ANXA9 facilitates S100A4 and promotes breast cancer progression through modulating STAT3 pathway.

Breast cancer has the highest global incidence and mortality rates among all cancer types. Abnormal expression of the Annexin family has been observed in different malignant tumors, including upregulated ANXA9 in breast cancer. We found highly expressed ANXA9 in metastatic breast cancer tissues, which is correlated with breast cancer progression. In vitro, the functional experiments indicated ANXA9 influenced breast cancer proliferation, motility, invasion, and apoptosis; in vivo, downregulation of ANXA9 suppressed breast cancer xenograft tumor growth and lung metastasis. Mechanically, on one side, we found that ANXA9 could mediate S100A4 and therefore regulate AKT/mTOR/STAT3 pathway to participate p53/Bcl-2 apoptosis; on the other side, we found ANXA9 transferred S100A4 from cells into the tumor microenvironment and mediated the excretion of cytokines IL-6, IL-8, CCL2, and CCL5 to participate angiogenesis via self- phosphorylation at site Ser2 and site Thr69. Our findings demonstrate significant involvement of ANXA9 in promoting breast cancer progression, thereby suggesting that therapeutic intervention via targeting ANXA9 may be effective in treating metastatic breast cancer.

K48-linked deubiquitination of VGLL4 by USP15 enhances the efficacy of tumor immunotherapy in triple-negative breast cancer.

Immunotherapy based on PD-1/PD-L1 antagonists has been demonstrated to be efficacious in inducing tumor remission in patients with triple-negative breast cancer (TNBC). However, tumor immune evasion caused by the PD-1/PD-L1 pathway inhibits the immunotherapeutic effect of PD-1/PD-L1 inhibitors against TNBC. Therefore, identifying potential targets for blocking the PD-1/PD-L1 pathway is a compelling strategy for TNBC treatment. Here, we discovered that VGLL4 could inhibit PD-L1 transcription by suppressing STAT3 activation, thereby enhancing the efficacy of anti-PD-1 antibody immunotherapy in TNBC. Low expression of USP15, a deubiquitinating enzyme of VGLL4, was associated with reduced CD8+ T cell infiltration and poor prognosis in TNBC patients. USP15 was found to inhibit PD-L1 transcription, leading to increased CD8+ T cell infiltration and thus enhancing the efficacy of TNBC immunotherapy. Furthermore, SART3 regulated VGLL4 stability and PD-L1 transcription by influencing the nuclear translocation of USP15. In conclusion, our study provides new insights into the biological regulation of PD-L1, identifies a previously unrecognized regulator of this critical immune checkpoint, and highlights potential therapeutic targets for overcoming immune evasion in TNBC.

LncRNA HOST2 promotes NSUN2-mediated breast cancer progression via interaction with ELAVL1.

Breast cancer (BC) is the most prevalent malignant tumor in women worldwide with high morbidity and mortality. NSUN2, a crucial RNA methyltransferase, plays a pivotal role in regulating the proliferation and metastasis of tumor cells. Our study demonstrated that NSUN2 is upregulated in BC tissues and cell lines, and its high expression is associated with a poor prognosis in BC patients. Knockout of NSUN2 exerted inhibitory effects on the proliferation and migration of BC cells in vitro and in vivo. Mechanistic investigations revealed that the RNA-binding protein ELAVL1 can bind to NSUN2 mRNA and increase its stability. Additionally, we identified HOST2, a long non-coding RNA, as a key player in blocking the ubiquitin-dependent proteasomal degradation of ELAVL1, thereby influencing the stability of NSUN2 mRNA. In conclusion, this study revealed for the first time that HOST2 maintains NSUN2 mRNA stability by blocking ubiquitin-dependent degradation of ELAVL1, which in turn affects BC progression. HOST2/ELAVL1/NSUN2 oncogenic cascade has the potential to be a novel therapeutic target for BC.

LINC01572 promotes triple-negative breast cancer progression through EIF4A3-mediated ß-catenin mRNA nuclear exportation.

