Control of muscle satellite cell function by specific exercise-induced cytokines and their applications in muscle maintenance.

Exercise is recognized to play an observable role in improving human health, especially in promoting muscle hypertrophy and intervening in muscle mass loss-related diseases, including sarcopenia. Recent rapid advances have demonstrated that exercise induces the release of abundant cytokines from several tissues (e.g., liver, muscle, and adipose tissue), and multiple cytokines improve the functions or expand the numbers of adult stem cells, providing candidate cytokines for alleviating a wide range of diseases. Muscle satellite cells (SCs) are a population of muscle stem cells that are mitotically quiescent but exit from the dormancy state to become activated in response to physical stimuli, after which SCs undergo asymmetric divisions to generate new SCs (stem cell pool maintenance) and commit to later differentiation into myocytes (skeletal muscle replenishment). SCs are essential for the postnatal growth, maintenance, and regeneration of skeletal muscle. Emerging evidence reveals that exercise regulates muscle function largely via the exercise-induced cytokines that govern SC potential, but this phenomenon is complicated and confusing. This review provides a comprehensive integrative overview of the identified exercise-induced cytokines and the roles of these cytokines in SC function, providing a more complete picture regarding the mechanism of SC homeostasis and rejuvenation therapies for skeletal muscle.

[Plectin Promotes the Migration of Hepatocellular Carcinoma Cells Through Inducing F-actin Polymerization]. / Plectin通过诱导F-actin聚合增强肝癌细胞的迁移能力.

Objective: To explore the relationship between the expression of plectin and the migration of hepatocellular carcinoma (HCC) cells and to elucidate the molecular mechanisms by which plectin expression affects the migration of HCC cells. Methods: First of all, Western blot was performed to determine the expression of plectin in normal hepatocytes and HCC cells. Secondly, a plectin-downregulated HCC cell strain was established and the control group (shNC group) and shPLEC group were set up. Each group was divided into a vehicle control group (shNC+DMSO group or shPLEC+DMSO group) and a F-actin cytoskeleton polymerization inducer Jasplakinolide group (shNC+Jasp group or shPLEC+Jasp group). Western blot was performed to determine the expression of plectin and epithelial-mesenchymal transition (EMT)-related proteins, including N-cadherin, vimentin, and E-cadherin. HCC cell migration was evaluated by Transwell assay. KEGG (Kyoto Encyclopedia of Genes and Genomes) was used to analyze the signaling pathways related to plectin gene. The polymerization of F-actin was analyzed by immunofluorescence assay. Results: Compared with the normal hepatocytes, HCC cells showed high expression of plectin. Compared with those in the shNC group, the expression of plectin in the shPLEC group was decreased (P<0.05), the migration ability of HCC cells was weakened (P<0.05), and the EMT process was inhibited (with the expression of N-cadherin and vimentin being decreased and the expression of E-cadherin being increased) (P<0.05). KEGG analysis showed that the regulation of cytoskeletal F-actin was most closely associated with plectin and cytoskeletal F-actin depolymerized in the shPLEC group. After treatment with Jasplakinolide, an inducer of F-actin cytoskeleton polymerization, the migration ability of HCC cells in the shPLEC+Jasp group was enhanced compared with that of shPLEC+DMSO group (P<0.05) and the EMT process was restored (with the expression of N-cadherin and vimentin being increased and the expression of E-cadherin being decreased) (P<0.05). In addition, the polymerization of cytoskeletal F-actin in HCC cells was also restored. Conclusion: Plectin is highly expressed in HCC cells. Plectin promotes the migration and the EMT of HCC cells through inducing F-actin polymerization.

Salinomycin and IR780-loaded upconversion nanoparticles influence biological behavior of liver cancer stem cells by persistently activating the MAPK signaling pathway.

