment of metastatic cancers.

Pancreatic cancer is a kind of malignant carcinoma with high mortality, which is devoid of early diagnostic biomarker and effective therapeutic methods. Recently, long non-coding RNAs (lncRNAs) have been reported as a crucial role in regulating the development of various kinds of tumors. Here, we found lncRNA small nuclear RNA host gene 12 (SNHG12) is highly expressed in pancreatic cancer tissues and cell lines through qRT-PCR, which suggested that SNHG12 possibly accelerates the progression of pancreatic cancer. Further study revealed that SNHG12 promoted cancer cells growth and invasion via absorbing miR-320b. Flow cytometry and transwell chamber assay were utilized to verify the promoting effects on proliferation and invasion that SNHG12 acts in pancreatic cancer cells. Evidence that SNHG12 increased cell invasive ability through up-regulated EMT process was lately obtained by Western blotting assay. Consequently, we extrapolated that SNHG12/miR-320b could be invoked as a promising early diagnostic hallmark and therapeutic strategy for pancreatic cancer.

MiRNAlet-7a is associated with the tumorigenesis of laryngeal squamous cell carcinoma (LSCC). Our study was designed to infer whether let-7a targets high-mobility AT-hook 2 (HMGA2) and suppresses laryngeal carcinoma cell proliferation, invasion, and migration. The expression levels of let-7a and HMGA2 were measured in 30 LSCC clinical specimens by qRT-PCR and their correlation was analyzed. Cell model and mice xenograft model with or without let-7a overexpression were constructed to evaluate the effects of let-7a on LSCC. Moreover, luciferase assay was performed to reveal the interaction between let-7a and HMGA2, which was further verified in xenograft. Let-7a was significantly down-regulated and HMGA2 was up-regulated in LSCC tissues compared with normal tissues (P