Influence of eye-related behavior on myopia among junior middle school students under the background of double reduction during the COVID-19 pandemic.

BACKGROUND: To investigate the changes in the unhealthy eye-related behaviors of junior middle school students during the COVID-19 pandemic and the double reduction policy and its relationship with myopia. METHODS: Data were obtained from the 2019-2022 Tianjin Children and Youth Myopia, Common Diseases and Health Influencing Factors Survey. Latent profile analysis (LPA) and a generalized linear model (GLM) were applied to analyze the effect of eye-related behavior classes on myopia. RESULTS: A total of 2508 junior middle school students were included. The types of eye-related behavior were categorized into the medium-healthy behavior group, heavy academic burden and near-eye behavior group, insufficient lighting group and high-healthy behavior group. Students with heavy academic burdens and near-eye behavior were more likely to develop myopia than were those in the high-healthy group (OR = 1.466, 95% CI = 1.203-1.787; P < 0.001). CONCLUSIONS: The dual reduction policy has a positive effect on improving unhealthy eye-related behaviors, and the prevention and control of myopia through the use of different combinations of eye-related behaviors are heterogeneous among junior middle school students. In the post-COVID-19 period, we should continue to implement a double reduction policy and formulate targeted eye-related behavior strategies to provide an important reference for the prevention and control of myopia among children and adolescents during public health emergencies in the future.

Effects of physical activity patterns on myopia among children and adolescents: A latent class analysis.

BACKGROUND: The daily physical activity (PA) patterns of children and adolescents are intricate and ambiguous, with varying effects on myopia resulting from different combinations of PA. This study aims to scrutinize the spectrum of PA patterns among children and adolescents and assess their impact on myopia. METHODS: Data sourced from the 2014 National Student Physical Fitness Survey (Tianjin segment) encompassed PA records and visual acuity measurements of participants. Latent Class Analysis and a generalized linear model were employed to investigate the relationship between PA categories and visual acuity across different educational stages. RESULTS: The study comprised 6465 primary and middle school students, among whom 50.13% were male. PA patterns were categorized into high (27.16%), medium (29.88%) and low visual acuity regulation groups (13.97%) and the nonmainstream group (28.99%). Following adjustments for sex, age, region and BMI, the medium visual acuity regulation group exhibited a lower risk of myopia (OR = 0.617, 95% CI = 0.424-0.897, p = 0.012; OR = 0.654, 95% CI = 0.438-0.976, p = 0.038) compared to the nonmainstream group among junior and senior middle school students. CONCLUSION: The efficacy of diverse PA patterns in mitigating myopia risk varies across educational stages and is influenced by sex-specific factors. It is imperative to advance myopia management strategies by emphasizing tailored PA interventions, discerning between PA patterns and delivering timely guidance and interventions tailored to distinct educational stages and sexes.

Modifying effects of green space on the relationships between air pollution and ischemic cerebrovascular event recurrence in Tianjin, China.

This study aimed to explore how air pollution and green space influence ICE recurrence and whether they might interact with each other. A case-cross design was used in this study, which was carried out in Tianjin, China. A total of 8306 patients with recurrent ICE were collected from 2019 to 2020. The maximum effects of PM2.5, PM10, SO2, NO2, CO were 1.012 (95%CI: 1.004, 1.019), 1.010 (95%CI: 1.004, 1.016), 1.035 (95%CI: 0.982, 1.091), 1.067 (95%CI: 1.043, 1.091) and 1.012 (95%CI: 1.004, 1.021) , respectively, and the risk was higher in males and in the 50-60 age group. In the stratification of greening, it was found that air pollution except O3 had the highest risk of ICE recurrence for those with lower green space. Our study found that air pollution (except O3) can increase the risk of ICE recurrence, and this risk can be reduced by increasing green space.

Follistatin is a crucial chemoattractant for mouse decidualized endometrial stromal cell migration by JNK signalling.

