Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor.

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.

Investigation of the α9-nicotinic receptor single nucleotide polymorphisms induced oncogenic properties and molecular mechanisms in breast cancer.

α9-nAChR, a subtype of nicotinic acetylcholine receptor, is significantly overexpressed in female breast cancer tumor tissues compared to normal tissues. Previous studies have proposed that specific single nucleotide polymorphisms (SNPs) in the CHRNA9 (α9-nAChR) gene are associated with an increased risk of breast cancer in interaction with smoking. The study conducted a breast cancer risk assessment of the α9-nAChR SNP rs10009228 (NM_017581.4:c.1325A > G) in the Taiwanese female population, including 308 breast cancer patients and 198 healthy controls revealed that individuals with the heterozygous A/G or A/A wild genotype have an increased susceptibility to developing breast cancer in the presence of smoking compared to carriers of the G/G variant genotype. Our investigation confirmed the presence of this missense variation, resulting in an alteration of the amino acid sequence from asparagine (N442) to serine (S442) to facilitate phosphorylation within the α9-nAchR protein. Additionally, overexpression of N442 (A/A) in breast cancer cells significantly enhanced cell survival, migration, and cancer stemness compared to S442 (G/G). Four-line triple-negative breast cancer patient-derived xenograft (TNBC-PDX) models with distinct α9-nAChR rs10009228 SNP genotypes (A/A, A/G, G/G) further demonstrated that chronic nicotine exposure accelerated tumor growth through sustained activation of the α9-nAChR downstream oncogenic AKT/ERK/STAT3 pathway, particularly in individuals with the A/G or A/A genotype. Collectively, our study established the links between genetic variations in α9-nAChR and smoking exposure in promoting breast tumor development. This emphasizes the need to consider gene-environment interactions carefully while developing effective breast cancer prevention and treatment strategies.

Functional variants of the pentraxin 3 gene are associated with the metastasis and progression of prostate cancer.

Age, ethnic background and genetic components have been identified as the established risks for prostate cancer (PCa). Pentraxin 3 (PTX3), originally identified as a pattern-recognition molecule for defence against infectious agents, has multiple functions in tissue repair and in the regulation of cancer-associated inflammation. In this study, we sought to investigate the impact of PTX3 gene variants on the development of PCa. Genotypes of four common single-nucleotide polymorphisms (SNPs) of PTX3 gene, including rs1840680, rs2305619, rs3816527 and rs2120243, were profiled among 705 PCa patients and 705 ethnicity-matched controls. In this study, we found that patients who carry at least one minor allele (C) of rs3816527 (AC and CC) tended to develop advanced forms of diseases (clinical large T stage, OR, 1.593, p = 0.032; pathologically-confirmed nodal spread, OR, 1.987, p = 0.011; metastatic tumour, OR, 3.896, p = 0.032) as compared with those homologous for the major allele (AA). Further stratification analysis showed that such association of rs3816527 with lymphatic and distal metastasis of PCa was accentuated in the younger age group (≤65 at diagnosis) but not seen in the older age group (>65 at diagnosis), suggesting an age-specific effect of PTX3 variants. Prediction of PTX3 protein structure implied that polymorphism may alter the quaternary organization and oligomerization of PTX3 protein. Moreover, our gene silencing experiments and survey of public datasets revealed that elevation of PTX3 levels in PCa was required for cell migration and associated with tumour metastasis. Our results highlight an association of PTX3 rs3816527 with the progression of PCa.

MAOB expression correlates with a favourable prognosis in prostate cancer, and its genetic variants are associated with the metastasis of the disease.

