The RNA binding protein MEX3A promotes tumor progression of breast cancer by post-transcriptional regulation of IGFBP4.

PURPOSE: Breast cancer (BC) is the most frequent malignant tumor in women worldwide with exceptionally high morbidity. The RNA-binding protein MEX3A plays a crucial role in genesis and progression of multiple cancers. We attempted to explore its clinicopathological and functional significance in BC in which MEX3A is expressed. METHODS: The expression of MEX3A detected by RT-qPCR and correlated the results with clinicopathological variables in 53 BC patients. MEX3A and IGFBP4 profile data of BC patients were downloaded from TCGA and GEO database. Kaplan-Meier (KM) analysis was used to estimate the survival rate of BC patients. Western Blot, CCK-8, EdU, colony formation and flow cytometry were performed to investigate the role of MEX3A and IGFBP4 in BC cell proliferation, invasion and cell cycle in vitro. A subcutaneous tumor mouse model was constructed to analyze in vivo growth of BC cells after MEX3A knockdown. The interactions among MEX3A and IGFBP4 were measured by RNA pull-down and RNA immunoprecipitation. RESULTS: The expression of MEX3A was upregulated in BC tissues compared to adjacent tissues and high expression of MEX3A was associated with poor prognosis. Subsequent in vitro studies demonstrated that MEX3A knockdown inhibited BC cells proliferation and migration, as well as xenograft tumor growth in vivo. The expression of IGFBP4 was significantly negatively correlated with MEX3A in BC tissues. Mechanistic investigation showed that MEX3A binds to IGFBP4 mRNA in BC cells, decreasing IGFBP4 mRNA levels, which further activated the PI3K/AKT and other downstream signaling pathways implicated cell cycle progression and cell migration. CONCLUSION: Our results indicate that MEX3A plays a prominent oncogenic role in BC tumorigenesis and progression by targeting IGFBP4 mRNA and activating PI3K/AKT signaling, which can be used as a novel therapeutic target for BC.

Knowledge, attitude, and practice toward self-control of dental plaque among patients with periodontal diseases: a cross-sectional study.

BACKGROUND: The development of periodontal disease is closely linked to individual oral healthcare behaviors. This study aimed to investigate the knowledge, attitude, and practice (KAP) toward the self-control of dental plaque among patients with periodontal diseases. METHODS: This cross-sectional study was conducted at Jinan Stomatological Hospital between July 2022 and September 2022 through a self-administrated questionnaire for patients with periodontal diseases. RESULTS: A total of 563 participants were included. Among them, 147 (26.11%) had gingivitis and 416 (73.89%) had periodontitis. Participants' knowledge, attitude, and practice scores were 8.71 ± 2.81 (range 0-12), 39.82 ± 3.69 (range 10-50), 33.13 ± 5.91 (range 11-55), respectively. The multivariate logistic regression analysis showed that the knowledge [odds ratio (OR) = 1.212, 95% confidence interval (CI): 1.097-1.339, P < 0.001], attitude (OR = 1.132, 95% CI: 1.070-1.198, P < 0.001), occupation, especially in the commercial and service industry (OR = 0.488, 95% CI: 0.221-1.080, P = 0.007), and income of 10,000-20,000 yuan (OR = 0.476, 95% CI: 0.258-0.877, P = 0.017) were independently associated with good practice. CONCLUSIONS: Chinese patients with periodontal diseases demonstrated satisfactory knowledge and attitudes regarding oral hygiene, but the practical aspects need more promotion and training, especially in daily brushing frequency, usage of oral irrigator and interdental brush. Individualized approach should consider patients' knowledge, attitudes, occupation and income level.

SERPINA5 promotes tumour cell proliferation by modulating the PI3K/AKT/mTOR signalling pathway in gastric cancer.