Follistatin (FST) and activin A as gonadal proteins exhibit opposite effects on follicle-stimulating hormone (FSH) release from pituitary gland, and activin A-FST system is involved in regulation of decidualization in reproductive biology. However, the roles of FST and activin A in migration of decidualized endometrial stromal cells are not well characterized. In this study, transwell chambers and microfluidic devices were used to assess the effects of FST and activin A on migration of decidualized mouse endometrial stromal cells (d-MESCs). We found that compared with activin A, FST exerted more significant effects on adhesion, wound healing and migration of d-MESCs. Similar results were also seen in the primary cultured decidual stromal cells (DSCs) from uterus of pregnant mouse. Simultaneously, the results revealed that FST increased calcium influx and upregulated the expression levels of the migration-related proteins MMP9 and Ezrin in d-MESCs. In addition, FST increased the level of phosphorylation of JNK in d-MESCs, and JNK inhibitor AS601245 significantly attenuated FST action on inducing migration of d-MESCs. These data suggest that FST, not activin A in activin A-FST system, is a crucial chemoattractant for migration of d-MESCs by JNK signalling to facilitate the successful uterine decidualization and tissue remodelling during pregnancy.

Transgastric Single-Incision Laparoscopic Resection for a Gastric Submucosal Tumor Located at the Cardia.

INTRODUCTION: Surgical treatment of gastric submucosal tumors (SMTs) located near the gastroesophageal junction can be technically challenging, especially regarding preservation of the integrity and function of the lower esophageal sphincter. We introduce a novel minimally invasive surgery, successfully performed in a patient with a gastric SMT located at the cardia. A 24-year-old lady presenting with acid reflux for 1 year underwent esophagogastroscopy that showed a gastric SMT located at the cardia. Endoscopic ultrasonography showed a 20×19 mm homogeneous hypoechoic lesion originating from the muscularis propria layer. Transgastric single-incision laparoscopic resection of the tumor was performed. CONCLUSION: Transgastric single-incision laparoscopic resection of gastric SMTs is technically feasible and safe. This presents an alternative surgical choice for resection for gastric SMTs located in difficult regions such as the fundus, cardia, or prepyloric antrum.

Source apportionment of heavy metals in PM2.5 samples and effects of heavy metals on hypertension among schoolchildren in Tianjin.

The prevalence of hypertension in children has increased significantly in recent years in China. The aim of this study was to provide scientific support to control ambient heavy metals (HMs) pollution and prevent childhood hypertension. In this study, ambient HMs in PM2.5 were collected, and 1339 students from Tianjin were randomly selected. Positive matrix factorization (PMF) was used to identify and determine the sources of HMs pollution. The generalized linear model, Bayesian kernel machine regression (BKMR) and the quantile g-computation method were used to analyze the relationships between exposure to HMs and the risk of childhood hypertension. The results showed that HMs in PM2.5 mainly came from four sources: soil dust, coal combustion, incineration of municipal waste and the metallurgical industry. The positive relationships between As, Se and Pb exposures and childhood hypertension risk were found. Coal combustion and incineration of municipal waste were important sources of HMs in the occurrence of childhood hypertension. Based on these accomplishments, this study could provide guidelines for the government and individuals to alleviate the damaging effects of HMs in PM2.5. The government must implement policies to control prime sources of HMs pollution.

Profiling the long noncoding RNA interaction network in the regulatory elements of target genes by chromatin in situ reverse transcription sequencing.

Long noncoding RNAs (lncRNAs) can regulate the activity of target genes by participating in the organization of chromatin architecture. We have devised a "chromatin-RNA in situ reverse transcription sequencing" (CRIST-seq) approach to profile the lncRNA interaction network in gene regulatory elements by combining the simplicity of RNA biotin labeling with the specificity of the CRISPR/Cas9 system. Using gene-specific gRNAs, we describe a pluripotency-specific lncRNA interacting network in the promoters of Sox2 and Pou5f1, two critical stem cell factors that are required for the maintenance of pluripotency. The promoter-interacting lncRNAs were specifically activated during reprogramming into pluripotency. Knockdown of these lncRNAs caused the stem cells to exit from pluripotency. In contrast, overexpression of the pluripotency-associated lncRNA activated the promoters of core stem cell factor genes and enhanced fibroblast reprogramming into pluripotency. These CRIST-seq data suggest that the Sox2 and Pou5f1 promoters are organized within a unique lncRNA interaction network that determines the fate of pluripotency during reprogramming. This CRIST approach may be broadly used to map lncRNA interaction networks at target loci across the genome.

