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Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/β-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/β-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer., Graphical abstract, lncRNA-DAW was driven by a liver-specific super-enhancer and frequently upregulated in liver cancer. lncRNA-DAW diminished PRC2-mediated repression of Wnt2 by antagonizing the function of EZH2, eventually leading to the activation of the Wnt/β-catenin pathway and cancer cell proliferation.

Schizophrenia (SZ) is characterized by a series of cognitive impairments, including automatic processing impairment of basic auditory information, indexed by mismatch negativity (MMN). Existing studies mainly focus on MMN induced by deviant of single acoustic features, and relatively few studies have focused on complex acoustic stimuli, especially speech-induced MMN. Many cognitive impairments in SZ are related to speech function. Thus, the present study aimed to examine the reduction of phonetic MMN in SZ as a potential biomarker and its relationship with illness course and functional outcomes. Electroencephalogram (EEG) signals were recorded from 32 SZ and 32 healthy controls (HC) in a double oddball paradigm, with /da/ as the standard stimulus and /ba/ and /du/ as the deviant stimuli. MMN was computed for vowel and consonant deviants separately. Clinical symptoms were assessed using the Positive and Negative Symptom Rating Scale (PANSS). Illness duration and illness relapse were acquired by combining clinical interviews and electronic medical records. Functional outcomes were assessed using the Global Assessment of Functioning scale (GAF). Compared with HC, SZ showed lower amplitudes of phonetic MMN, especially for vowel deviants. In addition, the MMN amplitude of the vowel deviant was significantly correlated with illness duration, illness relapse, and functional outcomes among patients with SZ. These findings indicate that the pre-attentive automatic phonetic processing of SZ was impaired for both consonants and vowels, while the vowel processing deficit may be the key speech processing deficit in SZ, which could depict the illness course and predict the functional outcomes.

Growing evidence supports a clear association between COVID-19 pandemic and mental health. However, little is known about the longitudinal course of psychopathology in young adults at different stages of the pandemic.This large-scale, longitudinal, population-based survey was conducted among college students in China. The rates of three mental health problems (acute stress, anxiety, and depressive symptoms), and their change patterns at two phases of the pandemic (early vs under-control) were measured. Predictors of changes in mental health symptoms were examined utilizing multivariate regression.Among the 164,101 college students who participated in the first wave survey (T1=during onset of outbreak), 68,685 (41.9%) completed a follow-up survey (T2=during remission). In the follow-up survey, the prevalence of probable acute stress (T1: 34.6%; T2: 16.4%) decreased, while the rates of depressive (T1: 21.6%; T2: 26.3%) and anxiety symptoms (T1: 11.4%; T2: 14.7%) increased. Senior students, with suspected or conformed cases in their community and COVID-19 related worries (all AORs1.20, ps0.001) were found to have a higher risk of developing mental health problems in at least one wave. Less physical exercise, low perceived social support, and a dysfunctional family were found to negatively impact psychological symptoms.Acute stress, anxiety, and depressive symptoms have been prevalent among college students during the COVID-19 epidemic, and showed a significant increase after the initial stage of the outbreak. Some college students, especially those with the risk factors noted above, exhibited persistent or delayed symptoms.

Cancer cells are abnormal cells that can reproduce and regenerate rapidly. They are characterized by unlimited proliferation, transformation and migration, and can destroy normal cells. To meet the needs for cell proliferation and migration, tumor cells acquire molecular materials and energy through unusual metabolic pathways as their metabolism is more vigorous than that of normal cells. Multiple carcinogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells, including glucose, lipid, and amino acid metabolism. The distinct metabolic signatures of cancer cells reflect that metabolic changes are indispensable for the genesis and development of tumor cells. In this review, we report the unique metabolic alterations in tumor cells which occur through various signaling axes, and present various modalities available for cancer diagnosis and clinical therapy. We further provide suggestions for the development of anti‐tumor therapeutic drugs.

MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional levels. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MicroRNA (miR)-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of mesenchymal stem cells (MSCs) derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed, whereas anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members, Wnt6 and Wnt10a, were identified as bona fide targets of miR-378, and their expression was decreased by this miRNA, which eventually induced the inactivation of Wnt/β-catenin signaling. Finally, the short hairpin (sh)-miR-378-modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate the healing process in vivo. In conclusion, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/β-catenin signaling, suggesting that miR-378 may be a potential therapeutic target for bone diseases., Graphical Abstract, Feng and his colleagues identified impaired bone development and BMSCs osteogenesis in miR-378 transgenic mice. They characterized that miR-378 isoforms directly repress two Wnt family members’ expression, which leads to deactivation of Wnt/β-catenin signaling during osteogenesis. They also demonstrated the effect of miR-378 inhibitor therapy on promoting bone formation in vivo.

Immunotherapies that target programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting that the mechanisms of the immune checkpoint pathways are not completely understood. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interactions with components of the endocytosis and nucleocytoplasmic transport pathways, regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune-response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune-response-related genes and, as a consequence, enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune-response gene expression, and thereby advocate targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.

Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.