The combination of chemotherapy and phototherapy has emerged as a promising therapeutic approach for enhancing the efficacy of cancer treatment and mitigating drug resistance. Salinomycin (SAL), a polyether antibiotic, exhibits potent cytotoxicity against chemotherapy-resistant cancer cells. IR780 iodide, a novel photosensitive reagent with excellent near-infrared (NIR) light absorption and photothermal conversion abilities, is suitable for use in photothermal therapy for cancers. However, both SAL and IR780 exhibit hydrophobic properties that limit their clinical applicability. Upconversion nanoparticles (UCNPs) are an emerging class of fluorescent probe materials capable of emitting high-energy photons upon excitation by low-energy NIR light. The UCNPs not only function as nanocarriers for drug delivery but also serve as light transducers to activate photosensitizers for deep-tissue photodynamic therapy. Here, to enhance the targeting and bioavailability of hydrophobic drugs in liver cancer stem cells (LCSCs), we employ distearoyl phosphorethanolamine-polyethylene glycol (DSPE-PEG) to encapsulate SAL and IR780 on the surface of UCNPs. Cell viability was evaluated using the CCK-8 assay. Cell migration was assessed by the Transwell Boyden Chamber. The activation of the mitogen-activated protein kinase (MAPK) signaling pathway was measured via western blot. The results demonstrated successful loading of both IR780 and SAL onto the UCNPs, and the SAL and IR780-loaded UCNPs (UISP) exhibited a robust photothermal effect under NIR light irradiation. The UISP effectively inhibited the viability of HCCLM3 and LCSCs. Under NIR light irradiation, the UISP further suppressed HCCLM3 viability but had no impact on LCSC viability; however, it could further inhibit LCSC migration. Meanwhile, under NIR light irradiation, the UISP persistently activated the MAPK pathway more significantly in LCSCs. These findings suggest that exposure to NIR light results in persistent activation of the MAPK pathway by UISP, thereby influencing the biological behavior of LCSCs and enhancing their therapeutic efficacy against liver cancer.

Targeting the mechano-microenvironment and liver cancer stem cells: a promising therapeutic strategy for liver cancer.

Over the past 2 decades, cancer stem cells (CSCs) have been identified as the root cause of cancer occurrence, progression, chemoradioresistance, recurrence, and metastasis. Targeting CSCs is a novel therapeutic strategy for cancer management and treatment. Liver cancer (LC) is a malignant disease that can endanger human health. Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer. In this review, we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells (LCSCs) in liver cancer progression. We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis. Finally, we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer. Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.

Mechanotransduction in response to ECM stiffening impairs cGAS immune signaling in tumor cells.

The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.

Simulated microgravity attenuates skin wound healing by inhibiting dermal fibroblast migration via F-actin/YAP signaling pathway.

Skin and its cell components continuously subject to extrinsic and intrinsic mechanical forces and are mechanical sensitive. Disturbed mechanical homeostasis may lead to changes in skin functions. Gravity is the integral mechanical force on the earth, however, how gravity contributes to the maintenance of skin function and how microgravity in space affects the wound healing are poorly understood. Here, using microgravity analogs, we show that simulated microgravity (SMG) inhibits the healing of cutaneous wound and the accumulation of dermal fibroblasts in the wound bed. In vitro, SMG inhibits the migration of human foreskin fibroblast cells (HFF-1), and decreases the F-actin polymerization and YAP (yes-associated protein) activity. The SMG-inhibited migration can be recovered by activating YAP or F-actin polymerization using lysophosphatidic acid (LPA) or jasplakinolide (Jasp), suggesting the involvement of F-actin/YAP signaling pathway in this process. In SMG rats, LPA treatment improves the cutaneous healing with increased dermal fibroblasts in the wound bed. Together, our results demonstrate that SMG attenuates the cutaneous wound healing by inhibiting dermal fibroblast migration, and propose the crucial role of F-actin/YAP mechano-transduction in the maintenance of skin homeostasis under normal gravity, and YAP as a possible therapeutic target for the skin care of astronauts in space.

Deep dissection of stemness-related hierarchies in hepatocellular carcinoma.

BACKGROUND: Increasing evidence suggests that hepatocellular carcinoma (HCC) stem cells (LCSCs) play an essential part in HCC recurrence, metastasis, and chemotherapy and radiotherapy resistance. Multiple studies have demonstrated that stemness-related genes facilitate the progression of tumors. However, the mechanism by which stemness-related genes contribute to HCC is not well understood. Here, we aim to construct a stemness-related score (SRscores) model for deeper analysis of stemness-related genes, assisting with the prognosis and individualized treatment of HCC patients.Further, we found that the gene LPCAT1 was highly expressed in tumor tissues by immunohistochemistry, and sphere-forming assay revealed that knockdown of LPCAT1 inhibited the sphere-forming ability of hepatocellular carcinoma cells. METHODS: We used the TCGA-LIHC dataset to screen stemness-related genes of HCC from the MSigDB database. Prognosis, tumor microenvironment, immunological checkpoints, tumor immune dysfunction, rejection, treatment sensitivity, and putative biological pathways were examined. Random forest created the SRscores model. The anti-PD-1/anti-CTLA4 immunotherapy, tumor mutational burden, medication sensitivity, and cancer stem cell index were compared between the high- and low-risk score groups. We also examined risk scores for different cell types using single-cell RNA sequencing data and correlated transcription factor activity in cancer stem cells with SRscores genes. Finally, we tested core marker expression and biological functions. RESULTS: Patients can be divided into two subtypes (Cluster1 and Cluster2) based on the TCGA-LIHC dataset's identification of 11 stemness-related genes. Additionally, a SRscores was developed based on subtypes. Cluster2 and the group with the lowest SRscores had superior survival and immunotherapy response than Cluster1 and the group with the highest SRscores. The group with a high SRscores was significantly more enriched in classical tumor pathways than the group with a low SRscores. Multiple transcription factors and SRscores genes are correlated. The core gene LPCAT1 is highly expressed in rat liver cancer tissues and promotes tumor cell sphere formation. CONCLUSION: A SRscores model can be utilized to predict the prognosis of HCC patients as well as their response to immunotherapy.