Monoamine oxidase B (MAOB), a neurotransmitter-degrading enzyme, was reported to reveal conflicting roles in various cancers. However, the functional role of MAOB and impacts of its genetic variants on prostate cancer (PCa) is unknown. Herein, we genotyped four loci of MAOB single-nucleotide polymorphisms (SNPs), including rs1799836 (A/G), rs3027452 (G/A), rs6651806 (A/C) and rs6324 (G/A) in 702 PCa Taiwanese patients. We discovered that PCa patients carrying the MAOB rs6324 A-allele exhibited an increased risk of having a high initial prostate-specific antigen (iPSA) level (>10 ng/mL). Additionally, patients with the rs3027452 A-allele had a higher risk of developing distal metastasis, particularly in the subpopulation with high iPSA levels. In a subpopulation without postoperative biochemical recurrence, patients carrying the rs1799836 G-allele had a higher risk of developing lymph node metastasis and recurrence compared to those carrying the A-allele. Furthermore, genotype screening in PCa cell lines revealed that cells carrying the rs1799836 G-allele expressed lower MAOB levels than those carrying the A-allele. Functionally, overexpression and knockdown of MAOB in PCa cells respectively suppressed and enhanced cell motility and proliferation. In clinical observations, correlations of lower MAOB expression levels with higher Gleason scores, advanced clinical T stages, tumour metastasis, and poorer prognosis in PCa patients were noted. Our findings suggest that MAOB may act as a suppressor of PCa progression, and the rs3027452 and rs1799836 genetic variants of MAOB are linked to PCa metastasis within the Taiwanese population.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

BACKGROUND: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.9 mg/kg alteplase). METHODS: We enrolled consecutive patients in the multicenter Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke who had received combined thrombolysis (within 4.5 hours of onset) and thrombectomy treatment from January 2019 to April 2023. The choice of low- or standard-dose alteplase was based on the physician's discretion. The outcomes included successful reperfusion (modified Thrombolysis in Cerebral Infarction score, 2b-3), symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score, and 90-day mortality. The outcomes between the 2 groups were compared using multivariable logistic regression and inverse probability of treatment weighting-adjusted analysis. RESULTS: Among the 2242 patients in the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke, 734 (33%) received intravenous alteplase. Patients in the low-dose group (n=360) were older, had more women, more atrial fibrillation, and longer onset-to-needle time compared with the standard-dose group (n=374). In comparison to low-dose alteplase, standard-dose alteplase was associated with a lower rate of successful reperfusion (81% versus 87%; adjusted odds ratio, 0.63 [95% CI, 0.40-0.98]), a numerically higher incidence of symptomatic intracerebral hemorrhage (6.7% versus 3.9%; adjusted odds ratio, 1.81 [95% CI, 0.88-3.69]), but better 90-day modified Rankin Scale score (functional independence [modified Rankin Scale score, 0-2], 47% versus 31%; adjusted odds ratio, 1.91 [95% CI, 1.28-2.86]), and a numerically lower mortality rate (9% versus 15%; adjusted odds ratio, 0.73 [95% CI, 0.43-1.25]) after adjusting for covariates. Similar results were observed in the inverse probability of treatment weighting-adjusted models. The results were consistent across predefined subgroups and age strata. CONCLUSIONS: Despite the lower rate of successful reperfusion and higher risk of symptomatic intracerebral hemorrhage with standard-dose alteplase, standard-dose alteplase was associated with a better functional outcome in patients receiving combined thrombolysis and thrombectomy.

cis-Golgi phosphate transporters harboring an EXS domain are essential for plant growth and development.

Cell wall synthesis and protein glycosylation require the import of nucleotide diphosphate-sugar conjugates into the Golgi that must be counterbalanced by phosphate (Pi) export. Numerous Golgi nucleotide-sugar transporters have been characterized, but transporters mediating Golgi Pi export remain poorly understood. We used plant and yeast genetics to characterize the role of 2 Arabidopsis (Arabidopsis thaliana) proteins possessing an EXS domain, namely ERD1A and ERD1B, in Golgi Pi homeostasis. ERD1A and ERD1B localized in cis-Golgi and were broadly expressed in vegetative and reproductive tissues. We identified ERD1 putative orthologs in algae, bryophytes, and vascular plants. Expressing ERD1A and ERD1B in yeast complemented the erd1 mutant phenotype of cellular Pi loss via exocytosis associated with reduced Golgi Pi export. The Arabidopsis erd1a mutant had a similar phenotype of apoplastic Pi loss dependent on exocytosis. ERD1A overexpression in Nicotiana benthamiana and Arabidopsis led to partial mislocalization of ERD1A to the plasma membrane and specific Pi export to the apoplastic space. Arabidopsis erd1a had defects in cell wall biosynthesis, which were associated with reduced shoot development, hypocotyl growth, cell wall extensibility, root elongation, pollen germination, pollen tube elongation, and fertility. We identified ERD1 proteins as Golgi Pi exporters that are essential for optimal plant growth and fertility.