BackgroundThe prevention of COVID-19 pandemic is highly complicated by the prevalence of asymptomatic and recurrent infection. Many previous immunological studies have focused on symptomatic and convalescent patients, while the immune responses in asymptomatic patients and re-detectable positive cases remain unclear.MethodsHere we comprehensively analyzed the peripheral T-cell receptor (TCR) repertoire of 54 COVID-19 patients in different phases, including asymptomatic, symptomatic, convalescent and re-detectable positive cases.ResultsWe found progressed immune responses from asymptomatic to symptomatic phase. Furthermore, the TCR profiles of re-detectable positive cases were highly similar to those of asymptomatic patients, which could predict the risk of recurrent infection.ConclusionTherefore, TCR repertoire surveillance has the potential to strengthen the clinical management and the immunotherapy development for COVID-19.FundingThe Science and Technology Innovation Project of Foshan Municipality (2020001000431) and the National Key Research and Development Project (2020YFA0708001).

Apigenin (API), a natural plant flavone, is abundantly found in common fruits and vegetables. As a bioactive flavonoid, API exhibits several activities including antiproliferation and anti-inflammation. A recent study showed that API could retard osteoporosis progress, indicating its role in the skeletal system. However, the detailed function and mechanism remain obscure. In the present study, API was found to promote osteogenic differentiation of mesenchymal stem cells (MSCs). And further investigation showed that API could enhance the expression of the critical transcription factor β-catenin and several downstream target genes of Wnt signaling, thus activated Wnt/β-catenin signaling. Using a rat femoral fracture model, API was found to improve new bone formation and accelerate fracture healing in vivo. In conclusion, our data demonstrated that API could promote osteogenesis in vitro and facilitate the fracture healing in vivo via activating Wnt/β-catenin signaling, indicating that API may be a promising therapeutic candidate for bone fracture repair.

Presently, optimal proportions and synergistic mechanisms of component-based Chinese medicines are critical for developing novel strategies to treat cardiovascular diseases (CVDs). A new multi-objective optimization algorithm based on uniform design (UD) and stepwise regression (SR) modeling is proposed to find the synergistic effect of orientin (Ori), quercitrin (Que) and vitexin (Vit), the three effective components from Polygonum orientale L., using the H9c2 cells injury induced by hypoxia/reoxygenation (H/R). The optimal proportion of these three components was calculated by simulated annealing (SA). In this research, the excellent combination named OQV-e (Ori: Que: Vit =12.55 μM: 39.99 μM: 19.99 μM) could exert significant cardioprotection against the H9c2 cells injury induced by H/R through increasing cell viability, decreasing leakage rate of lactate dehydrogenase (LDH) and the level of nitric oxide (NO). Moreover, western blot analysis revealed that OQV-e could activate autophagy by inhibiting the p-JNK/JNK signaling pathway, which showed that the method (UD-SR-SA) was a feasible strategy. Mathematical system modeling may be a considerable approach for the powerful mathematical analysis of the complex pharmacological effects of component-based Chinese medicines from herbal medicines, which might greatly enhance the efficiency to find new modern Chinese drugs for CVDs based on Chinese herbal medicine (CHM) with affirmative therapeutic effect.

Lichun Sun,1,* Kaixin Wang,2,* Lu Peng,1 Jinfang Zhang,2 Jie Yang,3 Juan Zhao,1 Jiang Xu,1 Jun Zheng,1 Yan Zeng1 1Department of Stomatology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People’s Republic of China; 2Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China; 3Department of Laboratory, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Zeng; Jun ZhengDepartment of Stomatology & Key Laboratory of Xinjiang Endemic and Ethnic Disease, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, People’s Republic of ChinaTel +86 18997732862; +86 18997737192Email zengyan910@gmail.com; haohaoay@yeah.netBackground: This study aimed to investigate the function and underlying molecular mechanism of N-α-acetyltransferase 10 protein (Naa10p) in cisplatin (CDDP) chemosensitivity in oral squamous cell carcinoma (OSCC).Methods: Salivary Naa10p levels in 76 OSCC patients undergoing CDDP-based chemotherapy were detected using enzyme-linked immunosorbent assay. Quantitative real-time polymerase chain reaction and Western blot were used to examine the expression of Naa10p in constructed CDDP-resistant OSCC cell (Cal-27/CDDP) lines and nude mouse model. In addition, the tumor volume and weight of nude mice were analyzed. Lentiviral system was employed to establish and identify OSCC cell lines with stable Naa10p interference or overexpression. MTT assay was used for drug sensitivity analysis. P-gp and Bcl-2 expression levels were tested by Western blot.Results: Higher salivary Naa10p expression was present in the complete response/partial response group (n=46) compared to the stable disease/progressive disease group (n=30) in OSCC patients receiving chemotherapy treatment. Naa10p expression was down-regulated in Cal-27/CDDP cells and tissues. Naa10p overexpression significantly reduced the expression level of drug-resistant molecules. Naa10p was related to CDDP resistance and enhanced CDDP sensitivity in OSCC according to drug sensitivity analysis and nude mouse model experiments.Conclusion: Naa10p plays a tumor suppressor gene role and is associated with CDDP resistance in OSCC. It can enhance CDDP sensitivity in OSCC and may be a potential target for OSCC chemotherapy.Keywords: N-α-acetyltransferase 10 protein, oral squamous cell carcinoma, cisplatin, chemosensitivity

Although targeting programmed death 1/programmed death ligand 1 (PD-1/PD-L1) has achieved durable responses and disease remission in patients with certain cancers, relatively low response rates and emerging resistance limit its clinical application. Hence, a more thorough understanding of regulatory mechanisms of the PD-1/PD-L1 axis is vital for developing combined therapeutic strategies to overcome hurdles of PD-1/PD-L1 blockade. Increasing evidence has demonstrated that PD-L1 can be secreted into the extracellular space or translocated into the nucleus, which also plays a critical role in regulating cancer immune evasion, tumorigenesis, and immunotherapy. In this review, we summarize these emerging roles of extracellular and nuclear PD-L1 and discuss future research directions and potential opportunities in translational medicine.