Tensile Overload Injures Human Alveolar Epithelial Cells through YAP/F-Actin/MAPK Signaling.

BACKGROUND: Explosion shockwaves can generate overloaded mechanical forces and induce lung injuries. However, the mechanism of lung injuries caused by tensile overload is still unclear. METHODS: Flow cytometry was used to detect the apoptosis of human alveolar epithelial cells (BEAS-2B) induced by tensile overload, and cell proliferation was detected using 5-ethynyl-2'-deoxyuridine (EdU). Immunofluorescence and Western blot analysis were used to identify the tensile overload on the actin cytoskeleton, proteins related to the mitogen-activated protein kinase (MAPK) signal pathway, and the Yes-associated protein (YAP). RESULTS: Tensile overload reduced BEAS-2B cell proliferation and increased apoptosis. In terms of the mechanism, we found that tensile overload led to the depolymerization of the actin cytoskeleton, the activation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase 1/2 (ERK1/2), and the upregulation of YAP expression. Jasplakinolide (Jasp) treatment promoted the polymerization of the actin cytoskeleton and reduced the phosphorylation of tension-overload-activated JNK and ERK1/2 and the apoptosis of BEAS-2B cells. Moreover, the inhibition of the JNK and ERK1/2 signaling pathways, as well as the expression of YAP, also reduced apoptosis caused by tensile overload. CONCLUSION: Our study establishes the role of the YAP/F-actin/MAPK axis in tensile-induced BEAS-2B cell injury and proposes new strategies for the treatment and repair of future lung injuries.

YY2-DRP1 Axis Regulates Mitochondrial Fission and Determines Cancer Stem Cell Asymmetric Division.

Cancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit-amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application. Here, through cross-omics analysis, yin yang 2 (YY2) is identified as a novel negative regulator of CSC maintenance. It is shown that YY2 is downregulated in stem-like tumor spheres formed by hepatocarcinoma cells and in liver cancer, in which its expression is negatively correlated with disease progression and poor prognosis. Furthermore, it is revealed that YY2 overexpression suppressed liver CSC asymmetric division, leading to depletion of the CSC pool and decreased tumor-initiating capacity. Meanwhile, YY2 knock-out in stem-like tumor spheres caused enrichment in mitochondrial functions. Mechanistically, it is revealed that YY2 impaired mitochondrial fission, and consequently, liver CSC asymmetric division, by suppressing the transcription of dynamin-related protein 1. These results unravel a novel regulatory mechanism of mitochondrial dynamic-mediated CSCs asymmetric division and highlight the role of YY2 as a tumor suppressor and a therapeutic target in antitumor treatment.

YAP Inhibition Alleviates Simulated Microgravity-Induced Mesenchymal Stem Cell Senescence via Targeting Mitochondrial Dysfunction.

Weightlessness in space leads to bone loss, muscle atrophy, and impaired immune defense in astronauts. Mesenchymal stem cells (MSCs) play crucial roles in maintaining the homeostasis and function of the tissue. However, how microgravity affects the characteristics MSCs and the related roles in the pathophysiological changes in astronauts remain barely known. Here we used a 2D-clinostat device to simulate microgravity. Senescence-associated-ß-galactosidase (SA-ß-gal) staining and the expression of senescent markers p16, p21, and p53 were used to evaluate the senescence of MSCs. Mitochondrial membrane potential (mΔΨm), reactive oxygen species (ROS) production, and ATP production were used to evaluate mitochondrial function. Western blot and immunofluorescence staining were used to investigate the expression and localization of Yes-associated protein (YAP). We found that simulated microgravity (SMG) induced MSC senescence and mitochondrial dysfunction. Mito-TEMPO (MT), a mitochondrial antioxidant, restored mitochondrial function and reversed MSC senescence induced by SMG, suggesting that mitochondrial dysfunction mediates SMG-induced MSC senescence. Further, it was found that SMG promoted YAP expression and its nuclear translocation in MSCs. Verteporfin (VP), an inhibitor of YAP, restored SMG-induced mitochondrial dysfunction and senescence in MSCs by inhibiting YAP expression and nuclear localization. These findings suggest that YAP inhibition alleviates SMG-induced MSC senescence via targeting mitochondrial dysfunction, and YAP may be a potential therapeutic target for the treatment of weightlessness-related cell senescence and aging.

