Ovarian cancer is a common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic role remains unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on the regulation of autophagic and apoptotic pathways in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using MTT and colony formation assays in SK-OV-3 cells. PKM2 expression was positively correlated with the severity of the tumor, and expression of pro-apoptotic proteins increased in SK-OV-3 cells following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by mTOR inhibition. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation of SK-OV-3 cells. Compound 3K treatment suppressed tumor progression in an in vivo xenograft model. Our findings suggest that the inhibition of PKM2 by compound 3K affected the Warburg effect and induced autophagic cell death. Therefore, use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer.

Alcohol abuse has a high impact on the mortality and morbidity related to a great number of diseases and is responsible for the development of alcoholic liver disease (ALD). It remains challenging to detect and evaluate its severity, which is crucial for prognosis. In this work, we studied if urinary EVs (uEVs) could serve in diagnose and evaluate cirrhosis in ALD. To this purpose, uEVs characterization by cryo-electron microscopy (Cryo-EM), Nanoparticle Tracking Analysis (NTA) and Western blotting (WB) was performed in a cohort of 21 controls and 21 cirrhotic patients. Then, proteomics of uEVs was carried out in a second cohort of 6 controls and 8 patients in order to identify new putative biomarkers for cirrhosis in ALD. Interestingly, uEVs concentration, size and protein composition were altered in cirrhotic patients. From a total of 1304 proteins identified in uEVs, 90 of them were found to be altered in cirrhotic patients. The results suggest that uEVs could be considered as a tool and a supplier of new biomarkers for cirrhosis in ALD, whose application would be especially relevant in chronic patients. Yet, further research is necessary to obtain more relevant result in clinical terms.

Background: Patients with endometriosis (EMs) have high risks of infertility and spontaneous abortion. How to remodel the fertility of patients with EMs has always been the hot spot and difficulty in the field of reproductive medicine. As an aglycone of ginsenosides, protopanaxadiol (PPD) possesses pleiotropic biological functions and has high medicinal values. We aimed to investigate the effect and potential mechanism of PPD in the treatment of EMs-associated infertility and spontaneous abortion. Methods: The EMs mice models were constructed by allotransplantation. The pregnancy rates, embryo implantation numbers and embryo resorption rates of control and EMs were counted. RNA sequencing, qRT-PCR, enzyme linked immunosorbent assay (ELISA) and FCM analysis were performed to screen and confirm the expression of endometrial receptivity/decidualization-related molecules, inflammation cytokines and NK cell function-related molecules in vitro and/or in vivo. The SWISS Target Prediction, STRING and Cytoscape were carried out to predict the potential cellular sensory proteins, the protein-protein interaction (PPI) network between sensory proteins and fertility-related molecules, respectively. Micro-CT detection, liver and kidney function tests were used to evaluate the safety. Results: Here, we observe that PPD significantly up-regulates endometrial receptivity-related molecules (e.g., Lif, Igfbp1, Mmps, collagens) and restricts pelvic inflammatory response (low levels of IL-12 and IFN-γ) of macrophage, and further remodel and improve the fertility of EMs mice. Additionally, PPD increases the expression of decidualization-related genes and Collagens, and promotes the proliferation, residence, immune tolerance and anagogic functions of decidual NK cells (low levels of CD16 and NKp30, high levels of Ki67, VEGF, TGF-β) in pregnant EMs mice, and further triggers decidualization, decidual NK cell-mediated maternal-fetal immune tolerance and angiogenesis, preventing pregnant EMs mice from miscarriage. Mechanically, these effects should be dependent on ESRs, PGR and other sensory proteins (e.g., AR). Compared with GnRHa (the clinic first-line drug for EMs), PPD does not lead to the decline of serum estrogen and bone loss. Conclusion: These data suggest that PPD prevents EMs-associated infertility and miscarriage in sex hormones receptors-dependent and independent manners possibly, and provides a potential therapeutic strategy with high efficiency and low side effects to remodels the fertility of patients with EMs.

Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau protein are the two hallmark proteins of Alzheimer's disease (AD), and the separate neurotoxicity of these proteins in AD has been extensively studied. However, interventions that target Aβ or tau individually have not yielded substantial breakthroughs. The interest in the interactions between Aβ and tau in AD is increasing, but related drug investigations are in their infancy. This review discusses how Aβ accelerates tau phosphorylation and the possible mechanisms and pathways by which tau mediates Aβ toxicity. This review also describes the possible synergistic effects between Aβ and tau on microglial cells and astrocytes. Studies suggest that the coexistence of Aβ plaques and phosphorylated tau is related to the mechanism by which Aβ facilitates the propagation of tau aggregation in neuritic plaques. The interactions between Aβ and tau mediate cognitive dysfunction in patients with AD. In summary, this review summarizes recent data on the interplay between Aβ and tau to promote a better understanding of the roles of these proteins in the pathological process of AD and provide new insights into interventions against AD.

The phenotypic transformation of hepatic myofibroblasts (MFs) is involved in the whole process of the progression and regression of liver fibrosis. Notch signaling has been demonstrated to modulate the fibrosis. In this study, we found that Notch signaling in MFs was overactivated and suppressed with the progression and regression of hepatic fibrosis respectively, by detecting Notch signaling readouts in MFs. Moreover, we inactivated Notch signaling specifically in MFs with Sm22αCreER-RBPjflox/flox mice (RBPjMF-KO), and identified that MFs-specific down-regulation of Notch signaling significantly alleviated CCl4-induced liver fibrosis during the progression and regression. During the progression of liver fibrosis, MFs-specific blockade of Notch signaling inhibited the activation of HSCs to MFs and increases the expression of MMPs to reduce the deposition of ECM. During the regression of fibrosis, blocking Notch signaling in MFs increased the expression of HGF to promote proliferation in hepatocytes and up-regulated the expression of pro-apoptotic factors, Ngfr and Septin4, to induce apoptosis of MFs, thereby accelerating the reversal of fibrosis. Collectively, the MFs-specific disruption of Notch signaling attenuates liver fibrosis by modulating fibrosis progression and regression, which suggests a promising therapeutic strategy for liver fibrosis.

The functions of dual-specificity phosphatase 9 (DUSP9) in hepatic steatosis and metabolic disturbance during nonalcoholic fatty liver disease were discussed in our prior study. However, its roles in the pathophysiology of pressure overload-induced cardiac hypertrophy remain to be illustrated. This study attempted to uncover the potential contributions and underpinning mechanisms of DUSP9 in cardiac hypertrophy. Utilizing the gain-and-loss-of-functional approaches of DUSP9 the cardiac phenotypes arising from the pathological, echocardiographic, and molecular analysis were quantified. The results showed increased levels of DUSP9 in hypertrophic mice heart and angiotensin II treated cardiomyocytes. In accordance with the results of cellular hypertrophy in response to angiotensin II, cardiac hypertrophy exaggeration, fibrosis, and malfunction triggered by pressure overload was evident in the case of cardiac-specific conditional knockout of DUSP9. In contrast, transgenic mice hearts with DUSP9 overexpression portrayed restoration of the hypertrophic phenotypes. Further explorations of molecular mechanisms indicated the direct interaction of DUSP9 with ASK1, which further repressed p38 and JNK signaling pathways. Moreover, blocking ASK1 with ASK1-specific inhibitor compensated the pro-hypertrophic effects induced by DUSP9 deficiency in cardiomyocytes. The main findings of this study suggest the potential of DUSP9 in alleviating cardiac hypertrophy at least partially by repressing ASK1, thereby looks promising as a prospective target against cardiac hypertrophy.