BACKGROUND: Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN. METHODS: In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants. RESULTS: The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models. CONCLUSIONS: In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN–PI3K signaling axis. (Funded by the National Institutes of Health and others.)

Upregulation of programmed death ligand 1 (PD-L1) helps tumor cells escape from immune surveillance, and therapeutic antibodies targeting PD-1/PD-L1 have shown better patient outcomes only in several types of malignancies. Recent studies suggest that the clinical efficacy of anti-PD-1/PD-L1 treatments is associated with PD-L1 levels; however, the underlying mechanism of high PD-L1 protein levels in cancers is not well defined. Here, we report that the deubiquitinase OTUB1 positively regulates PD-L1 stability and mediates cancer immune responses through the PD-1/PD-L1 axis. Mechanistically, we demonstrate that OTUB1 interacts with and removes K48-linked ubiquitin chains from the PD-L1 intracellular domain in a manner dependent on its deubiquitinase activity to hinder the degradation of PD-L1 through the ERAD pathway. Functionally, depletion of OTUB1 markedly decreases PD-L1 abundance, reduces PD-1 protein binding to the tumor cell surface, and causes increased tumor cell sensitivity to human peripheral blood mononuclear cells (PBMCs)-mediated cytotoxicity. Meanwhile, OTUB1 ablation-induced PD-L1 destabilization facilitates more CD8(+) T cells infiltration and increases the level of IFN-γ in serum to enhance antitumor immunity in mice, and the tumor growth suppression by OTUB1 silencing could be reversed by PD-L1 overexpression. Furthermore, we observe a significant correlation between PD-L1 abundance and OTUB1 expression in human breast carcinoma. Our study reveals OTUB1 as a deubiquitinating enzyme that influences cancer immunosuppression via regulation of PD-L1 stability and may be a potential therapeutic target for cancer immunotherapy.

Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. However, the effective pharmacological approaches remain scanty in clinical practice. As a bioactive flavonoid, apigenin (API) is enriched in common fruits and vegetables. Although pharmacological activities of API have been widely investigated, its biological function in HCC remains obscure. In the present study, we found that API strongly suppressed cell growth and induced apoptosis in HCC cells. Using a xenograft mice model, API was demonstrated to inhibit the in vivo tumor growth. It is known that the long non-coding RNA H19, which is frequently elevated in HCC, plays a vital role in mediating tumorigenesis and cancer progression. Our results demonstrated that H19 was down-regulated by API, and thereby induced the inactivation of the canonical Wnt/β-catenin signaling. In conclusion, our results demonstrated that API was able to suppress tumor growth of HCC through H19-mediated Wnt/β-catenin signaling regulatory axis, suggesting that API may be a promising candidate for developing novel therapeutic approaches against liver cancer.

Embryonic bone development is a complicated procedure and modulated by neuro-osteogenic interaction. Vasoactive intestinal peptide (VIP) was first identified as a neural vasodilator and further proved to possess multiple biological functions such as neurotransmitter and immune regulator. However, as a key peptide regulator presented in skeletal nerve fibers, the function of VIP on innervation and early bone development regulation has not fully been uncovered yet. In this study, the chick embryo has been used as an experimental model to address the effect of VIP on embryonic bone development. Our study results confirmed the innervation of peripheral nerve fibers into limb bone tissue, which was revealed by the detection of neurofilament (NF) and class III β-tubulin (TUJ-1) in bone tissue at various developing stages. The VIP mRNA and peptide expression level in bone tissue were also increased upon innervation progress. A chick embryonic chemical sympathectomy model was constructed by exposing chick embryos with neurotoxin 6-OHDA. The 6-OHDA exposure of the early chick embryo caused the reduction of neural crest formation and NF expression. 6-OHDA treatment also inhibited distal limb bone development as well as VIP expression. Furthermore, co-application of VIP with 6-OHDA exposure could rescue the inhibited osteogenesis activity and delayed bone development during embryogenesis. Taken together, these results reveal that VIP played an important role during innervation at early stage of bone development. VIP could restore chemical sympathectomy induced osteogenesis inhibition and bone development impair in chick embryos.

PD-L1, frequently expressed in human cancers, engages with PD-1 on immune cells and contributes to cancer immune evasion. As such, antibodies blocking the PD-1/PD-L1 interaction reactivate cytotoxic T cells to eradicate cancer cells. However, a majority of cancer patients fail to respond to PD-1/PD-L1 blockade with unclear underlying mechanism(s). Recent studies revealed that PD-L1 expression levels on tumor cells might affect the clinical response to anti-PD-1/PD-L1 therapies. Hence, understanding molecular mechanisms for controlling PD-L1 expression will be important to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade. In this review, we primarily focus on summarizing PD-L1 regulation and its potential roles in regulating anti-tumor immune response, with purpose to optimize anti-PD-1/PD-L1 therapies, benefiting a wider cancer patient population.