Surgery versus radiotherapy in octogenarians with stage Ia non­small cell lung cancer: propensity score matching analysis of the SEER database.

OBJECTIVES: To compare overall survival (OS) and cancer-specific survival (CSS) outcomes of surgery with radiotherapy in octogenarians with stage Ia non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients aged ≥ 80 years with clinical stage Ia (T1N0M0) NSCLC between 2012 and 2017 were identified from the population-based Surveillance, Epidemiology, and End Results (SEER) database. Patients were assigned into surgery and radiotherapy groups. Multivariate Cox regression analysis was used to identify survival-associated factors. Treatment groups were adjusted by propensity score matching (PSM) analysis while OS and CSS outcomes were compared among groups by Kaplan-Meier analysis. RESULTS: A total of 1641 patients were identified, with 46.0% in the surgical group and 54.0% in the radiotherapy group. Compared to surgery, radiotherapy-treated patients were older, later diagnosed, had more often unmarried, more squamous cell carcinoma, more unknown grade and increased tumor sizes. Radiotherapy was associated with a significantly worse OS, compared to surgery (hazard ratio 2.426; 95% CI 2.003-2.939; P < .001). After PSM, OS (P < 0.001) and CSS (P < 0.001) were higher in the surgery group. The 1-, 3-, and 5-year OS rates of surgical and radiotherapy group were 90.0%, 76.9%, 59.9%, and 86.0%, 54.3%, 28.0%, respectively. The 1-, 3-, and 5-year CSS rates of surgical and radiotherapy group were 94.5%, 86.1%, 78.0% and 90.7%, 74.5%, 61.0%, respectively. There were no survival differences between the matched surgery without lymph node examination (LNE) and radiotherapy group, as well as between the matched surgery and radiotherapy who were recommended but refused surgery group. CONCLUSIONS: In octogenarians with stage Ia NSCLC, surgery with lymph node dissection offers better OS and CSS outcomes than radiotherapy.

CypB promotes cell proliferation and metastasis in endometrial carcinoma.

BACKGROUND: The molecular pathogenesis of endometrial cancer is not completely understood. CypB upregulated in many cancers, however, its role in endometrial carcinoma has not been studied. Here, we determine the effect of CypB on the growth of endometrial cancer. METHODS: In this study, we examined the expression of CypB in endometrial cancer tissues using immunohistochemistry. CypB silenced in HEC-1-B cell line by shRNA. CCK-8, colony formation assays, wound healing assays, and transwell analysis were performed to assess its effect on tumor cell proliferation and metastasis. Furthermore, microarray analysis was carried out to compare the global mRNA expression profile between the HEC-1-B and CypB-silenced HEC-1-B cells. Gene ontology and KEGG pathway enrichment analysis were performed to determine the potential function of differentially expressed genes related to CypB. RESULTS: We found that CypB was upregulated in endometrial cancer, inhibit CypB expression could significantly suppress cell proliferation, metastasis, and migration. We identified 1536 differentially expressed genes related to CypB (onefold change, p < 0.05), among which 652 genes were upregulated and 884 genes were downregulated. The genes with significant difference in top were mainly enriched in the cell cycle, glycosphingolipid biosynthesis, adherens junctions, and metabolism pathways. CONCLUSION: The results of our study suggest that CypB may serve as a novel regulator of endometrial cell proliferation and metastasis, thus representing a novel target for gene-targeted endometrial therapy. TRIAL REGISTRATION: YLYLLS [2018] 008. Registered 27 November 2017.

Inhibitory effect of activin A on IL-9 production by mouse NK cells through Smad3 signaling.