Rac GTPase activating protein 1 (RACGAP1) has been characterized in the pathogenesis and progression of several malignancies, however, little is known regarding its role in the development of gallbladder cancer (GBC). This investigation seeks to describe the role of RACGAP1 and its associated molecular mechanisms in GBC. It was found that RACGAP1 was highly expressed in human GBC tissues, which was associated to poorer overall survival (OS). Gene knockdown of RACGAP1 hindered tumor cell proliferation and survival both in vitro and in vivo. We further identified that RACGAP1 was involved in DNA repair through its binding with DNA ligase 3 (LIG3), a crucial component of the alternative-non-homologous end joining (Alt-NHEJ) pathway. RACGAP1 regulated LIG3 expression independent of RhoA activity. RACGAP1 knockdown resulted in LIG3-dependent repair dysfunction, accumulated DNA damage and Poly(ADP-ribosyl) modification (PARylation) enhancement, leading to increased apoptosis and suppressed cell growth. We conclude that RACGAP1 exerts a tumor-promoting role via binding LIG3 to reduce apoptosis and facilitate cell growth in GBC, pointing to RACGAP1 as a potential therapeutic target for GBC.

Adult mammalian hearts show limited capacity to proliferate after injury, while zebrafish are capable to completely regenerate injured hearts through the proliferation of spared cardiomyocytes. BMP and Notch signaling pathways have been implicated in cardiomyocyte proliferation during zebrafish heart regeneration. However, the molecular mechanism underneath this process as well as the interaction between these two pathways remains to be further explored. In this study we showed BMP signaling was activated after ventricle ablation and acted epistatic downstream of Notch signaling. Inhibition of both signaling pathways differentially influenced ventricle regeneration and cardiomyocyte proliferation, as revealed by time-lapse analysis using a cardiomyocyte-specific FUCCI (fluorescent ubiquitylation-based cell cycle indicator) system. Further experiments revealed that inhibition of BMP and Notch signaling led to cell-cycle arrest at different phases. Overall, our results shed light on the interaction between BMP and Notch signaling pathways and their functions in cardiomyocyte proliferation during cardiac regeneration.

Exosomes are nanoscale membrane vesicles, which carry biologically active substances of their cell of origin and play an important role in signal transduction and intercellular communication. At present, exosomes have been identified as a promising non-invasive liquid biopsy biomarker in the tissues and circulating blood of nasopharyngeal carcinoma (NPC) and found to participate in regulating pathophysiological process of the tumor. We here review recent insights gained into the molecular mechanisms of exosome-induced cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance and chemotherapy resistance in the development and progression of NPC, as well as the clinical application of exosomes as diagnostic biomarkers and therapeutic agents. We also discuss the limitations and challenges in exosome application. We hope this review may provide some references for the use of exosomes in clinical intervention.

The efficacy of tocilizumab on the prognosis of severe/critical COVID-19 patients is still controversial so far. We aimed to delineate the inflammation characteristics of severe/critical COVID-19 patients and determine the impact of tocilizumab on hospital mortality. Here, we performed a retrospective cohort study which enrolled 727 severe or critical inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Huoshenshan Hospital (Wuhan, China), among which 50 patients received tocilizumab. This study confirmed that most recovered patients manifested relatively normal inflammation levels at admission, whereas most of the deceased cases presented visibly severe inflammation at admission and even progressed into extremely aggravated inflammation before their deaths, proved by some extremely high concentrations of interleukin-6, procalcitonin, C-reactive protein and neutrophil count. Moreover, based on the Cox proportional-hazards models before or after propensity score matching, we demonstrated that tocilizumab treatment could lessen mortality by gradually alleviating excessive inflammation and meanwhile continuously enhancing the levels of lymphocytes within 14 days for severe/critical COVID-19 patients, indicating potential effectiveness for treating COVID-19.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a persistent global threat. The transmission of SARS-CoV-2 is wide and swift. Rapid detection of the viral RNA and effective therapy are imperative to prevent the worldwide spread of the new infectious disease. Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR)- CRISPR-associated protein (Cas) system is an RNA-directed adaptive immune system, and it has been transformed into a gene editing tool. Applications of CRISPR-Cas system involves in many fields, such as human gene therapy, drug discovery and disease diagnosis. Under the background of COVID-19 pandemic, CRISPR-Cas system shows hidden capacity to fight the emergency in many aspects. This review will focus on the role of gene editing in COVID-19 diagnosis and treatment. We will describe the potential use of CRISPR-Cas-based system in combating COVID-19, from diagnosis to treatment. Furthermore, the limitation and perspectives of this novel technology are also evaluated.