Endoplasmic reticulum calnexins participate in the primary root growth response to phosphate deficiency.

Accumulation of incompletely folded proteins in the endoplasmic reticulum (ER) leads to ER stress, activates ER protein degradation pathways, and upregulates genes involved in protein folding. This process is known as the unfolded protein response (UPR). The role of ER protein folding in plant responses to nutrient deficiencies is unclear. We analyzed Arabidopsis (Arabidopsis thaliana) mutants affected in ER protein quality control and established that both CALNEXIN (CNX) genes function in the primary root response to phosphate (Pi) deficiency. CNX1 and CNX2 are homologous ER lectins promoting protein folding of N-glycosylated proteins via the recognition of the GlcMan9GlcNAc2 glycan. Growth of cnx1-1 and cnx2-2 single mutants was similar to that of the wild type under high and low Pi conditions, but the cnx1-1 cnx2-2 double mutant showed decreased primary root growth under low Pi conditions due to reduced meristematic cell division. This phenotype was specific to Pi deficiency; the double mutant responded normally to osmotic and salt stress. Expression of CNX2 mutated in amino acids involved in binding the GlcMan9GlcNAc2 glycan failed to complement the cnx1-1 cnx2-2 mutant. The root growth phenotype was Fe-dependent and was associated with root apoplastic Fe accumulation. Two genes involved in Fe-dependent inhibition of primary root growth under Pi deficiency, the ferroxidase LOW PHOSPHATE 1 (LPR1) and P5-type ATPase PLEIOTROPIC DRUG RESISTANCE 2 (PDR2) were epistatic to CNX1/CNX2. Overexpressing PDR2 failed to complement the cnx1-1 cnx2-2 root phenotype. The cnx1-1 cnx2-2 mutant showed no evidence of UPR activation, indicating a limited effect on ER protein folding. CNX might process a set of N-glycosylated proteins specifically involved in the response to Pi deficiency.

Therapeutic efficacy of 180-W GreenLight laser photoselective vaporization of the prostate for storage symptoms concomitant with benign prostatic obstruction and a search for outcome predictors.

PURPOSE: Benign prostatic obstruction (BPO) is the most common cause of lower urinary tract symptoms among men. GreenLight photoselective vaporization of the prostate (GL-PVP) using a 180-W Xcelerated performance system (XPS) laser is a well-established method for treating BPO-induced voiding symptoms. However, its therapeutic effects on storage symptoms remain unclear. This study aimed to analyze the storage outcomes in patients who underwent 180-W XPS GL-PVP for BPO and to identify outcome predictors. MATERIALS AND METHODS: Patients who underwent 180-W XPS GL-PVP for BPO between May 2018 and May 2021 were retrospectively reviewed. Data on clinical characteristics, prostate volume, preoperative and postoperative International Prostate Symptom Scores (IPSS), and preoperative urodynamic parameters were collected. A favorable storage outcome was defined as ≥50% reduction in the IPSS storage subscore. RESULTS: Ninety-nine male patients were included, with a mean age of 69.4 ± 9.6 years and a baseline prostatic volume of 75.9 ± 33.1 mL. The IPSS total, storage, and voiding subscores significantly decreased after GL-PVP (all p < 0.001). Seventy-two patients achieved favorable storage outcome at 6 months. Multivariate analysis revealed that detrusor underactivity was predictive of unfavorable storage outcomes (p = 0.022), while IPSS voiding-to-storage subscore ratio >1.25 and the presence of detrusor overactivity were predictive of favorable storage outcomes (p = 0.008 and 0.033, respectively). CONCLUSION: 180-W XPS GL-PVP provided excellent outcomes in both voiding and storage lower urinary tract symptoms concomitant with BPO. Preoperative IPSS and multichannel urodynamic parameters including detrusor overactivity and underactivity are valuable predictors of postoperative storage outcomes.