Interleukin-9 (IL-9) is a cytokine secreted by T-helper (Th)9 cells, and activin A can enhance Th9 cell differentiation. However, whether activin A affects IL-9 production by natural killer (NK) cells remains unclear. Herein, we found that not only Th cells, but also CD3-CD49b+NKp46+ NK cells of Balb/c mice produced IL-9. Although activin A promoted IL-9 expression in CD4+ Th cells, it inhibited IL-9 production by CD49b+NKp46+ NK cells in mice. Furthermore, the enzyme-linked immunosorbent assay (ELISA) results showed that mouse NK cells could secrete mature IL-9 protein, and activin A inhibited IL-9 release by NK cells. Additionally, activin A inhibited interferon (IFN)-γ production in splenic NK cells in mice, but promoted IL-2 production, and did not alter the production of IL-10. Western blotting results showed that levels of activin type IIA receptor (ActRIIA), Smad3 and phosphorylated-Smad3 (p-SMAD3) protein increased in activin A-treated splenic NK cells, compared with that in control NK cells. The inhibitory effects of activin A on IL-9 production by NK cells were attenuated in the presence of activin antagonist follistatin (FST) or Smad3 knockdown to NK cells. These data suggest that although activin A up-regulates IL-9 expression in Th cells, it inhibits IL-9 production in NK cells through Smad3 signaling.

Activin A regulates activities of peripheral blood natural killer cells of mouse in an autocrine and paracrine manner.

Activin A, a multifunctional cytokine of transforming growth factor-ß (TGF-ß) superfamily, can be produced by the diverse immune cells. NK cells in peripheral blood are one of the major immune cells applied to cancer therapy in recent years. However, whether activin A can be produced by natural killer (NK) cells and be involved in regulation of peripheral blood NK cells activities of mouse are not well characterized. Here, we found that activin type IIA and IIB receptors and signaling molecules Smad2, 3 were expressed in peripheral blood NK cells of mouse by flow cytometry and RT-PCR. The cultured blood NK cells of mouse not only produced activin ßA chain protein by intracellular cytokine staining, but also secreted mature activin A protein by enzyme-linked immunosorbent assay (ELISA), and the production was promoted by IL-2. In addition, IL-2 as a positive control obviously promoted IFNγ production of mouse blood NK cells in vitro. However, activin A suppressed IFNγ production, but enhanced IL-2 synthesis and did not alter IL-10 production. Moreover, we found that activin A significantly suppressed the ability of NK cells to lyse target cells. These data revealed that blood NK cells of mouse were not only the target cells in response to activin A, but also the source of activin A, suggesting that activin A may play an important role in regulation of NK cells activities of mouse in an autocrine / paracrine manner.

Preventable Deaths in Multiple Trauma Patients: The Importance of Auditing and Continuous Quality Improvement.

BACKGROUND: Management errors during pre-hospital care, triage process and resuscitation have been widely reported as the major source of preventable and potentially preventable deaths in multiple trauma patients. Common tools for defining whether it is a preventable, potentially preventable or non-preventable death include the Advanced Trauma Life Support (ATLS®) clinical guideline, the Injury Severity Score (ISS) and the Trauma and Injury Severity Score (TRISS). Therefore, these surrogated scores were utilized in reviewing the study's trauma services. METHODS: Trauma data were prospectively collected and retrospectively reviewed from January 1, 2018, to December 31, 2018. All cases of trauma death were discussed and audited by the Hospital Trauma Committee on a regular basis. Standardized form was used to document the patient's management flow and details in every case during the meeting, and the final verdict (whether death was preventable or not) was agreed and signed by every member of the team. The reasons for the death of the patients were further classified into severe injuries, inappropriate/delayed examination, inappropriate/delayed treatment, wrong decision, insufficient supervision/guidance or lack of appropriate guidance. RESULTS: A total of 1913 trauma patients were admitted during the study period, 82 of whom were identified as major trauma (either ISS > 15 or trauma team was activated). Among the 82 patients with major trauma, eight were trauma-related deaths, one of which was considered a preventable death and the other 7 were considered unpreventable. The decision from the hospital's performance improvement and patient safety program indicates that for every trauma patient, basic life support principles must be followed in the course of primary investigations for bedside trauma series X-ray (chest and pelvis) and FAST scan in the resuscitation room by a person who meets the criteria for trauma team activation recommended by ATLS®. CONCLUSION: Mechanisms to rectify errors in the management of multiple trauma patients are essential for improving the quality of trauma care. Regular auditing in the trauma service is one of the most important parts of performance improvement and patient safety program, and it should be well established by every major trauma center in Mainland China. It can enhance the trauma management processes, decision-making skills and practical skills, thereby continuously improving quality and reducing mortality of this group of patients.