Rationale: Corticosteroid resistance (CR) seriously affects the therapeutic effects of steroids on many chronic inflammatory disorders, including airway allergy. The mechanism of CR development is unclear. Recent research indicates that livin, an apoptosis inhibitor, is associated with the regulation in cell activities. This study investigates the role of livin in the inducing and sustaining CR in the airway mucosa. Methods: Nasal epithelial cells (NECs) were isolated from surgically removed nasal mucosal tissues of patients with allergic rhinitis (AR) and nasal polyps with or without CR. Differentially expressed genes in NECs were analyzed by the RNA sequencing. A CR mouse model was developed to test the role of livin in CR development. Results: The results showed that NECs of AR patients with CR expressed high levels of livin, that was positively correlated with the thymic stromal lymphopoietin (TSLP) expression and the high Ras activation status in NECs. Livin and Ras activation mutually potentiating each other in the inducing and sustaining the TSLP expression in NECs. TSLP induced eosinophils and neutrophils to express glucocorticoid receptor-β (GRβ). Eosinophils and neutrophils with high CRβ expression were resistant to corticosteroids. Depletion of livin or inhibition of TSLP markedly attenuated CR and airway allergy. Conclusions: Livin facilitates CR development in the airways by promoting TSLP expression in epithelial cells and the GRβ expression in eosinophils and neutrophils. Depletion of livin or inhibiting TSLP attenuates CR development and inhibits airway allergy, this has the translational potential to be used in the treatment of airway allergy.

Renal ischemia-reperfusion injury (IRI) is one of the underlying causes of acute kidney injury and also an unavoidable problem in renal transplantation. Lots of miRNAs and targets have been found to participate in some post-transcriptional processes in renal IRI, however, the detailed knowledge of miRNA targets and mechanism is unknown. In this study, miR-124 was found inhibited and PARP1 was overexpressed in renal IRI cells and mouse models. Dual-luciferase reporter assay revealed that miR-124 post-transcriptionally regulated PAPR1 3'UTR activity. Our results also demonstrated miR-124 negatively regulated PARP1 which played a role in necroptosis of renal ischemia-reperfusion injury by activating TNFα. TNFα induced the RIP1/RIP3 necroptosis signaling pathway to aggravate the renal injury. Collectively, these studies identified PARP1 as a direct target of miR-124 and activated RIP1/RIP3 necroptosis signaling pathway through TNFα. It elucidated the protective effect of miR-124 in renal ischemia-reperfusion injury, which demonstrated the regulatory mechanism of miR-124/PARP1 in renal injury and exhibited the potential as a novel therapeutic for the treatment of renal IRI.

Gonadal trans-differentiation from ovary to testis occurs in a same individual, suggesting a role of epigenetic regulation. However, histone modifications concerning the sex reversal process remain elusive. We analyzed histone modifications using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chromatin immunoprecipitation followed by sequencing (ChIP-seq) technology was used to test chromatin immunoprecipitation of gonads. Western blot analysis was performed to analyze protein expression. Immunofluorescence analysis was conducted to localize proteins in gonadal tissues. Here, we report a developmental atlas of histone modifications in the gonadal differentiation, including acetylation, methylation, and ubiquitination. We provided a detail distribution map of these modification sites including novel histone modifications along histones H2a, H2b, H3, and H4, and revealed their relationship with types of gonadal differentiation. We then determined a testis-enriched histone modification site, H2b monoubiquitination at K120, and its association with spermatogenesis. ChIP-seq demonstrated that the modification was highly enriched in the male sex-determining gene dmrt1 (doublesex and mab-3 related transcription factor 1), in particular, in its exon regions, suggesting its role in transcriptional regulation of dmrt1 in testis. Together, these data not only provide a new resource for epigenetic study in gonadal development, but also define an association of histone modifications with gonadal differentiation from ovary to testis.