BROAD VITREOMACULAR ATTACHMENT-INDUCED MACULAR HOLE: Structural Changes and Surgical Outcome.

PURPOSE: This study aims to describe the structural changes and surgical outcomes of full-thickness macular holes (FTMHs) induced by vitreomacular traction with broad vitreomacular attachment (VMA). METHODS: A retrospective analysis of idiopathic FTMHs from October 2010 to May 2022 was conducted. Patients with FTMHs and no retinal detachment (RD) induced by broad VMA (the study group) were compared with a control group consisting of typical FTMHs with focal VMA. RESULTS: Thirty-one eyes had broad VMA-associated FTMH, among which seven eyes (22%) were with concurrent RD. Among the total of 24 cases without RD, 8 (33%) exhibited schisis. The incidence of lamellar holes associated epithelial proliferation and multiple membrane traction was significantly higher in the study group. One hundred percent FTMH closure was observed postoperatively in both groups. Although the postoperative visual acuity was not significantly different, the study group showed a greater ellipsoid zone disruption length. CONCLUSION: Broad VMA-induced FTMHs are characterized by diverse macular structural changes, including schisis and macular detachment. These FTMHs are associated with a higher incidence of lamellar holes associated epithelial proliferation and multiple membrane traction. Surgical outcomes for FTMHs induced by broad VMA are similar to those induced by typical focal VMA, with both groups demonstrating a 100% hole-closure rate.

Association between high-density lipoprotein and functional outcome of ischemic stroke patients in a Taiwanese population.

Despite recent findings indicating a paradoxical association between high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease (CVD) mortality, the impact of HDL-C on subsequent outcomes after ischemic stroke remains unclear. The study aims to investigate the relationships between HDL-C levels and post-stroke functional outcomes while examining the potential modifying influence of HDL-C-related single nucleotide polymorphisms identified through genome-wide association studies. This cohort study included 1,310 patients diagnosed with acute ischemic stroke (AIS), all of whom had their admission serum lipid profile and genotyping information. Participants were categorized into four groups based on gender and HDL-C level. Prognostic outcomes were assessed using a modified Rankin Scale (mRS) at 1, 3, and 12 months post-admission. Multivariate logistic regression and restricted cubic spline regression analysis were used to assess the associations between HDL-C levels and outcomes. The mean age of patients was 61.17 ± 12.08 years, and 69.31% were men. After adjusting confounders, patients with the highest HDL-C level group had a significantly higher risk of poor functional outcomes at 1, 3, and 12 months following stroke compared to the reference group. Restricted cubic splines depicted a nonlinear association between HDL-C levels and poor prognosis in both men and women. The ABCA1 gene rs2575876 AA genotype combined with abnormal HDL-C levels exhibited a significantly heightened risk of post-stroke adverse outcomes at 1 and 3 months compared to patients with normal HDL-C levels and GG + GA genotype. These findings suggest that the combined effects of ABCA1 genetic variants with either low or high HDL-C levels could further heighten this risk.

Surgical outcomes and intraoperative parameters of 3D visualization system versus conventional microscopes for macular surgery in highly myopic eyes, a prospective randomized clinical trial.

PURPOSE: To investigate the surgical outcomes and intraoperative parameters of 3D visualization system for macular diseases in highly myopic eyes. METHODS: In this single-center, prospective, randomized, comparative interventional study, 40 highly myopic eyes (axial length > 26mm) were randomly assigned to either a 3D visualization system or a conventional microscope (CM) group. Surgical outcomes and intraoperative parameters, including the number of indocyanine green (ICG) injections, surgical time, and epiretinal membrane (ERM)/ internal limiting membrane (ILM) peeling time, were compared. RESULTS: The 3D group required significantly fewer ICG injections (1.3 ± 0.5 vs. 2.3 ± 0.7, p < 0.001), had shorter ERM/ILM peeling times (522.8 ± 258.0 vs. 751.8 ± 320.2 sec, p < 0.05), and experienced fewer intraoperative retinal hemorrhages (0 vs. 7 cases, p < 0.05) compared to the CM group. Anatomical and functional outcomes were comparable between the two groups. CONCLUSION: The 3D system exhibited a lower number of ICG injections, shorter ERM/ILM peeling times and a reduced incidence of intraoperative retinal hemorrhages, suggesting the 3D visualization system may offer advantages for macular surgery in highly myopic eyes.