SERPINA5 belongs to the serine protease inhibitor superfamily and has been reported to be lowly expressed in a variety of malignancies. However, few report of SERPINA5 in gastric cancer has been found. The purpose of this study was to determine the role of SERPINA5 in GC and to investigate potential tumorigenic mechanisms. We performed qPCR to determine the level of SERPINA5 expression in GC. We used public databases to evaluate whether SERPINA5 could be utilized to predict overall survival and disease-free survival in GC patients. We also knocked down the expression of SERPINA5 and evaluated its effect on cell proliferation and migration. Furthermore, we explored the signal pathways and regulatory mechanisms related to SERPINA5 functions. According to our findings, SERPINA5 was shown to exhibit high expression in GC. Notably, SERPINA5 was prognostic in GC with high expression being unfavourable. SERPINA5 was further observed to promote GC tumorigenesis by modulating GC cell proliferation ability. Mechanically, SERPINA5 could inhibit CBL to regulate the PI3K/AKT/mTOR signalling pathway, thereby promoting GC carcinogenesis progression. These results highlight the important role of SERPINA5 in GC cell proliferation and suggest that SERPINA5 could be a novel target for GC treatment and a predictor for GC prognosis.

LGR6 Acts as an Oncogene and Induces Proliferation and Migration of Gastric Cancer Cells.

Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) belongs to the G protein-coupled receptor family, and it exhibits up-regulated expression in various types of human cancer. However, there are few reports of LGR6 contributing to gastric cancer (GC). Herein, we investigated the function of LGR6 and associated tumorigenic mechanisms in GC. LGR6 expression in GC was analyzed in the cancer genome atlas (TCGA) dataset and further confirmed in GC cell lines and fifteen paired tissue samples via quantitative real-time polymerase chain reaction (qRT-PCR). LGR6 expression was knocked down via small interfering RNA (siRNA), after which the impacts of silencing LGR6 on cell function were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), cell colony formation, wound-healing, and cell cycle assays. Western blot was performed to explore signaling pathways and regulatory mechanisms associated with LGR6 function. In this study, we showed that LGR6 was at higher levels in GC cell lines and gastric adenocarcinoma tissues. We found that silencing LGR6 in MKN-45 and BGC-823 cells inhibited cell proliferation and migration ability, which accompanied with an obvious regulation of MMP-9, ß-catenin, CCNA2, CDK-2, and ERK1/2. In conclusion, this study demonstrated that LGR6 could act as an oncogene and may be a therapeutic target in GC.

MicroRNA-145 suppresses gastric cancer progression by targeting Hu-antigen R.

Hu-antigen R (HuR) is involved in the carcinogenesis and progression of multiple types of cancer. However, its precise role in gastric cancer (GC) and the relevant molecular mechanism remain largely unclear. In the present study, we found that HuR expression level was higher in GC tissues and cell lines than in adjacent normal tissues and normal gastric epithelial cell lines, and this elevated expression was found to have a significant association with lymph node metastasis. Moreover, silencing HuR with RNA interference inhibited cell viability and induced cell apoptosis through the apoptosis-related regulators (Bcl-2 and Bax) in GC cells. In addition, bioinformatic analysis revealed that HuR expression was inversely correlated with miR-145 expression in GC tissue samples, and HuR was identified as a direct target of miR-145 with the dual-luciferase reporter. Enforced expression of miR-145 inhibited the HuR expression at both mRNA and protein levels and induced similar biologic effects of silencing HuR in GC cells. Additionally, we also found that restoration of HuR could eliminate the effects induced by miR-145 in GC cells. Taken together, these findings demonstrate the exact role of the miR-145-HuR axis in the progression of GC and indicate a potential target for GC therapy.

Expression scoring of a small-nucleolar-RNA signature identified by machine learning serves as a prognostic predictor for head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high mortality and poor prognosis due to a lack of predictive markers. Increasing evidence has demonstrated small nucleolar RNAs (snoRNAs) play an important role in tumorigenesis. The aim of this study was to identify a prognostic snoRNA signature of HNSCC. Survival-related snoRNAs were screened by Cox regression analysis (univariate, least absolute shrinkage and selection operator, and multivariate). The predictive value was validated in different subgroups. The biological functions were explored by coexpression analysis and gene set enrichment analysis (GSEA). One hundred and thirteen survival-related snoRNAs were identified, and a five-snoRNA signature predicted prognosis with high sensitivity and specificity. Furthermore, the signature was applicable to patients of different sexes, ages, stages, grades, and anatomic subdivisions. Coexpression analysis and GSEA revealed the five-snoRNA are involved in regulating malignant phenotype and DNA/RNA editing. This five-snoRNA signature is not only a promising predictor of prognosis and survival but also a potential biomarker for patient stratification management.