Background Florfenicol is a derivative of chloramphenicol that is used only for the treatment of animal diseases. A key resistance gene for florfenicol, floR, can spread among bacteria of the same and different species or genera through horizontal gene transfer. To analyze the potential transmission of resistance genes between animal and human pathogens, we investigated floR in Klebsiella pneumoniae isolates from patient samples. floR in human pathogens may originate from animal pathogens and would reflect the risk to human health of using antimicrobial agents in animals. Methods PCR was used to identify floR-positive strains. The floR genes were cloned, and the minimum inhibitory concentrations (MICs) were determined to assess the relative resistance levels of the genes and strains. Sequencing and comparative genomics methods were used to analyze floR gene-related sequence structure as well as the molecular mechanism of resistance dissemination. Results Of the strains evaluated, 20.42% (67/328) were resistant to florfenicol, and 86.96% (20/23) of the floR-positive strains demonstrated high resistance to florfenicol with MICs ≥512 μg/mL. Conjugation experiments showed that transferrable plasmids carried the floR gene in three isolates. Sequencing analysis of a plasmid approximately 125 kb in size (pKP18–125) indicated that the floR gene was flanked by multiple copies of mobile genetic elements. Comparative genomics analysis of a 9-kb transposon-like fragment of pKP18–125 showed that an approximately 2-kb sequence encoding lysR-floR-virD2 was conserved in the majority (79.01%, 83/105) of floR sequences collected from NCBI nucleotide database. Interestingly, the most similar sequence was a 7-kb fragment of plasmid pEC012 from an Escherichia coli strain isolated from a chicken. Conclusions Identified on a transferable plasmid in the human pathogen K. pneumoniae, the floR gene may be disseminated through horizontal gene transfer from animal pathogens. Studies on the molecular mechanism of resistance gene dissemination in different bacterial species of animal origin could provide useful information for preventing or controlling the spread of resistance between animal and human pathogens. Electronic supplementary material The online version of this article (10.1186/s13756-018-0415-0) contains supplementary material, which is available to authorized users.

Long noncoding RNAs (lncRNA) have been demonstrated to extensively participate in a wide spectrum of biological activities ranging from embryogenesis and cancer progression. HOX transcript antisense RNA (Hotair), an lncRNA located in the HOXC locus, has been reported to play an important role in carcinogenesis. As a well-known oncogene, it potentiates cancer metastasis and tumor progression. And it also serves as a biomarker for poor prognosis and tumor recurrence. In this study, Hotair was found to be upregulated in colorectal cancer (CRC) cells and clinical specimens. Further investigation showed that knockdown of Hotair dramatically suppressed cell proliferation and colony formation, suggesting that Hotair may stimulate tumorigenesis of CRC. The enhancer of zeste homolog 2 (EZH2), a regulator of epigenetic modification, was upregulated in CRC cells and clinical samples. And the silence of EZH2 significantly suppressed cell viability and colony formation. Furthermore, the RNA immunoprecipitation assay revealed that Hotair directly bound EZH2 in CRC cells. In conclusion, Hotair mediated tumorigenesis via recruiting EZH2, which might shed light on the development of a novel therapeutic approach for patients with CRC.

Ethnopharmacological relevance Da Chuanxiong Formula (DCXF) is one of the famous herb pairs that contains dried rhizomes of Ligusticum chuanxiong Hort. and Gastrodia elata Bl. in the mass ratio of 4:1. This classic representative traditional Chinese medicine has been widely used to treat brain diseases like headache and migraine caused by blood stasis and wind pathogen. However, the therapeutic effect of DCXF on traumatic brain injury (TBI) has not been reported yet. Aim of study The present study was performed to investigate the neuroprotective effects of DCXF and its underlying mechanisms in the controlled cortical impact (CCI)-induced TBI rat model. Materials and methods Male Sprague-Dawley rats were divided into four groups: Sham, TBI control, 1X DCXF (520.6 mg/kg) and 5X DCXF (2603.0 mg/kg). Two treatment groups (1X and 5X DCXF) were intragastrically administered daily for 7 days before CCI-induced TBI and then DCXF treatments were continued post-TBI until the animal behavioral tests, including Morris water maze test, acceleration rotarod motor test and CatWalk quantitative gait analysis test, were done. The brain water content and blood brain barrier (BBB) integrity were measured by wet-dry weight method and Evans blue method, respectively. The number of neuron cells, neural stem cells (NSCs), GFAP positive cells (astrocyte) as well as Iba-1 positive cells (microglia) were determined by histology and immunohistochemistry. Results Treatment with DCXF significantly improved the learning ability and memory retention in Morris water maze test, and remarkably enhanced motor performances in acceleration rotarod motor test and catwalk quantitative gait analysis test after TBI. Moreover, DCXF treatment was able to reduce BBB permeability, brain edema, microglia and astrocyte activation, improve the proliferation of NSCs and decrease neurons loss in the brain with TBI. Conclusions The present study demonstrated that DCXF treatment could decrease BBB leakage and brain edema, reduce neuron loss, microglia and astrocyte activation, and increase NSCs proliferation, which may contribute to the cognitive and motor protection of DCXF in the TBI rats. It is the first time to provide potentially underlying mechanisms of the neuroprotective effect of DCXF on TBI-induced brain damage and functional outcomes.