The effects of activin A on the migration of human breast cancer cells and neutrophils and their migratory interaction.

Activin A belongs to the superfamily of transforming growth factor beta (TGFß) and is a critical regulatory cytokine in breast cancer and inflammation. However, the role of activin A in migration of breast cancer cells and immune cells was not well characterized. Here, a microfluidic device was used to examine the effect of activin A on the migration of human breast cancer cell line MDA-MB-231 cells and human blood neutrophils as well as their migratory interaction. We found that activin A promoted the basal migration but impaired epidermal growth factor (EGF)-induced migration of breast cancer cells. By contrast, activin A reduced neutrophil chemotaxis and transendothelial migration to N-Formyl-Met-Leu-Phe (fMLP). Finally, activin A promoted neutrophil chemotaxis to the supernatant from breast cancer cell culture. Collectively, our study revealed the different roles of activin A in regulating the migration of breast cancer cells and neutrophils and their migratory interaction. These findings suggested the potential of activin A as a therapeutic target for inflammation and breast cancers.

Effects of AMPD1 gene C34T polymorphism on cardiac index, blood pressure and prognosis in patients with cardiovascular diseases: a meta-analysis.

BACKGROUND: The meta-analysis was aimed to evaluate the effects of AMPD1 gene C34T polymorphism on cardiac function indexes, blood pressure and prognosis in patients with cardiovascular diseases (CVD). METHODS: Eligible studies were retrieved through a comprehensive search of electronic databases and manual search. Then the high-quality studies met the rigorous inclusion and exclusion criteria, as well as related to the subject was selected for the study. Comprehensive data analyses were conducted using STATA software 12.0. RESULTS: The study results revealed that CVD patients with CT + TT genotype of AMPD1 C34T polymorphism presented elevated left ventricular ejection fraction (LVEF) (%) and reduced left ventricular end diastolic dimension (LVEDD) (mm) as compared with CC genotype, moreover, the subgroup analysis found that the LVEF (%) was markedly higher in heart failure (HF) patients carrying CT + TT genotype than CC genotype. Besides, the systolic blood pressure (SBP) (mmHg) in CVD patients with CT + TT genotype was obviously decreased in contrast with the CC genotype. Patients suffered from HF with different genotypes (CT + TT and CC) of AMPD1 C34T polymorphism exhibited no significant differences in total survival rate and cardiac survival rate. CONCLUSIONS: Our current meta-analysis indicated that the T allele of AMPD1 gene C34T polymorphism may be correlated with LVEF, LVEDD and SBP, which plays a protective role in the cardiac functions and blood pressure in CVD patients, but had no effects on total survival rate and cardiac survival rate for HF.

Late Miocene episodic lakes in the arid Tarim Basin, western China.

The Tibetan Plateau uplift and Cenozoic global cooling are thought to induce enhanced aridification in the Asian interior. Although the onset of Asian desertification is proposed to have started in the earliest Miocene, prevailing desert environment in the Tarim Basin, currently providing much of the Asian eolian dust sources, is only a geologically recent phenomenon. Here we report episodic occurrences of lacustrine environments during the Late Miocene and investigate how the episodic lakes vanished in the basin. Our oxygen isotopic (δ(18)O) record demonstrates that before the prevailing desert environment, episodic changes frequently alternating between lacustrine and fluvial-eolian environments can be linked to orbital variations. Wetter lacustrine phases generally corresponded to periods of high eccentricity and possibly high obliquity, and vice versa, suggesting a temperature control on the regional moisture level on orbital timescales. Boron isotopic (δ(11)B) and δ(18)O records, together with other geochemical indicators, consistently show that the episodic lakes finally dried up at ∼4.9 million years ago (Ma), permanently and irreversibly. Although the episodic occurrences of lakes appear to be linked to orbitally induced global climatic changes, the plateau (Tibetan, Pamir, and Tianshan) uplift was primarily responsible for the final vanishing of the episodic lakes in the Tarim Basin, occurring at a relatively warm, stable climate period.