Expression and clinical value of PD-L1 which is regulated by BRD4 in tongue squamous cell carcinoma.

The programmed cell death-ligand-1 (PD-L1) and bromodomain protein 4 (BRD4) are frequently overexpressed in cancer and have even been shown to act synergistically. The aim of this study was to determine their potential oncogenic role .in tongue squamous cell carcinoma (TSCC). We detected significantly higher expression levels of both PD-L1 and BRD4 in TSCC tissues compared to normal tissues (P ≤ .05). In addition, the high levels of PD-L1 were significantly associated with increased tumor lymphatic metastasis (P ≤ .05), tumor staging (P ≤ .01), as well as BRD4 expression (P ≤ .05). Genetic and pharmacological inhibition of BRD4 in TSCC cells not only reduced their growth rate but also PD-L1 levels (P ≤ .05), while overexpression of BRD4 upregulated PD-L1. Bioinformatics analysis showed that c-MYC and CDK9 were interactive partners of both BRD4 and PD-L1. While c-MYC clearly modulated the expression of PD-L1, as well as reversed the inhibitory effects of JQ1, no obvious association was observed between CDK9 and PD-L1. We report a novel regulatory axis consisting of BRD4, PD-L1, and c-MYC that likely drives TSCC progression, and is a potential prognostic marker and/or therapeutic target for TSCC.

MicroRNA-1297 inhibits proliferation and promotes apoptosis in gastric cancer cells by downregulating CDC6 expression.

Gastric cancer (GC), one of the most common malignant tumors and the second most common leading cause of cancer-related death worldwide, is a biologically heterogeneous disease accompanied by various genetic and epigenetic alterations. However, the molecular mechanisms underlying this disease are complex and not completely understood. Increasing studies have shown that aberrant microRNA (miRNA) expression is associated with GC tumorigenesis and growth. MiR-1297 has been confirmed to be a cancer suppressor in diverse tumors in humans. However, to date, the function and mechanism of miR-1297 in GC have not been determined. Here, we found that the expression of miR-1297 was significantly reduced in GC tissues or GC cell lines compared with paracarcinoma normal tissue or normal cell lines. Exogenic overexpression of miR-1297 in GC cell lines can inhibit cell proliferation and colony formation and induce apoptosis, and inhibition of miR-1297 in GC cell lines can promote cell proliferation and colony formation, and reduce apoptosis in vitro. We further confirmed that miR-1297 acted as a tumor suppressor through targeting cell division control protein 6 (CDC6) in GC. Moreover, the inverse relationship between miR-1297 and CDC6 was verified in GC cell lines. Our results indicated that miR-1297 is a potent tumor suppressor in GC, and its antiproliferative and gene-regulatory effects are, in part, mediated through its downstream target gene, CDC6. These findings implied that miR-1297 might be used as a novel therapeutic target of GC.

Comprehensive analysis of presurgical factors predicting psychiatric disorders in patients with refractory temporal lobe epilepsy and mesial temporal sclerosis underwent cortico-amygdalohippocampectomy.

BACKGROUND: This study aimed to evaluate the predictive value of presurgical factors for psychiatric disorders (PD) in refractory temporal lobe epilepsy and mesial temporal sclerosis (TLE-MTS) patients underwent cortico-amygdalohippocampectomy (CAH). METHODS: A total of 98 refractory TLE-MTS patients underwent CAH were consecutively enrolled in this cohort study. Several presurgical factors were recorded, such as married status, employment status, highest education, disease duration, family history of epilepsy, and disorganized VEEG background activity. RESULTS: There were 17 (17.3%) refractory TLE-MTS patients occurring PD after CAH, including 8 (8.2%) mood disorders, 7 (7.1%) anxiety disorders, 8 (8.2%) psychoses, and 1 (1.0%) interictal dysphoric disorder. Employed status correlated with low PD occurrence, while disease duration and asymmetric VEEG background activity positively correlated with PD occurrence. Multivariate logistic analysis revealed employed status (P = 0.009) could independently predict lower PD occurrence, while highest education (P = 0.027), disease duration (P = 0.028), seizure frequencies (P = 0.015), and asymmetric VEEG background activity (P = 0.034) could independently predict higher PD occurrence. Receiver operating characteristic curve showed combination of these five factors (area under curve (AUC) = 0.871, 95%CI: 0.783-0.960) disclosed a great predictive value of PD occurrence. The sensitivity and specificity were 70.6% and 92.6% at the best cutoff point. In addition, the percentage of PD was increased with higher Engel classification (P = 0.003). CONCLUSION: Employed status, highest education, disease duration, seizure frequencies, and asymmetric VEEG background activity correlate with PD occurrence independently in epileptic patients.