Type 2 diabetes mellitus (T2DM) is closely associated with cardiovascular diseases (CVD), including atherosclerosis, hypertension and heart failure. Some anti-diabetic medications are linked with an increased risk of weight gain or hypoglycemia which may reduce the efficacy of the intended anti-hyperglycemic effects of these therapies. The recently developed receptor agonists for glucagon-like peptide-1 (GLP-1RAs), stimulate insulin secretion and reduce glycated hemoglobin levels without having side effects such as weight gain and hypoglycemia. In addition, GLP1-RAs demonstrate numerous cardiovascular protective effects in subjects with or without diabetes. There have been several cardiovascular outcomes trials (CVOTs) involving GLP-1RAs, which have supported the overall cardiovascular benefits of these drugs. GLP1-RAs lower plasma lipid levels and lower blood pressure (BP), both of which contribute to a reduction of atherosclerosis and reduced CVD. GLP-1R is expressed in multiple cardiovascular cell types such as monocyte/macrophages, smooth muscle cells, endothelial cells, and cardiomyocytes. Recent studies have indicated that the protective properties against endothelial dysfunction, anti-inflammatory effects on macrophages and the anti-proliferative action on smooth muscle cells may contribute to atheroprotection through GLP-1R signaling. In the present review, we describe the cardiovascular effects and underlying molecular mechanisms of action of GLP-1RAs in CVOTs, animal models and cultured cells, and address how these findings have transformed our understanding of the pharmacotherapy of T2DM and the prevention of CVD.

Today mitochondria are considered much more than a energy plant in cells. Mitochondrial transplantation therapy has been an active research area for treating mitochondria-associated diseases from animal studies to clinical trials. However, the specific mechanism involved in the anti-tumor activity of healthy mitochondria remain to be characterized. Here we investigate the signal mechanism and gender difference of mitochondrial transplantation therapy against malignant melanoma. In the study, we administrated intact mitochondria extracted from mouse livers respectively to the mice bearing malignantly subcutaneous and metastatic melanoma, and identified the signal mechanism responsible for the mitochondrial treatment through transcriptomic analysis. Meanwhile, the efficiency of female mitochondria and male mitochondria was compared in the cultured melanoma cells and transplanted melanoma in mice. The results suggested that the mitochondria significantly inhibited the tumor cell proliferation in vitro through cell cycle arrest and induction of cell apoptosis. In the melanoma-bearing mice, the mitochondria retard the tumor growth and lung migration, and the transcriptomic analysis indicated that general chromosome silencing was strongly associated with the mitochondria against melanoma after the mitochondrial transplantation on the metastasis melanoma. Moreover, the anti-tumor activity of mitochondria from female animals was more efficient in comparison to the males, and the female mitochondria could probably induce more persuasive mitochondria-nuclear communication than the mitochondria from male mice. The study identifies the anti-tumor mechanism of the mitochondrial transplantation therapy, and provides a novel insight into the effect of mitochondria from different gender.

Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.

The transient receptor potential cation channel subfamily V member 1 (TRPV1) is a transmembrane protein that can be activated by various physical and chemical stimuli and is associated with pain transduction. In recent years, TRPV1 was discovered to play essential roles in cancer tumorigenesis and development, as TRPV1 expression levels are altered in numerous cancer cell types. Several investigations have discovered direct associations between TRPV1 and cancer cell proliferation, cell death, and metastasis. Furthermore, about two dozen TRPV1 agonists/antagonists are under clinical trial, as TRPV1 is a potential drug target for treating various diseases. Hence, more researchers are focusing on the effects of TRPV1 agonists or antagonists on cancer tumorigenesis and development. However, both agonists and antagonists may reveal anti-cancer effects, and the effect may function via or be independent of TRPV1. In this review, we provide an overview of the impact of TRPV1 on cancer cell proliferation, cell death, and metastasis, as well as on cancer therapy and the tumor microenvironment, and consider the implications of using TRPV1 agonists and antagonists for future research and potential therapeutic approaches.