As a regulator of osteogenesis, microRNA-218 (miR-218) is reported to promote osteogenesis of mesenchymal stem cells (MSCs). However, the in vivo osteogenic effect of miR-218 remains elusive. In this study, miR-218 was confirmed to promote osteogenic differentiation of MSCs by stimulating the alkaline phosphatase activity, calcium nodule formation, and osteogenic marker gene expression. For in vivo study, the miR-218-overexpressing BMSCs were locally administrated into the fracture sites in a femur fracture mouse model. Based on the X-rays, micro-computed tomography, mechanical testing, histology, and immunohistochemistry examinations, miR-218 overexpression improved new bone formation and accelerated fracture healing. These findings suggest that miR-218 may be a promising therapeutic target for bone repair in future clinical applications.

As a primate-specific microRNA, miR-637 has been discovered for nearly 10 years. Our previous study demonstrated that miR-637 acted as a suppressor in hepatocellular carcinoma. However, its biomedical significance in pancreatic cancer remains obscure. In the present study, miR-637 was found to be significantly downregulated in pancreatic ductal adenocarcinoma (PDAC) cell lines and most of the PDAC specimens. Furthermore, the enforced overexpression of miR-637 dramatically inhibited cell proliferation and induced apoptosis of PDAC cells. Akt1, as a serine/threonine-protein kinase, has been identified as an oncogene in multiple cancers including pancreatic cancer. Our data confirmed that Akt1 was a novel target for miR-637, and its knockdown also induced cell growth inhibition and apoptosis in PDAC cells. In conclusion, our data indicated that miR-637 acted as a tumor-suppressor in PDAC, and the suppressive effect was mediated, at least partially, by suppressing Akt1 expression.

ObjectivesAs one of the heat-stable enterotoxins, Staphylococcal enterotoxin C2 (SEC2) is synthesized by Staphylococcus aureus, which has been proved to inhibit the growth of tumour cells, and is used as an antitumour agent in cancer immunotherapy. Although SEC2 has been reported to promote osteogenic differentiation of human mesenchymal stem cells (MSCs), the in vivo function of SCE2 in animal model remains elusive. The aim of this study was to further elucidate the in vivo effect of SCE2 on fracture healing.Materials and MethodsRat MSCs were used to test the effects of SEC2 on their proliferation and osteogenic differentiation potentials. A rat femoral fracture model was used to examine the effect of local administration of SEC2 on fracture healing using radiographic analyses, micro-CT analyses, biomechanical testing, and histological analyses.ResultsWhile SEC2 was found to have no effect on rat MSCs proliferation, it promoted the osteoblast differentiation of rat MSCs. In the rat femoral fracture model, the local administration of SEC2 accelerated fracture healing by increasing fracture callus volumes, bone volume over total volume (BV/TV), and biomechanical recovery. The SEC2 treatment group has superior histological appearance compared with the control group.ConclusionThese data suggest that local administration of SEC2 may be a novel therapeutic approach to enhancing bone repair such as fracture healing. Cite this article: T. Wu, J. Zhang, B. Wang, Y. Sun, Y. Liu, G. Li. Staphylococcal enterotoxin C2 promotes osteogenesis of mesenchymal stem cells and accelerates fracture healing. Bone Joint Res 2018;7:179–186. DOI: 10.1302/2046-3758.72.BJR-2017-0229.R1.

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass and deterioration of bone microarchitecture, which results in increased bone fragility and fracture risk. Casein kinase 2-interacting protein-1 (CKIP-1) is a protein that plays an important role in regulation of bone formation. The effect of CKIP-1 on bone formation is mainly mediated through negative regulation of the bone morphogenetic protein pathway. In addition, CKIP-1 has an important role in the progression of osteoporosis. This review provides a summary of the recent studies on the role of CKIP-1 in osteoporosis development and treatment. Cite this article: X. Peng, X. Wu, J. Zhang, G. Zhang, G. Li, X. Pan. The role of CKIP-1 in osteoporosis development and treatment. Bone Joint Res 2018;7:173–178. DOI: 10.1302/2046-3758.72.BJR-2017-0172.R1.

Beta-tricalcium phosphate (β-TCP) has been widely used for bone regeneration for many years. However, there are few studies on the osteoconduction ability of different shaped β-TCP scaffolds. In this study, we compared the osteoconductive potential between the tubular and cylindrical β-TCP scaffolds in long bone defect animal model. The results showed that more regenerated bone and a better healing property were observed in tubular group than that in cylindrical group. By hematoxylin-eosin staining, the central part of the callus was more compacted in tubular group. And moreover, the increased osteocalcin and osterix expression were found in tubular group, suggesting more vigorous regeneration of bone defect. These results demonstrated that tubular β-TCP scaffold would be more benefit to promote bone regeneration, indicating that tubular β-TCP scaffold has a good potential for long bone defect repair in clinical practice. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1934-1940, 2018.