EGFR-mediated signaling pathway influences the sensitivity of oral squamous cell carcinoma to JQ1.

Inhibiting BRD4 has emerged as a promising anticancer strategy, and inhibitors such as JQ1 can suppress cell growth in oral squamous cell carcinoma (OSCC). However, the mechanism through which JQ1 exerts its anticancer activity has not been reported. Moreover, JQ1 does not markedly inhibit proliferation and increase apoptosis in OSCC when used as a monotherapy. Herein, we explore the mechanism of JQ1 in OSCC and probe ways to increase its therapeutic potential. In this study, we used two cell lines, Cal27, and Scc25. We found that BRD4 was highly expressed in OSCC tissues when compared with adjacent non-tumor tissues, and JQ1 worked through the EGFR-mediated signaling pathway in tumor cells. Furthermore, we demonstrated that JQ1 induced an increased treatment effect in vitro and in vivo when combined with a PI3K inhibitor. Interestingly, subsequent mechanistic analyses indicated that further suppressing EGFR and BRD4 expression was instrumental to this functional synergism. Moreover, we found that upregulating EGFR expression by EGF stimulation protected cells treated with JQ1 from apoptosis, while knockdown of EGFR before addition of JQ1 successfully mimicked the combination treatment results. In summary, our findings revealed that JQ1 can act by inhibiting the EGFR-mediated signaling pathway, and EGFR expression influences the sensitivity of OSCC to JQ1. Regarding clinical use, this study demonstrates that BRD4 is a novel therapeutic target and EGFR can be used as a biomarker to identify the most appropriate anti-BRD4 treatment strategy in OSCC.

Hypermethylation of miR-338-3p and Impact of its Suppression on Cell Metastasis Through N-Cadherin Accumulation at the Cell -Cell Junction and Degradation of MMP in Gastric Cancer.

BACKGROUND/AIMS: MicroRNAs (miRNAs) have been well studied in human carcinogenesis and cancer progression. Our previous study showed the down-regulation of miR-338-3p expression in human gastric cancer (GC). However, the reasons of this dysregulation remain largely unclear. METHODS: Bisulfite sequence analysis was performed to explore the methylation status of the promoter region of miR-338-3p. Cell wound-healing and transwell assays were performed to examine the capacity of cell migration and cell interaction. A dual-luciferase reporter was used to validate the bioinformatics-predicted target gene of miR-338-3p. Western blotting, RNA interference, and immunofluorescence (IF) were used to evaluate the expression of MMPs and the location of N-cadherin to determine the mechanism underlying miR-338-3p-induced anti-tumor effects. RESULTS: miR-338-3p was epigenetically silenced, and this loss of expression was significantly correlated with the Borrmann Stage in GC. Restoring miR-338-3p expression in BGC-823 cells inhibited cell migration and invasion. Moreover, Ras-related protein (Rab-14) and Hedgehog acyltransferase (Hhat) were identified as direct targets of miR-338-3p. Both enforced expression of miR-338-3p and small interfering RNA induced Rab14-mediated accumulation of N-cadherin in the cell -cell junctions or Hhat-associated matrix metalloproteinase (MMP) degradation, which may underline the metastasis defects caused by loss of miR-338-3p in GC. CONCLUSION: These data indicate that miR-338-3p functions as a tumor suppressor in GC, and that the hypermethylation status of its CpG island might be a novel potential strategy for treating GC.