Nanooptics of Plasmonic Nanomatryoshkas: Shrinking the Size of a Core-Shell Junction to Subnanometer.

Quantum effects in plasmonic systems play an important role in defining the optical response of structures with subnanometer gaps. Electron tunneling across the gaps can occur, altering both the far-field optical response and the near-field confinement and enhancement. In this study, we experimentally and theoretically investigate plasmon coupling in gold "nanomatryoshka" (NM) nanoparticles with different core-shell separations. Plasmon coupling effects between the core and the shell become significant when their separation decreases to 15 nm. When their separation decreases to below 1 nm, the near- and far-field properties can no longer be described by classical approaches but require the inclusion of quantum mechanical effects such as electron transport through the self-assembled monolayer of molecular junction. In addition, surface-enhanced Raman scattering measurements indicate strong electron-transport induced charge transfer across the molecular junction. Our quantum modeling provides an estimate for the AC conductances of molecules in the junction. The insights acquired from this work pave the way for the development of novel quantum plasmonic devices and substrates for surface-enhanced Raman scattering.

F-box protein complex FBXL19 regulates TGFß1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation.

BACKGROUND: Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFß1 is associated with poor prognosis of esophageal cancer. TGFß1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFß1-induced E-cadherin down-regulation in esophageal cancer cells. METHODS: FBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFß1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining. RESULTS: Overexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFß1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFß1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype. CONCLUSIONS: Collectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFß1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFß1 signaling, thus suppressing esophageal tumorigenesis.

The role and mechanism of action of activin A in neurite outgrowth of chicken embryonic dorsal root ganglia.

Activin A, a member of the transforming growth factor ß (TGFß) superfamily, plays an essential role in neuron survival as a neurotrophic and neuroprotective factor in the central nervous system. However, the effects and mechanisms of action of activin A on the neurite outgrowth of dorsal root ganglia (DRG) remain unclear. In the present study, we found that activin A is expressed in DRG collected from chicken embryos on embryonic day 8 (E8). Moreover, activin A induced neurite outgrowth of the primary cultured DRG and maintained the survival of monolayer-cultured DRG neurons throughout the observation period of ten days. Follistatin (FS), an activin-binding protein, significantly inhibited activin A-induced neurite outgrowth of DRG, but failed to influence the effect of nerve growth factor (NGF) on DRG neurite outgrowth. Furthermore, the results showed that activin A significantly upregulated mRNA expression of activin receptor type IIA (ActRIIA) and calcitonin gene-related peptide (CGRP) in DRG, and stimulated serotonin (5-HT) production from DRG, indicating that activin A might induce DRG neurite outgrowth by promoting CGRP expression and stimulating 5-HT release. These data suggest that activin A plays an important role in the development of DRG in an autocrine or paracrine manner.

Role of ATF3 in synergistic cancer cell killing by a combination of HDAC inhibitors and agonistic anti-DR5 antibody through ER stress in human colon cancer cells.

Histone deacetylase inhibitors (HDACIs) are promising agents for cancer therapy. However, the mechanism(s) responsible for the efficacy of HDACIs have not yet to be fully elucidated. Death receptor 5 (DR5) is a transmembrane receptor containing death domain that triggers cell death upon binding to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or agonistic anti-DR5 monoclonal antibody, and the combination of TRAIL/agonistic anti-DR5 monoclonal antibody and agents that increase the expression of DR5 is expected as a novel anticancer therapeutic strategy. Here we report that six different HDACIs activated endoplasmic reticulum (ER) stress sensor PERK and eIF2α and induced the ATF4/ATF3/CHOP pathway in p53-deficient human colon cancer cells. This resulted in an increased expression of DR5 on the cell surface and sensitized cells to apoptosis by agonistic anti-DR5 monoclonal antibody. Stress response gene ATF3 was required for efficient DR5 induction by HDACIs, and DR5 reporter assay showed that ATF3 play crucial role for the HDACIs-induced activation of DR5 gene transcription. These provide important mechanistic insight into how HDACIs exhibit pro-apoptotic activity in clinical anti-cancer treatments when they are used in combination with other therapeutic strategies.