// Yu-Xin Sun 1, 2, 3, * , Jin-Fang Zhang 2, 3, * , Jia Xu 4 , Liang-Liang Xu 2 , Tian-Yi Wu 2 , Bin Wang 2 , Xiao-Hua Pan 1 and Gang Li 1, 2, 3, 5 1 Department of Orthopaedics and Traumatology, Bao-An District People’s Hospital, Shenzhen, PR China 2 Department of Orthopaedics & Traumatology, Li Ka Shing Institute of Health Sciences and Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, PR China 3 The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, PR China 4 Department of Orthopaedics Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, PR China 5 Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China * These authors have contributed equally to this work Correspondence to: Xiao-Hua Pan, email: 568282414@qq.com Gang Li, email: gangli@cuhk.edu.hk Keywords: distraction osteogenesis, mesenchymal stem cells, microRNAs, miR-144 Received: July 14, 2017 Accepted: August 17, 2017 Published: September 18, 2017 ABSTRACT Distraction osteogenesis (DO), one of effective therapies for bone regeneration, has been received more attention in recent years. However, the underlying mechanism remains elusive. Recently, microRNAs (miRNAs) have been reported to play important roles in regulating osteogenesis and bone formation. We therefore provided the hypothesis that miRNAs could involve in the DO-mediated bone regeneration. After successfully established the DO model of rats, a miRNA microarray was performed to find the differently expressed miRNAs in DO and control groups in this study. As one of the most downregulated miRNAs, miR-144-3p was found to be decreased during osteogenic differentiation in mesenchymal stem cells of rats (rBMSCs) and DO model. And miR-144-3p overexpression suppressed the osteogenesis while its inhibitor promoted osteogenesis. Furthermore, Connexin-43, an essential regulator for osteogenesis, was validated to be a novel target for miR-144-3p. Finally, miR-144-3p inhibitor modified MSCs promoted mineralization of distracted bone in rat DO model. In conclusion, miR-144-3p was found to regulate osteogenesis and inhibition of miR-144-3p resulted in acceleration of mineralization of DO, which not only give clues to understanding the mechanism of DO but also provide a potential therapeutic target in clinical practice.

Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as a novel cancer therapeutic, is being tested in phase II and III clinical trials; however, TRAIL resistance remains a big obstacle preventing its clinical application. Considering that TRAIL-induced apoptosis through death receptors DR4 and DR5, their activation may be an alternative pathway to suppress TRAIL resistance. In this study, a negative correlation between DR5 expression and TRAIL resistance was observed, and miR-133a was predicted to be the most promising candidate to suppress DR5 expression. Further investigation demonstrated that miR-133a knockdown dramatically suppressed TRAIL resistance in glioblastoma in vitro and in vivo. An NF-κB family member, phosphorylated IκBα (P-IκBα), was shown to be stimulated by miR-133a, leading to the activation of this signaling. Finally, miR-133a was found to be inversely correlated with DR5 expression in human clinical specimens. In conclusion, our data demonstrate that miR-133a promotes TRAIL resistance in glioblastoma by suppressing DR5 expression and activating NF-κB signaling. Keywords: microRNA-133, TRAIL, DR5, NF-κB signaling, glioblastoma multiforme

Tendons are a mechanosensitive tissue, which enables them to transmit to bone forces that are derived from muscle. Patients with tendon injuries, such as tendinopathy or tendon rupture, were often observed with matrix degeneration, and the healing of tendon injuries remains a challenge as a result of the limited understanding of tendon biology. Our study demonstrates that the stretch-mediated activation channel, cystic fibrosis transmembrane conductance regulator (CFTR), was up-regulated in tendon-derived stem cells (TDSCs) during tenogenic differentiation under mechanical stretching. Tendon tissues in CFTR-dysfunctional DF508 mice exhibited irregular cell arrangement, uneven fibril diameter distribution, weak mechanical properties, and less matrix formation in a tendon defect model. Moreover, both tendon tissues and TDSCs isolated from DF508 mice showed significantly decreased levels of tendon markers, such as scleraxis, tenomodulin, Col1A1 (collagen type I α 1 chain), and decorin Furthermore, by RNA sequencing analysis, we demonstrated that Wnt/β-catenin signaling was abnormally activated in TDSCs from DF508 mice, thereby further activating the pERK1/2 signaling pathway. Of most importance, we found that intervention in pERK1/2 signaling could promote tenogenic differentiation and tendon regeneration both in vitro and in vivo Taken together, our study demonstrates that CFTR plays an important role in tenogenic differentiation and tendon regeneration by inhibiting the β-catinin/pERK1/2 signaling pathway. The therapeutic strategy of intervening in the CFTR/β-catenin/pERK1/2 regulatory axis may be helpful for accelerating tendon injury healing, which has implications for tendon injury management.-Liu, Y., Xu, J., Xu, L., Wu, T., Sun, Y., Lee, Y.-W., Wang, B., Chan, H.-C., Jiang, X., Zhang, J., Li, G. Cystic fibrosis transmembrane conductance regulator mediates tenogenic differentiation of tendon-derived stem cells and tendon repair: accelerating tendon injury healing by intervening in its downstream signaling.