Comparison of endoscopic third ventriculostomy versus cerebrospinal fluid shunt procedures for the treatment of pediatric hydrocephalus in Taiwan.

PURPOSE: Pediatric hydrocephalus is the most common cause of surgically treatable neurological disease in children. Controversies exist whether endoscopic third ventriculostomy (ETV) or cerebrospinal fluid (CSF) shunt placement is the most appropriate treatment for pediatric hydrocephalus. This study aimed to compare the risk of re-operation and death between the two procedures. METHODS: We performed a retrospective population-based cohort study and included patients younger than 20-years-old who underwent CSF shunt or ETV for hydrocephalus from the Taiwan National Health Insurance Research Database. RESULTS: A total of 3,555 pediatric patients from 2004 to 2017 were selected, including 2,340 (65.8%) patients that received CSF shunt placement and 1215 (34.2%) patients that underwent ETV. The incidence of all-cause death was 3.31 per 100 person-year for CSF shunt group and 2.52 per 100 person-year for ETV group, with an adjusted hazard ratio (HR) of 0.79 (95% confidence interval [CI] = 0.66-0.94, p = 0.009). The cumulative incidence competing risk for reoperation was 31.2% for the CSF shunt group and 26.4% for the ETV group, with an adjusted subdistribution HR of 0.82 (95% CI = 0.70-0.96, p = 0.015). Subgroup analysis showed that ETV was beneficial for hydrocephalus coexisting with brain or spinal tumor, central nervous system infection, and intracranial hemorrhage. CONCLUSION: Our data indicates ETV is a better operative procedure for pediatric hydrocephalus when advanced surgical techniques and instruments are available.

Macular Structure Characteristics in Unilateral Idiopathic Full-Thickness Macular Hole and the Healthy Fellow Eyes.

INTRODUCTION: This study aimed to investigate the macular structure and foveal pit characteristics in the unilateral full-thickness macular hole (FTMH) patients and healthy fellow eyes. METHODS: Our retrospective investigation included patients with unilateral FTMH as the study group, and age- and sex-matched individuals without vitreomacular diseases as the control group, all from one medical center. FTMHs were categorized into those with epiretinal proliferation, those without epiretinal proliferation, or those lacking vitreomacular separation. Macular parameters including foveal base width (FBW), central foveolar thickness (CFT), central subfield thickness (CST), central subfield volume, and retinal artery trajectory (RAT) were measured via optical coherence tomography and fundus photography. Comparisons of these parameters were made among lesioned eyes, contralateral healthy eyes and normal controls, as well as among different subgroups. RESULTS: Sixty-eight unilateral FTMH patients (39 women and 29 men) and 68 normal controls were enrolled. The fellow eyes of unilateral FTMH showed larger FBWs (446.8 ± 98.2 µm) than controls (338.4 ± 80.6 µm, p < 0.001). The lesioned and fellow eyes of unilateral FTMH had smaller RAT values (0.19 ± 0.06 and 0.14 ± 0.04) than controls (0.37 ± 0.14, p < 0.001), indicating wider RAT in both groups. No significant macular structure parameter differences were observed among different FTMH subgroups. Females exhibited larger FBW, thinner CFT and CST, and wider RAT than the age-matched males (p < 0.05). CONCLUSIONS: Patients with unilateral FTMH had a wider RAT in both the lesioned and healthy eyes and a wider FBW in their healthy fellow eyes than in controls. Such macular structure characteristics may be prone to macular hole formation.

Age- and gender-dependent impact of titanium vertebral augmentation implants combined with cementing on subsequent vertebral fracture incidence: A comparative study with cementing alone.