Signal Pathways in Cancer.

Cancer is a major health-threatening disease and is the second leading cause of death worldwide; the prevention and treatment of cancer remains one of the most challenging problems clinically [...].

Metabolic dependency of non-small cell lung cancer cells affected by three-dimensional scaffold and its stiffness.

Three-dimensional (3D) extracellular matrix (ECM) microenvironment is an important regulator of the stiffness of the tumors. Cancer cells require heterogeneous metabolic phenotypes to cope with resistance in the malignant process. However, how the stiffness of the matrix affects the metabolic phenotypes of cancer cells, is lacking. In this study, the young's modulus of the synthesized collagen-chitosan scaffolds was adjusted according to the percentage ratio of collagen to chitosan. We cultured non-small cell lung cancer (NSCLC) cells in four different microenvironments (two-dimensional (2D) plates, stiffest 0.5-0.5 porous collagen-chitosan scaffolds, middle stiff 0.5-1 porous collagen-chitosan scaffolds, and softest 0.5-2 porous collagen-chitosan scaffolds) to investigate the influence of the difference of 2D and 3D cultures as well as the 3D scaffolds with different stiffnesses on the metabolic dependency of NSCLC cells. The results revealed that NSCLC cells cultured in 3D collagen-chitosan scaffolds displayed higher capacity of mitochondrial metabolism and fatty acid metabolism than that cultured in 2D culture. The metabolic response of NSCLC cells is differential for 3D scaffolds with different stiffnesses. The cells cultured in middle stiff 0.5-1 scaffolds displayed a higher potential of mitochondrial metabolism than that of stiffer 0.5-0.5 scaffolds and softer 0.5-2 scaffolds. Furthermore, NSCLC cells culture in 3D scaffolds displayed drug resistance compared with that in 2D culture which maybe via the hyperactivation of the mTOR pathway. Moreover, the cells cultured in 0.5-1 scaffolds showed higher ROS levels, which were counterbalanced by an equally high expression of antioxidant enzymes when compared to the cells grown in 2D culture, which may be regulated by the increased expression of PGC-1α. Together, these results demonstrate that differences in the microenvironments of cancer cells profoundly impact their metabolic dependencies.

Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy.

Cell migration is crucial for physiological and pathological processes such as morphogenesis, wound repair, immune response and cancer invasion/metastasis. There are many factors affecting cell migration, and the regulatory mechanisms are complex. Rac1 is a GTP-binding protein with small molecular weight belonging to the Rac subfamily of the Rho GTPase family. As a key molecule in regulating cell migration, Rac1 participates in signal transduction from the external cell to the actin cytoskeleton and promotes the establishment of cell polarity which plays an important role in cancer cell invasion/metastasis. In this review, we firstly introduce the molecular structure and activity regulation of Rac1, and then summarize the role of Rac1 in cancer invasion/metastasis and other physiological processes. We also discuss the regulatory mechanisms of Rac1 in cell migration and highlight it as a potential target in cancer therapy. Finally, the current state as well as the future challenges in this area are considered. Understanding the role and the regulatory mechanism of Rac1 in cell migration can provide fundamental insights into Rac1-related cancer progression and further help us to develop novel intervention strategies for cancer therapy in clinic.

Mechanical stretch promotes tenocyte migration via chromatin remodelling-mediated nuclear morphology changes.

Wound healing and function recovery of injured tendons are still a big challenge for orthopaedic surgery. Evidence in clinic shows that early controlled motion has significant favourable effects on tendon healing; however, the mechanisms involved in are not fully understood. In the present study, it was shown that an appropriate mechanical stretch (10% strain, 0.5 Hz for 1 h) evidently promotes rat tenocyte migration and nuclear morphology changes. The farther research discovered that mechanical stretch had no effect on Lamin A/C expression, but it could promote chromatin decondensation. Moreover, the histone modification plays an important role in mechanical stretch-mediated chromatin decondensation. Inhibition histone modification could inhibit mechanical stretch-promoted nuclear morphology changes and tenocyte migration. These results indicating that mechanical stretch may promote tenocyte migration via chromatin remodelling-mediated nuclear morphology changes, which contribute to a better understanding of the role of mechanical stretch on tenocyte migration and repair of injured tendon.

Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer.

Introduction: Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success. Methods: In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells. Results: The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity. Conclusions: Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.

Mechanical stretch facilitates tenomodulin expression to induce tenocyte migration via MAPK signaling pathway.

Tenomodulin (Tnmd) is a type II transmembrane glycoprotein that regulates tendon development and maturation. Our previous study indicated that mechanical stretch could induce Tnmd expression to promote tenocyte migration, associated with reinforcement of fibrous actin (F-actin) stress fibers and chromatin decondensation. However, the detailed molecular mechanisms of this processes are far from clear. Activation of mitogen-activated protein kinase (MAPK) signaling occurs in response to various extracellular stimuli and controls a large number of fundamental cellular processes. The present study we investigated the influence of MAPK signaling on mechanical stretch-induced Tnmd expression and its action way. Expression and activities of extracellular signal-related kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 MAPK (p38) were determined by Western blot. Cell migration was detected by Transwell assay. Immunofluorescence staining was used to detect F-actin stress fibers. Nuclear chromatin decondensation was detected by in situ DNaseI sensitivity assay. It was found that mechanical stretch promoted Tnmd expression by activating ERK1/2, JNK and p38 signaling. The inhibition of the ERK1/2, JNK or p38 repressed mechanical stretch-promoted tenocyte migration and mechanical stretch-induced reinforcement of F-actin stress fibers. However, only ERK1/2 and p38 inhibitor could repress mechanical stretch-induced chromatin decondensation, and the JNK inhibitor had no significant effect. Moreover, latrunculin (Lat A), the most widely used reagent to depolymerize actin filaments, could inhibit the stretch-induced chromatin decondensation. Taken together, our findings elucidated a molecular pathway by which a mechanical signal is transduced via activation of MAPK signaling to influence reinforcement of F-actin stress fibers and chromatin decondensation, which could further lead Tnmd expression to promote tenocyte migration.

The Biological Roles and Molecular Mechanisms of Long Non-Coding RNA MEG3 in the Hallmarks of Cancer.

Long non-coding RNAs (lncRNAs) are critical regulators in various biological processes involved in the hallmarks of cancer. Maternally expressed gene 3 (MEG3) is lncRNA that regulates target genes through transcription, translation, post-translational modification, and epigenetic regulation. MEG3 has been known as a tumor suppressor, and its downregulation could be found in various cancers. Furthermore, clinical studies revealed that impaired MEG3 expression is associated with poor prognosis and drug resistance. MEG3 exerts its tumor suppressive effect by suppressing various cancer hallmarks and preventing cells from acquiring cancer-specific characteristics; as it could suppress tumor cells proliferation, invasion, metastasis, and angiogenesis; it also could promote tumor cell death and regulate tumor cell metabolic reprogramming. Hence, MEG3 is a potential prognostic marker, and overexpressing MEG3 might become a potential antitumor therapeutic strategy. Herein, we summarize recent knowledge regarding the role of MEG3 in regulating tumor hallmarks as well as the underlying molecular mechanisms. Furthermore, we also discuss the clinical importance of MEG3, as well as their potential in tumor prognosis and antitumor therapeutic strategies.

Nanocarriers for drug-delivery systems using a ureido-derivatized polymer gatekeeper for temperature-controlled spatiotemporal on-off drug release.

Accidental chemotherapy extravasation exacerbates the side effects of anticancer drugs. Therefore, drug-delivery nanocarriers should be designed to avoid persistent drug release at off-target sites and promote burst drug release at on-target. Considering these requirements, poly(allylamine)-co-poly(allylurea) (PAU), a ureido-derivatized temperature responsive polymer with upper critical solution temperature (UCSTs), is an ideal material. This report describes the fabrication, characterization, and in vitro cellular toxicity of PAU polymer-grafted magnetic mesoporous silica nanoparticles as drug-delivery nanocarriers. A UCST of 43 °C and an ultranarrow transition temperature range of 39-43 °C was realized, ensuring that the nanocarriers suppressed undesirable leakage to below 10 % of the drug loading for 8 h in the absence of a thermal stimulus. A drug release burst of up to 75 % of the drug loading was achieved within 30 min after the stimulus, reducing the viability of the in vitro cancer cells to 12 %. Therefore, the ureido-derivatized polymer is one of the most suitable gatekeepers for drug-delivery nanocarriers.