Long noncoding RNAs have been reported to be involved in the development of breast cancer. LINC01572 was previously reported to promote the development of various tumors. However, the potential biological function of LINC01572 in breast cancer remains largely unknown. R language was used to perform bioinformatic analysis of The Cancer Genome Atlas data. The expression level of RNAs was examined by RT-qPCR. The effect of knocking down or overexpression LINC01572 in triple-negative breast cancer (TNBC) cell lines was evaluated by detecting cell proliferation, migrant action. RNA immunoprecipitation assay and RNA pull-down assay were performed to explore the regulatory relationship between LINC01572, EIF4A3, and ß-catenin. Bioinformatics analysis identifies LINC01572 as an oncogene of breast cancer. LINC01572 is over-expressed in TNBC tissues and cell lines, correlated with poor clinical prognosis in BC patients. Cell function studies confirmed that LINC01572 facilitated the proliferation and migration of TNBC cells in both vivo and vitro. Mechanistically, ß-catenin mRNA and EIF4A3 combine spatially to form a complex, LINC01572 helps transport this complex from the nucleus to the cytoplasm, thereby facilitating the translation of ß-catenin. Our findings confirm that LINC01572 acts as a tumor promoter and may act as a biomarker in TNBC. In addition, novel molecular regulatory relationships involving LINC01572/EIF4A3/ß-catenin are critical to the development of TNBC, which led to a new understanding of the mechanisms of TNBC progression and shows a new target for precision treatment for TNBC.

Effectiveness and Safety of Chinese Herbal Injections Combined with SOX Chemotherapy Regimens for Advanced Gastric Cancer: a Bayesian Network Meta-Analysis.

Background: Randomized controlled trials (RCTs) have demonstrated that combining Chinese herbal injections (CHIs) with oxaliplatin plus tegafur (SOX) chemotherapy regimens improves clinical effectiveness and reduces adverse reactions in patients with advanced gastric cancer (AGC). These RCTs highlight the potential applications of CHIs and their impact on AGC patient prognosis. However, there is insufficient comparative evidence on the clinical effectiveness and safety of different CHIs when combined with SOX. Therefore, we performed a network meta-analysis to rank the clinical effectiveness and safety of different CHIs when combined with SOX chemotherapy regimens. This study aimed to provide evidence for selecting appropriate CHIs in the treatment of patients with AGC. Methods: We searched eight databases from their inception until March 2023. Surface Under the Cumulative Ranking Curve (SUCRA) probability values were used to rank the treatment measures, and the Confidence in Network Meta-Analysis (CINeMA) software assessed the grading of evidence. Results: A total of 51 RCTs involving 3,703 AGC patients were identified. Huachansu injections + SOX demonstrated the highest clinical effectiveness (SUCRA: 78.17%), significantly reducing the incidence of leukopenia (93.35%), thrombocytopenia (80.19%), and nausea and vomiting (95.15%). Shenfu injections + SOX improved Karnofsky's Performance Status (75.59%) and showed a significant reduction in peripheral neurotoxicity incidence (88.26%). Aidi injections + SOX were most effective in reducing the incidence of liver function damage (75.16%). According to CINeMA, most confidence rating results were classified as "low". Conclusion: The combination of CHIs and SOX shows promising effects in the treatment of AGC compared to SOX alone. Huachansu and Shenfu injections offer the greatest overall advantage among the CHIs, while Aidi injections are optimal for reducing the incidence of liver damage. However, further rigorous RCTs with larger sample sizes and additional pharmacological studies are necessary to reinforce these findings.

Chinese herbal injections in combination with radiotherapy for advanced pancreatic cancer: A systematic review and network meta-analysis.