// Yuyong Tan 1, 2 , Yanpeng Ci 2, 3 , Xiangpeng Dai 2 , Fei Wu 2, 4 , Jianping Guo 2 , Deliang Liu 1 , Brian J. North 2 , Jirong Huo 1 and Jinfang Zhang 2 1 Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha 410011, P.R. China 2 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA 3 School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, P.R. China 4 Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China Correspondence to: Brian J. North, email: bnorth@bidmc.harvard.edu Jirong Huo, email: hjr198@hotmail.com Jinfang Zhang, email: jzhang17@bidmc.harvard.edu Keywords: HDAC6, SPOP, Cullin 3, ubiquitination, tumorigenesis Received: March 29, 2017 Accepted: April 15, 2017 Published: May 24, 2017 ABSTRACT The histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3 SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines. Furthermore, we demonstrated that Cullin 3-based ubiquitin E3 ligase(s) primarily reduced the stability of HDAC6. Importantly, we identified SPOP, an adaptor protein of Cullin 3 family E3 ligases, specifically interacted with HDAC6, and promoted its poly-ubiquitination and subsequent degradation in cells. Notably, cancer-derived SPOP mutants disrupted their binding with HDAC6 and thereby failed to promote HDAC6 degradation. More importantly, increased cellular proliferation and migration in SPOP -depleted HCT116 colon cancer cells could be partly reversed by additional depletion of HDAC6 , suggesting that HDAC6 is a key downstream effector for SPOP tumor suppressor function. Together, our data identify the tumor suppressor SPOP as an upstream negative regulator for HDAC6 stability, and SPOP loss-of-function mutations might lead to elevated levels of the HDAC6 oncoprotein to facilitate tumorigenesis and metastasis in various human cancers.

// Yi Liu 1 , Wei-Mao Wang 2 , Ying-Fei Lu 3 , Lu Feng 3 , Li Li 1 , Ming-Zhu Pan 1 , Yu Sun 4 , Chun-Wai Suen 2 , Wei Guo 5 , Jian-Xin Pang 6 , Jin-Fang Zhang 2, 3, 7 and Wei-Ming Fu 6, 7 1 Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, China 2 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China 3 Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China 4 Shenzhen Enhance Techology Co. Ltd., Shenzhen, Guangdong, China 5 Shenzhen Ritzcon Biological Techology Co. Ltd., Shenzhen, Guangdong, China 6 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China 7 Guangzhou Institute of Advanced Technology, Chinese Academy of Sciences, Guangzhou, Guangdong, China Correspondence to: Wei-Ming Fu, email: fuweiming76@smu.edu.cn Jian-Xin Pang, email: pjx@smu.edu.cn Keywords: Usp5, epatocellular carcinoma, proliferation, migration, P14 Received: September 06, 2016 Accepted: March 28, 2017 Published: April 06, 2017 ABSTRACT As deubiquitinases, several ubiquitin specific protease members have been reported to mediate tumorigenesis. Although ubiquitin specific protease 5 (Usp5) was previously demonstrated to suppress p53 transcriptional activity and DNA repair, its role in carcinogenesis remains elusive. In this study, we sought to define a novel role of Usp5 in tumorigenesis. It was found that Usp5 was significantly upregulated in hepatocellular carcinoma (HCC) cells and most clinical specimens. Further functional investigation also showed that Usp5 knockdown suppressed cell proliferation, migration, drug resistance and induced apoptosis; on the other hand, Usp5 overexpression promoted colony formation, migration, drug resistance and tumorigenesis. Additionally, the inactivated p14 ARF -p53 signaling was observed in Usp5 overexpressed HCC cells, while this signaling was activated by Usp5 knockdown. Therefore, our data demonstrated that Usp5 contributed to hepatocarcinogenesis by acting as an oncogene, which provides new insights into the pathogenesis of HCC and explores a promising molecular target for HCC diagnosis and therapy.

Summary Tendon is a tissue that transmits force from muscle to bone. Chronic or acute tendon injuries are very common, and are always accompanied by pain and a limited range of motion in patients. In clinical settings, management of tendon injuries still remains a big challenge. Cell therapies, such as the application of stem cells for tenogenic differentiation, were suggested to be an ideal strategy for clinical translation. However, there is still a lack of specific methods for tenogenic differentiation due to the limited understanding of tendon biology currently. This review focuses on the summary of current published strategies for tenogenic differentiation, such as the application of growth factors, mechanical stimulation, biomaterials, coculture, or induced pluripotent stem cells. Current clinical applications of stem cells for treatment of tendon injuries and their limitations have also been discussed in this review.

Distraction osteogenesis (DO) is a widely applied technique in orthopedics surgery, which involves rapid stem cell migration, homing, and differentiation. Interactions between the chemokine receptor Cxcr4 and its ligand, stromal derived factor-1 (SDF-1), regulate hematopoietic stem cell trafficking to the ischemic area and induce their subsequent differentiation. Here, we examined SDF-1 expression and further investigated the role of SDF-1/Cxcr4 signaling antagonist AMD3100 during bone regeneration in rat DO model. The results showed that expression levels of SDF-1 and osteogenic genes were higher in DO zones than in the fracture zones, and SDF-1 expression level was the highest at the termination of the distraction phase. Radiological, mechanical, and histological analyses demonstrated that the local administration of AMD3100 (400 μM) to DO rats significantly inhibited new bone formation. In the rat bone marrow mesenchymal stem cells culture, comparing to the group treated with osteogenic induction medium, AMD3100 supplement led to a considerable decrease in the expression of alkaline phosphatase and early osteogenic marker genes. However, the amount of calcium deposits in rat MSCs did not differ between the groups. Therefore, our study demonstrated that the DO process induced higher expression of SDF-1, which collated to rapid induction of callus formation. Local application of SDF-1/Cxcr4 signaling antagonist AMD3100 significantly inhibited bone mineralization and osteogenesis in DO, which may represent a potential therapeutic approach to the enhancement of bone consolidation in patients undergoing DO.