PURPOSE: To compare vertebroplasty (VP) and kyphoplasty (KP) with a titanium implantable vertebral augmentation device (TIVAD) in symptomatic subsequent vertebral compression fracture (SVCF) incidence among osteoporotic vertebral compression fracture (OVCF) patients stratified by age and sex. METHODS: This retrospective cohort study involved OVCF patients aged ≥ 50, who underwent KP with TIVAD or VP in our hospital from 2014 to 2019. Subgroup analysis was conducted to evaluate the efficacy of KP with TIVAD and VP in patients stratified by age and sex. RESULTS: The study included 472 patients (VP group: 303; TIVAD group: 169). SVCF incidence rates were 15.2% for VP group and 14.8% for TIVAD group (P = 0.87). In subgroup analysis, TIVAD group showed significantly lower SVCF incidence than VP group in women aged 50-70 (2.1% vs 14.3%; P = 0.03) and had significantly higher SVCF incidence than VP group in women aged > 70 (24.2% vs 13.1%; P = 0.02). In men, adjacent SVCF incidence was significantly lower in TIVAD group than VP group (0% vs 14.1%; P = 0.03). CONCLUSION: Compared to VP, TIVAD is associated with lower symptomatic SVCF rate in men and younger women aged 50-70 but not in older women aged > 70. Age and gender may influence SVCF incidence. LEVEL OF EVIDENCE: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

Genetics in neovascular age-related macular degeneration susceptibility and treatment response to anti-VEGF intravitreal injection: A case series study.

BACKGROUND: To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response. METHODS: This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. RESULTS: In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). CONCLUSIONS: Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.

Loss of MTA2-mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK-MMP7 axis.

The expression of metastasis tumor-associated protein 2 (MTA2) and protein tyrosine kinase 7 (PTK7) is associated with hepatocellular carcinoma (HCC) progression. However, the functional effect and mechanism through which MTA2 regulates PTK7-mediated HCC progression remains unclear. Here, we found that MTA2 knockdown significantly down-regulated PTK7 expression in HCC cells (SK-Hep-1 and PLC/PRF/5). Data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases show that the PTK7 expression level was higher in HCC tissues than in normal liver tissues. In HCC patients, the PTK7 expression level clearly correlated with tumor stage and grade, lower overall survival (OS) correlated positively with MTA2 level, and PTK7 expression acted as a downstream factor for MTA2 expression. In addition, matrix metalloproteinase 7 (MMP7) expression was closely regulated by PTK7, and the mRNA and protein expression levels of MTA2 and PTK7 correlated positively with lower OS. MMP7 downregulation by PTK7 knockdown clearly decreased the migration and invasion abilities of HCC cells. In HCC cells, recombinant human MMP7 reversed the PTK7 knockdown-induced suppression of migration and invasion. Furthermore, deactivation of FAK using siFAK or FAK inhibitor (PF-573228, PF) synergistically contributed to PTK7 knockdown-inhibited FAK activity, MMP7 expression, and the migration and invasion abilities of HCC cells. Collectively, our findings show that PTK7 mediates HCC progression by regulating the MTA2-FAK-MMP7 axis and may be a diagnostic value for HCC patients.

Corosolic acid inhibits metastatic response of human renal cell carcinoma cells by modulating ERK/MMP2 signaling.

Corosolic acid (CA), a plant-derived pentacyclic triterpenoid, has potent anti-inflammatory, anti-metabolic, and anti-neoplastic actions against a variety of human cancers. However, the specific mechanism by which CA inhibits the progression of renal cell carcinoma (RCC) is yet unclear. We found that CA (≤8 µM) had no influence on either the growth or viability of RCC cell lines (786-O, ACHN, and Caki-1) or normal HK2 cells. However, in a dose-dependent manner, CA prevented the invasion and migration of RCC cells. Human protease array analysis showed that CA reduced MMP2 expression. At increasing concentrations of CA, the expression of MMP2 was dose-dependently reduced, as shown by western blot and RT-PCR analyses as well as immunofluorescence staining. CA also stimulated ERK1/2 phosphorylation in 786-O and Caki-1 cells. Transfection of CA-treated RCC cells with siRNA-ERK restored MMP2 protein expression and the motility and invasion capabilities of RCC cells. Molecular docking study results showed that CA and MMP2 interact strongly. These findings elucidate the mechanism by which CA prevents RCC cells from migrating and invading, and these findings indicate that CA may be a potential anti-metastatic therapy for RCC.