CREBRF promotes the proliferation of human gastric cancer cells via the AKT signaling pathway.

Gastric cancer (GC) is one of the most common malignant cancer around the world, however the mechanisms is still unclear. In the present study, we investigated the function of CREB3 regulatory factor (CREBRF) in human GC and explored its relevant molecular mechanism. We found that CREBRF was highly expressed in primary GC tissues and the expression level was associated with the clinicopathologic characteristics of GC. CREBRF silencing inhibited GC cell proliferation and induced G1/G0 to S phase cell cycle arrest through regulating Cyclin A, Cyclin D1 and CDK2 expressions. Furthermore, the results showed that knockdown of CREBRF suppressed the activation of AKT signaling pathway. We further discovered that activating of AKT rescued the effect of CREBRF silencing on cell growth and drove cell re-enter into the S phase of the cell cycle with SC79 (a AKT activator). Taken together, our study demonstrated that CREBRF might promote GC cell proliferation and induce G1-S phase transition through activating AKT signaling pathway. These findings suggest that CREBRF acts as a novel oncogene and may be a potential therapeutic target in therapy of GC.

MeCP2 regulated glycogenes contribute to proliferation and apoptosis of gastric cancer cells.

Aberrant glycogene and glycan expression is intimately associated with carcinogenesis, invasion, and metastasis of gastric cancer (GC); however the regulatory mechanisms for glycogenes in GC cells remain unclear. Methyl-CpG-binding protein 2 (MeCP2) regulates genes by binding to methylated promoters, and in our previous work we found that it is overexpressed in GC cell lines and tissues, functioning as an oncogene. In this study we detected the expression of 212 glycogenes in MeCP2 silenced GC cells versus control using the Agilent Whole Human Genome Microarray and mining the data through bioinformatic analysis. A total of 10 glycogenes exhibited increased expression (FC ≥ 2, P < 0.05), while 16 showed decreased expression (FC ≤ 2, P < 0.05) in the MeCP2 silenced cells, which corresponded to down-regulation of Lewis antigens (UEA-I), T/Tn antigens (PNA), and mature N-glycans (PHA-E and PHA-E+L) and up-regulation of lactosylceramide, a precursor oligosaccharide of N-glycans. Examination of the TCGA Gastric Cancer databases demonstrated that nine glycogenes (24.6%) were oppositely regulated by MeCP2 in MeCP2 knockdown BGC-823 cells relative to their expression level in GC tissues, and might be downstream genes of MeCP2. Individual gene analysis suggested that neutral alpha-glucosidase AB (GANAB) knockdown can rescue the effects of MeCP2 overexpression on GC cells. MeCP2 promotes GANAB by binding to the second methylated CpG island (206 bp, -12916 to -13122) of the GANAB promoter. In conclusion, glycogenes can be either up- or down-regulated by MeCP2 directly or indirectly to alter the glycopatterning and affect the proliferation and apoptosis of GC cells.

Magnetic Resonance Imaging (MRI) Evaluation for Anterior Disc Displacement of the Temporomandibular Joint.

BACKGROUND Magnetic resonance imaging (MRI) is the criterion standard imaging technique for visualization of the temporomandibular joint (TMJ) region, and is currently considered the optimum modality for comprehensive evaluation in patients with temporomandibular joint disorder (TMD). This study was aimed at finding the value of MRI in pre-clinical diagnosis of TMJ disc displacement. MATERIAL AND METHODS Patients primarily diagnosed as having anterior disc displacement by clinical symptoms and X-ray were selected in the present study. MRI was used to evaluate surrounding anatomical structures and position, as well as morphological and signal intensity change between patients and normal controls. RESULTS Posterior band position was significantly different between the patient group and control group. At the maximum opened-mouth position, the location of disc intermediate zone returned to normal. At closed-mouth position, the thickness of anterior and middle, but not posterior, band increased. The motion range of the condyle in the anterior disc displacement without reduction (ADDWR) patient group was significantly less than the value in the anterior disc displacement with reduction (ADDR) patient group and the control group. Whether at closed-mouth position or maximum opened-mouth position, the exudate volume in the patient group was greater than in the normal group. CONCLUSIONS MRI can be successfully used to evaluate multiple morphological changes at different mouth positions of normal volunteers and patients. The disc-condyle relationship can serve as an important indicator in assessing anterior disc displacement, and can be used to distinguish disc displacement with or without reduction.