Bone defect regeneration is a complex process that involves the coordination of a variety of different type of cells. As bone tissues are innervated and rich in nerve fibers, the neuropeptides released from various never fibers could regulate bone development, metabolism, and remodeling. Among all the neuropeptides, vasoactive intestinal peptide (VIP) could modulate the functions of both osteoblasts and osteoclasts, and may play a vital role in bone marrow mesenchymal stem cell (BMSC) osteogenesis during bone repair. In this study, we investigated the role of VIP in bone formation and the mechanisms of VIP in mediating BMSC osteogenic differentiation, and its possibility in clinical application of bone defect reconstruction. Our in vitro study results indicated that VIP promoted BMSC osteogenic differentiation by activating Wnt/β-catenin signaling pathway in BMSCs. VIP could also stimulate tube formation of EA.hy926 endothelial cell and increase vascular endothelial growth factor (VEGF) expression in BMSCs. Furthermore, in the rat skull defect model, VIP-conjugated functionalized hydrogel significantly enhanced cranial bone defect repair compared with the control group, with increased bone formation and angiogenesis. Taken together, as a member of neuropeptides, VIP could promote the BMSCs osteogenesis and angiogenesis differentiation in vitro and stimulate bone repair in vivo by activating Wnt/β-catenin signaling pathway. The knowledge obtained from this study emphasized the close association between innervation and bone repair process, and VIP may be a potential therapeutic agent for augmenting bone repair.

SKP1-cullin-1-F-box-protein (SCF) E3 ubiquitin ligase complex is responsible for the degradation of proteins in a strictly regulated manner, through which it exerts pivotal roles in regulating various key cellular processes including cell cycle and division, apoptosis, and differentiation. The substrate specificity of the SCF complex largely depends on the distinct F-box proteins, which function in either tumor promotion or suppression or in a context-dependent manner. Among the 69 F-box proteins identified in human genome, FBW7, SKP2, and β-TRCP have been extensively investigated among various types of cancer in respective of their roles in cancer development, progression, and metastasis. Moreover, several specific inhibitors have been developed to target those E3 ligases, and their efficiency in tumors has been determined. In this review, we provide a summary of the roles of SCF E3 ligases in cancer development, as well as the potential application of miRNA or specific inhibitors for cancer therapy.

Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. Here, we find that hCINAP is involved in the repair of double-stranded DNA breaks (DSB) and that its expression correlates with AML prognosis. Following DSB, hCINAP is recruited to damage sites where it promotes SENP3-dependent deSUMOylation of NPM1. This in turn results in the dissociation of RAP80 from the damage site and CTIP-dependent DNA resection and homologous recombination. NPM1 SUMOylation is required for recruitment of DNA repair proteins at the early stage of DNA-damage response (DDR), and SUMOylated NPM1 impacts the assembly of the BRCA1 complex. Knockdown of hCINAP also sensitizes a patient-derived xenograft (PDX) mouse model to chemotherapy. In clinical AML samples, low hCINAP expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hCINAP during the DNA-damage response and its role in AML resistance to therapy., Acute myeloid leukemia cells are often resistant to radiotherapy and chemotherapy. Here, the authors suggest that hCINAP contributes to the resistance of acute myeloid leukemia cells by regulating SUMOylation of Nucleophosmin during the DNA-damage response.

MicroRNAs (miRNAs) have been reported to serve as silencers to repress gene expression at post-transcriptional level. Multiple miRNAs have been demonstrated to play important roles in osteogenesis. MiR-378, a conserved miRNA, was reported to mediate bone metabolism and influence bone development, but the detailed function and underlying mechanism remain obscure. In this study, the miR-378 transgenic (TG) mouse was developed to study the role of miR-378 in osteogenic differentiation as well as bone formation. The abnormal bone tissues and impaired bone quality were displayed in the miR-378 TG mice, and a delayed healing effect was observed during bone fracture of the miR-378 TG mice. The osteogenic differentiation of MSCs derived from this TG mouse was also inhibited. We also found that miR-378 mimics suppressed while anti-miR-378 promoted osteogenesis of human MSCs. Two Wnt family members Wnt6 and Wnt10a were identified as bona fide targets of miR-378, and their expression were decreased by this miRNA, which eventually induced the inactivation of Wnt/β-catenin signaling. Finally, the sh-miR-378 modified MSCs were locally injected into the fracture sites in an established mouse fracture model. The results indicated that miR-378 inhibitor therapy could promote bone formation and stimulate healing process in vivo. In conclude, miR-378 suppressed osteogenesis and bone formation via inactivating Wnt/β-catenin signaling, suggesting miR-378 may be a potential therapeutic target for bone diseases.

Supporting tumor suppression The protein PTEN is a phosphatase and tumor suppressor whose activity is often decreased in human cancers. Thus, reactivating such a protein could potentially be an effective therapy against cancer. Lee et al. identified a ubiquitin E3 ligase (WWP1) as a PTEN-interacting protein that modifies PTEN and inhibits its tumor suppressive activity (see the Perspective by Parsons). Depletion of WWP1 increased dimerization and membrane recruitment of PTEN. A natural compound found to be a pharmacological inhibitor of WWP1 inhibited tumor growth in a mouse model of prostate cancer. Thus, reactivation of the tumor suppressor PTEN may provide a strategy for battling tumors. Science , this issue p. eaau0159 ; see also p. 633