Background: Advanced pancreatic cancer (APC) is a fatal disease with limited treatment options. This study aims to evaluate the effectiveness and safety of different Chinese herbal injections (CHIs) as adjuvants for radiotherapy (RT) in APC and compare their treatment potentials using network meta-analysis. Methods: We systematically searched three English and four Chinese databases for randomized controlled trials (RCTs) from inception to July 25, 2023. The primary outcome was the objective response rate (ORR). Secondary outcomes included Karnofsky performance status (KPS) score, overall survival (OS), and adverse events (AEs). The treatment potentials of different CHIs were ranked using the surface under the cumulative ranking curve (SUCRA). The Cochrane RoB 2 tool and CINeMA were used for quality assessment and evidence grading. Results: Eighteen RCTs involving 1199 patients were included. Five CHIs were evaluated. Compound Kushen injection (CKI) combined with RT significantly improved ORR compared to RT alone (RR 1.49, 95 % CrI 1.21-1.86). Kanglaite (KLT) plus RT (RR 1.58, 95 % CrI 1.20-2.16) and CKI plus RT (RR 1.49, 95 % CrI 1.16-1.95) were associated with improved KPS score compared to radiation monotherapy, with KLT+RT being the highest rank (SUCRA 72.28 %). Regarding AEs, CKI plus RT was the most favorable in reducing the incidence of leukopenia (SUCRA 90.37 %) and nausea/vomiting (SUCRA 85.79 %). Conclusions: CKI may be the optimal choice of CHIs to combine with RT for APC as it may improve clinical response, quality of life, and reduce AEs. High-quality trials are necessary to establish a robust body of evidence. Protocol registration: PROSPERO, CRD42023396828.

miR-186-ANXA9 signaling inhibits tumorigenesis in breast cancer.

Breast cancer (BC) ranks as the highest incidence among cancer types in women all over the world. MicroRNAs (miRNAs) are a class of short endogenous non-coding RNA in cells mostly functioning to silence the target mRNAs. In the current study, a miRNA screening analysis identified miR-186-5p to be downregulated in human breast cancer tumors. Functional studies in vitro demonstrated that overexpression of miR-186-5p inhibited cellular proliferation and induced cell apoptosis in multiple breast cancer cell lines including MDA-MB-231, MCF-7, and BT549 cells. Transplantation of the miR-186-5p-overexpressing MDA-MB-231 cells into nude mice significantly inhibited mammary tumor growth in vivo. Sequence blast analysis predicted annexin A9 (ANXA9) as a target gene of miR-186-5p, which was validated by luciferase reporter assay, QRT-PCR analysis, and western blot. Additional gene expression analysis of clinical tumor samples indicated a negative correlation between miR-186-5p and ANXA9 in human breast cancer. Knockdown of ANXA9 mimicked the phenotype of miR-186-5p overexpression. Reintroduction of ANXA9 back rescued the miR-186-5p-induced cell apoptosis. In addition, miR-186-5p decreased the expression of Bcl-2 and increased the expression of p53, suggesting a mechanism regulating miR-186-5p-induced cellular apoptosis. In summary, our study is the first to demonstrate miR-186-5p-ANXA9 signaling in suppressing human breast cancer. It provided a potential therapeutic target in breast cancer.

Mechanism of Chinese botanical drug Dizhi pill for myopia: An integrated study based on bioinformatics and network analysis.

To identify the active constituents, core targets, immunomodulatory functions and potential mechanisms of Dizhi pill (DZP) in the treatment of myopia. The active constituents and drug targets of DZP were searched in the TCMSP, Herb databases and correlational studies. The targets of myopia were searched in the TTD, Genecards, OMIM and Drugbank databases. Gene expression profile data of GSE136701 were downloaded from the GEO database and subjected to WGCNA and DEG analysis to screen for significant modules and targets of myopia. Intersectional targets of myopia and DZP and core targets of myopia were analyzed through the String database. The GO and KEGG enrichment analyses of the interested targets were conducted. Cibersort algorithm was used for immune infiltration analysis to investigate the immunomodulatory functions of DZP on myopia. Autodock was used to dock the important targets and active constituents. Eight targets (STAT3, PIK3CA, PIK3R1, MAPK1, MAPK3, HSP90AA1, MIP, and LGSN) and 5 active constituents (Quercetin, Beta-sitosterol, Diincarvilone A, Ferulic acid methyl ester, and Naringenin) were identified from DZP. In pathways identified by the GO and KEGG enrichment analyses, "ATP metabolic process" and "AGE-RAGE diabetes complication signaling" pathways were closely related to the mechanisms of DZP in the treatment of myopia. Molecular docking showed that both the intersectional targets and core targets of myopia could bind stably and spontaneously with the active constituents of DZP. This study suggested that the mechanisms of DZP in the treatment of myopia were related to active constituents: Quercetin, Beta-sitosterol, Diincarvilone A, Ferulic acid methyl ester and Naringenin, intersectional targets: STAT3, PIK3CA, PIK3R1, MAPK1, MAPK3, and HSP90AA1, core targets of myopia: MIP and LGSN, AGE-RAGE signaling pathway, positive regulation of ATP metabolic process pathway and immunomodulatory functions.