Magnetic resonance imaging of temporomandibular joint: morphometric study of asymptomatic volunteers.

BACKGROUND: The aims of this study were to determine the best suited magnetic resonance imaging scanning plane, scanning sequence, and imaging modality for the evaluation of the temporomandibular joint (TMJ) and quantitatively assess the relationship of articular disk position to condyle position. METHODS: One hundred four TMJs in 52 symptom-free heads were examined by magnetic resonance imaging. The best scanning plane, scanning sequence, and scanning parameter were determined according to the imaging time and image quality. Bilateral symmetry of the articular disk and mandibular condyle was measured by using the automatic measurement of 3.0-T GE Excite Signa MR scanner. RESULTS: Fast spin-echo sequence, oblique sagittal imaging plane, and proton density imaging were the best suited scanning sequence, scanning planes, and imaging modality, respectively. The thicknesses of the anterior and posterior bands and for the intermediate zone were not statistically different for both sides. The posterior band of the disk was found to originate in an area adjacent to the 12-o'clock position of the condyle (± 5 degrees), whereas the anterior band of the disk originated adjacent to 1-o'clock position (28 ± 6 degrees). The anteroposterior diameter and mediolateral diameter of the condylar processes were not statistically different for both sides. The axial condylar angle between the plane of the greatest mediolateral diameter of the condylar processes and the midsagittal plane were also not statistically different for both sides. CONCLUSIONS: The magnetic resonance images can depict clearly major regional anatomic structures and position in the TMJ, which can be used in the early diagnosis for the TMJ disorder.

MicroRNA-302b Enhances the Sensitivity of Hepatocellular Carcinoma Cell Lines to 5-FU via Targeting Mcl-1 and DPYD.

MiR-302b is a member of miR-302-367 cluster. The miR-302-367 cluster played important roles in maintaining pluripotency in human embryonic stem cells (hESCs) and has been proved to be capable of suppressing cell growth in several types of cancer cell lines including Hepatocellular Carcinoma (HCC) Cell lines. However, the role that miR-302b plays in the 5-Fluorouracil (5-FU) sensitivity of HCC has not been known. This study showed that miR-302b could enhance the sensitivity to 5-FU in HCC cell lines and verified its two putative targeted genes responsible for its 5-FU sensitivity.

LAMC2 mitigates ER stress by enhancing ER-mitochondria interaction via binding to MYH9 and MYH10.

Highly proliferative and metastatic tumors are constantly exposed to both intrinsic and extrinsic factors that induce adaptation to stressful conditions. Chronic adaptation to endoplasmic reticulum (ER) ER stress is common to many different types of cancers, and poses a major challenge for acquired drug resistance. Here we report that LAMC2, an extracellular matrix protein upregulated in many types of cancers, is localized in the ER of lung, breast, and liver cancer cells. Under tunicamycin-induced ER stress, protein level of LAMC2 is upregulated. Transfection of cancer cells with LAMC2 resulted in the attenuation of ER stress phenotype, accompanied by elevation in mitochondrial membrane potential as well as reduction in reactive oxygen species (ROS) levels and apoptosis. In addition, LAMC2 forms protein complexes with MYH9 and MYH10 to promote mitochondrial aggregation and increased ER-mitochondria interaction at the perinuclear region. Moreover, overexpression of LAMC2 counteracts the effects of ER stress and promotes tumor growth in vivo. Taken together, our results revealed that in complex with MYH9 and MYH10, LAMC2 is essential for promoting ER-mitochondria interaction to alleviate ER stress and allow cancer cells to adapt and proliferate under stressful conditions. This study provides new insights and highlights the promising potential of LAMC2 as a therapeutic target for cancer treatment.

SETD7 Promotes Cell Proliferation and Migration via Methylation-mediated TAF7 in Clear Cell Renal Cell Carcinoma.