Long non-coding RNAs (lncRNAs) play key roles in various human cancers. We aimed to determine the key lncRNAs mediating colorectal cancer (CRC) progression. We identified some lncRNAs aberrantly expressed in CRC tissues by using lncRNA microarrays and demonstrated that SH3PXD2A-AS1 was one of the most highly overexpressed lncRNAs in CRC. We further aimed to explore the roles and possible molecular mechanisms of SH3PXD2A-AS1 in CRC. RNA ISH revealed that SH3PXD2A-AS1 was overexpressed in CRC compared with adjacent normal colon tissues and indicated poor prognosis in CRC. Functional analyses showed that SH3PXD2A-AS1 enhanced cell proliferation, angiogenesis, and metastasis. Mechanistically, SH3PXD2A-AS1 can directly interact with p53 protein and regulate p53-mediated gene transcription in CRC. We provided mechanistic insights into the regulation of SH3PXD2A-AS1 on p53-mediated gene transcription and suggested its potential as a new prognostic biomarker and target for the clinical management of CRC.

Nasopharyngeal carcinoma (NPC) is known for its potential to progress to the lymph nodes and distant metastases at an early stage. As an important regulator in tumorigenesis biological processes, the functions of lncRNA in NPC tumor development remain largely unclear. In this research, the expression of EPB41L4A-AS2 in NPC tissues and cells was analyzed via real-time quantitative polymerase chain reaction (qRT-PCR). CCK8, colony formation, and EDU experiments were used to determine the viability of NPC cells. Transwell and wound healing assays were performed to test NPC cell migration and invasion. RNA pull-down and mass spectrometry analysis were used to identify potential binding proteins. Then, a popliteal lymph node metastasis model was established to test NPC metastasis. EPB41L4A-AS2 is repressed by transforming growth factor-beta, which is downregulated in NPC cells and tissue. It is associated with the presence of distant metastasis and adverse outcomes. The univariate and multivariate survival assays confirmed that EPB41L4A-AS2 expression was an independent predictor of progression-free survival (PFS) in patients with NPC. Biological analyses showed that overexpression of EPB41L4A-AS2 reduced the metastasis and invasion of NPC in vitro and in vivo, but had no significant effect on cell proliferation. Mechanistically, in the nucleus we identified that EPB41L4A-AS2 relies on binding to YBX1 to reduce the stability of Snail mRNA to enhance the expression of E-cadherin and reverse the progression of epithelial-to-mesenchymal transition (EMT). In the cytoplasm, we found that EPB41L4A-AS2 blocked the invasion and migration of NPC cells by promoting LATS2 expression via sponging miR-107. In a whole, the findings of this study help to further understand the metastasis mechanism of NPC and could help in the prevention and treatment of NPC metastasis.

Gamma-Aminobutyric Acid Type B Receptor (GABABR) plays essential roles in tumor progression. However, the function of GABABR in colorectal cancer (CRC) needs further clarification. As the main part of GABABR, GABABR1 expression was identified significantly lower in tumor tissues than those in non-tumor normal tissues and that CRC patients with high GABABR1 expression lived longer. Further studies indicated that knockdown of GABABR1 elevated CRC cell proliferation, migration, and invasion. Furthermore, knockdown of GABABR1 activated the expression of the epithelial-mesenchymal transition (EMT)-related proteins N-cadherin and Vimentin, whereas decrease the protein level of E-cadherin. In addition, activation of Hippo/YAP1 signaling contributes to the GABABR1 down-regulation promoted proliferation, migration, invasion and EMT in CRC cells. At last, we verified the contribution of Hippo/YAP1 signaling in the GABABR1 down-regulation impaired biological phenotype of colon cancer cells in vivo. In summary, these data indicate that GABABR1 impairs the migration and invasion of CRC cells by inhibiting EMT and the Hippo/YAP1 pathway, suggesting that GABABR1 could be a potential therapeutic target for CRC.