HO-3867, a curcumin analog, elicits cell apoptosis and p38-mediated caspase activation in hepatocellular carcinoma.

HO-3867, a synthetic curcumin analog, has displayed various tumor-suppressive characteristics and improved bioabsorption over its parent compound. However, its influences on the development of hepatocellular carcinoma (HCC) are poorly defined. To address this, we tested the anticarcinogenic impact of HO-3867 and investigated the underlying mechanisms in fighting liver cancer. Our result demonstrated that HO-3867 reduced the viability of HCC cells, accompanied by promotion of cell cycle arrest at the sub-G1 stage and apoptotic responses. Furthermore, a distinctive profile of apoptosis associated proteins, encompassing elevated heme oxygenase-1 (HO-1) level and caspase activation, was detected in HO-3867-stimulated HCC cells. In addition, such HO-3867-mediated elevation in caspase activation was dampened by pharmacological suppression of p38 activities. Taken together, our findings unveiled that HO-3867 triggered cell cycle arrest and apoptotic events in liver cancer, involving a p38-mediated activation of caspase cascades. These data highlighted a usefulness of curcumin or its analogs on the management of hepatocarcinogenesis.

Sorafenib, a Tyrosine Kinase Inhibitor, Synergistically Enhances the Ferroptosis Effects of Asiatic Acid in Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide. Asiatic acid (AA) is a natural triterpene, which is recognized as effect of antioxidant and antitumor. Sorafenib (Sor), an orally target drug, has been applicate for the HCC therapy. However, the synergistic effect of AA and Sor on human HCC is still unclear. Here, we explore the effect of combined treatment with AA and Sor in the HCC cell line SK-HEP-1 and HepG2. Compared with treating alone, our results demonstrated that AA combined with Sor synergistically inhibited proliferative rates in MTT assay and colony formation assay. We also found that AA combined with Sor in HCC cells strongly caused cell cycle arrest in G0/G1 phase and affected the protein level of cyclin D1 and SKP2. Furthermore, combination treatment strongly enhanced ferroptosis through cellular accumulation of iron ions, lipid peroxidation, and ferroptosis-related proteins (GPX4 and FTH1) in HCC cells. In addition, the combined treatment resulted in higher phosphorylation of JNK1/2 in the promotion of ferroptosis than drug treatment alone. These results indicate that AA combined with Sor synergistically improved ferroptosis in HCC cells through the regulation of JNK1/2 signaling. Taken together, the combinatorial strategy may serve as the potential treatment in HCC.

Tricetin suppresses the cell migration and BMP-6 expression through p38 signaling pathways in human retinal pigment epithelium cells.

Proliferative vitreoretinopathy (PVR) is a visual-threatening disease, which cause from the migration of retinal pigment epithelium (RPE). Tricetin, a family of flavonoids, can inhibit the metastasis of several cancers. Herein, we aim to evaluate the possible effect of tricetin on inhibiting ARPE-19 cells migration. The Boyden chamber assay, wound healing assay, RNA sequencing, and Western blot analysis were applied in our experiment. The results revealed that tricetin inhibited the cell migration abilities of ARPE-19 cells. Moreover, using RNA sequencing technology, we revealed that tricetin repressed bone morphogenetic protein-6 (BMP-6) gene expressions in ARPE-19 cells. Overexpression of BMP-6 resulted in significant restoration of cell migration capabilities of tricetin-treated ARPE-19 cells. Furthermore, tricetin suppressed the phosphorylation of the p38 signaling pathway. Moreover, blocking the p38 pathway also inhibits BMP-6 expression and migration in the ARPE-19 cells. In conclusion, this study revealed that tricetin inhibits the ARPE-19 cell migration mainly via the suppression of BMP-6 expression and p38 signaling pathway.