SET domain containing 7(SETD7), a member of histone methyltransferases, is abnormally expressed in multiple tumor types. However, the biological function and underlying molecular mechanism of SETD7 in clear cell renal cell carcinoma (ccRCC) remain unclear. Here, we explored the biological effects of SETD7-TAF7-CCNA2 axis on proliferation and metastasis in ccRCC. We identified both SETD7 and TAF7 were up-regulated and significantly promoted the proliferation and migration of ccRCC cells. Concurrently, there was a significant positive correlation between the expression of SETD7 and TAF7, and the two were colocalized in the nucleus. Mechanistically, SETD7 methylates TAF7 at K5 and K300 sites, resulting in the deubiquitination and stabilization of TAF7. Furthermore, re-expression of TAF7 could partially restore SETD7 knockdown inhibited ccRCC cells proliferation and migration. In addition, TAF7 transcriptionally activated to drive the expression of cyclin A2 (CCNA2). And more importantly, the methylation of TAF7 at K5 and K300 sites exhibited higher transcriptional activity of CCNA2, which promotes formation and progression of ccRCC. Our findings reveal a unique mechanism that SETD7 mediated TAF7 methylation in regulating transcriptional activation of CCNA2 in ccRCC progression and provide a basis for developing effective therapeutic strategies by targeting members of SETD7-TAF7-CCNA2 axis.

AURKB/CDC37 complex promotes clear cell renal cell carcinoma progression via phosphorylating MYC and constituting an AURKB/E2F1-positive feedforward loop.

As the second most common malignant tumor in the urinary system, renal cell carcinoma (RCC) is imperative to explore its early diagnostic markers and therapeutic targets. Numerous studies have shown that AURKB promotes tumor development by phosphorylating downstream substrates. However, the functional effects and regulatory mechanisms of AURKB on clear cell renal cell carcinoma (ccRCC) progression remain largely unknown. In the current study, we identified AURKB as a novel key gene in ccRCC progression based on bioinformatics analysis. Meanwhile, we observed that AURKB was highly expressed in ccRCC tissue and cell lines and knockdown AURKB in ccRCC cells inhibit cell proliferation and migration in vitro and in vivo. Identified CDC37 as a kinase molecular chaperone for AURKB, which phenocopy AURKB in ccRCC. AURKB/CDC37 complex mediate the stabilization of MYC protein by directly phosphorylating MYC at S67 and S373 to promote ccRCC development. At the same time, we demonstrated that the AURKB/CDC37 complex activates MYC to transcribe CCND1, enhances Rb phosphorylation, and promotes E2F1 release, which in turn activates AURKB transcription and forms a positive feedforward loop in ccRCC. Collectively, our study identified AURKB as a novel marker of ccRCC, revealed a new mechanism by which the AURKB/CDC37 complex promotes ccRCC by directly phosphorylating MYC to enhance its stability, and first proposed AURKB/E2F1-positive feedforward loop, highlighting AURKB may be a promising therapeutic target for ccRCC.

Crosstalk between extracellular vesicles and tumor-associated macrophage in the tumor microenvironment.

In concert with hijacking key genes to drive tumor progression, cancer cells also have the unique ability to dynamically interact with host microenvironment and discreetly manipulate the surrounding stroma, also known as the tumor microenvironment (TME), to provide optimal conditions for tumor cells to thrive and evade host immunity. Complex cellular crosstalk and molecular signaling between cancer cells, surrounding non-malignant cells, and non-cellular components are involved in this process. While intercellular communication traditionally centers around chemokines, cytokines, inflammatory mediators, and growth factors, emerging pathways involving extracellular vesicles (EVs) are gaining increasing attention. The immunosuppressive TME is created and maintained in part by the large abundance of tumor-associated macrophages (TMAs), which are associated with drug resistance, poor prognosis, and have emerged as potential targets for cancer immunotherapy. TMAs are highly dynamic, and can be polarized into either M1 or M2-like macrophages. EVs are efficient cell-cell communication molecules that have been catapulted to the center of TMA polarization. In this article, we provide detailed examination of the determinative role of EVs in sustaining the TME through mediating crosstalk between tumor cells and tumor-associated macrophages.