Background: Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) allow entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells and play essential roles in cancer therapy. However, the functions of ACE2 and TMPRSS2 in kidney cancer remain unclear, especially as kidneys are targets for SARS-CoV-2 infection. Methods: UCSC Xena project, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases (GSE30589 and GSE59185) were searched for gene expression in human tissues, gene expression data, and clinical information. Several bioinformatics methods were utilized to analyze the correlation between ACE2 and TMPRSS2 with respect to the prognosis of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP). Results: ACE2 expression was significantly upregulated in tumor tissue, while its downregulation was associated with low survival in KIRC and KIRP patients. TMPRSS2 was downregulated in KIRC and KIRP, and its expression was not correlated with patient survival. According to clinical risk factor-based prediction models, ACE2 exhibits predictive accuracy for kidney cancer prognosis and is correlated with metabolism and immune infiltration. In an animal model, ACE2 expression was remarkably downregulated in SARS-CoV-2-infected cells compared to in the control. Conclusion: ACE2 expression is highly correlated with various metabolic pathways and is involved in immune infiltration.it plays a crucial role than TMPRSS2 in diagnosing and prognosis of kidney cancer patients. The overlap in ACE2 expression between kidney cancer and SARS-CoV-2 infection suggests that patients with KIRC or KIRP are at high risk of developing serious symptoms.

There is a continued need for investigating the roles of microRNAs (miRNAs) and their targets on the progression of gastric cancer (GC), especially metastasis. Here, we performed an integrated study to identify dysregulated miRNAs critical for GC development and progression. miR-135b was determined as a promising biomarker for GC. The expression level of miR-135b was increased among GC cell lines, patient tumor tissues, serum samples, and correlation with aggravation of the GC patients. The in vitro functional assays demonstrated overexpression of miR-135b promoted cell proliferation, migration and invasion in GC, while miR-135b inhibition led to the opposite results. CAMK2D was found to be the direct target of miR-135b, serving as a tumor suppressor in GC cells. Based on our and public datasets, we confirmed the attenuation of CAMK2D expression in GC tissues. And, the expression levels of miR-135b and CAMK2D were closely associated with prognosis of GC patients. Ectopic expression of miR-135b resulted in the down-regulation of CAMK2D. Additionally, CAMK2D was a prerequisite for miR-135b to promote GC cells proliferation and migration by regulating the EMT process, which was confirmed by the in vivo experiments. Importantly, in vivo injection of miR-135b antagomir significantly repressed the tumor growth and metastasis of xenograft models, which suggested that the miR-135b antagomir were promising for clinical applications. Taken together, these results indicate that miR-135b/CAMK2D axis drives GC progression by EMT process remodeling, suggesting that miR-135b may be utilized as a new therapeutic target and prognostic marker for GC patients.

Background: Estrogen-related receptor-α (ESRRA) is an orphan nuclear receptor, expressing at high level in exuberant metabolism organs and acting as transcription factor. High expression was found in many malignances but no research was done in gastric cancer (GC), where lipid metabolism disorder is common. Methods: Kaplan-Meier plot was utilized to find the relationship between ESRRA expression and patients' prognoses. The expression level of ESRRA was measured by real-time PCR. The protein expression levels were tested with western-blot and immunohistochemistry. Cell cycle and apoptosis was identified with flow cytometry. RNA-seq, bioinformatics analysis, dual-luciferase assay and ChIP assay were used to predict and validate ESRRA's target gene and binding motif. Animal models were also introduced in our study. Results: ESRRA expression is notably higher in GC cell lines and high ESRRA levels are correlated to poor prognoses. ESRRA silencing decreased GC cell viability, migration, and invasion capacities. Its downstream gene DSN1 was spotted by RNA-seq and confirmed by later bioinformatics analyses, dual-luciferase, and ChIP assays. Western-blot showed G2M arrest caused by ESRRA silencing was via CDC25C-CDK1-Cyclin B1 pathway. Conclusion: ESRRA/DSN1/CDC25C-CDK1-Cyclin B1 is of great importance in GC development. ESRRA could be a potential target as well as prognostic marker in GC.