Severe fever with thrombocytopenia syndrome virus induces platelet activation and apoptosis via a reactive oxygen species-dependent pathway.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) and with a high fatality rate. Thrombocytopenia is a major clinical manifestation observed in SFTS patients, but the underlying mechanism remains largely unclear. Here, we explored the effects of SFTSV infection on platelet function in vivo in severely infected SFTSV IFNar-/- mice and on mouse and human platelet function in vitro. Results showed that SFTSV-induced platelet clearance acceleration may be the main reason for thrombocytopenia. SFTSV-potentiated platelet activation and apoptosis were also observed in infected mice. Further investigation showed that SFTSV infection induced platelet reactive oxygen species (ROS) production and mitochondrial dysfunction. In vitro experiments revealed that administration of SFTSV or SFTSV glycoprotein (Gn) increased activation, apoptosis, ROS production, and mitochondrial dysfunction in separated mouse platelets, which could be effectively ameliorated by the application of antioxidants (NAC (N-acetyl-l-cysteine), SKQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) and resveratrol). In vivo experiments showed that the antioxidants partially rescued SFTSV infection-induced thrombocytopenia by improving excessive ROS production and mitochondrial dysfunction and down-regulating platelet apoptosis and activation. Furthermore, while SFTSV and Gn directly potentiated human platelet activation, it was completely abolished by antioxidants. This study revealed that SFTSV and Gn can directly trigger platelet activation and apoptosis in an ROS-MAPK-dependent manner, which may contribute to thrombocytopenia and hemorrhage during infection, but can be abolished by antioxidants.

Investigation into the current status of cleaning, disinfection, and sterilization of da Vinci surgical instruments-a cross-sectional survey.

Background: In recent years, the use of robotic-assisted surgery has developed rapidly in China and is now widely used in many clinical fields. However, da Vinci robotic surgical instruments are more precise, expensive, and complex than ordinary laparoscopes, have less instrument configuration, involve restrictions on the duration of use, and have cleanliness requirements for supporting instruments. The purpose of this study was to analyze and summarize the current status of cleaning, disinfection, and maintenance of da Vinci robotic surgical instruments in China to improve the management of these devices. Methods: A questionnaire survey on the use of da Vinci robotic-assisted surgery at medical institutions in China was designed, distributed, and analyzed. The survey included items regarding general information, management of instrument handling personnel, instrument handling techniques, guidelines, and references for instrument handling. The results and conclusions were formed from the data generated by the analysis system and the answers of respondents to the open-ended questions. Results: (I) All surgical instruments used in domestic surgery practice were imported. There were 25 hospitals that conduct more than 500 da Vinci robotic-assisted surgeries every year. (II) In a relatively high proportion of medical institutions, nurses continued to be responsible for the processes of cleaning (46%), disinfection (66%), and low-temperature sterilization (50%). (III) A total of 62% of the surveyed institutions used fully manual methods for cleaning instruments, and 30% of the ultrasonic cleaning equipment in surveyed institutions did not comply with the standard. (IV) A total of 28% of surveyed institutions used only visual inspection to evaluate cleaning efficacy. Only 16-32% of surveyed institutions regularly used adenosine triphosphate (ATP), residual protein, and other methods to detect sterilization of cavities in instruments. (V) In 60% of the surveyed institutions, robotic surgical instruments have been damaged. Conclusions: Cleaning efficacy detection methods of robotic surgical instruments were not uniform and standardized. The management of device protection operations should be further regulated. In addition, further study of relevant guidelines and specifications as well as the training of operators is warranted.

CircRNF10-DHX15 interaction suppressed breast cancer progression by antagonizing DHX15-NF-κB p65 positive feedback loop.

BACKGROUND: Breast cancer (BC) is a common threat to women. The continuous activation of nuclear factor kappa B (NF-κB) signaling pathway contributes to the development of BC. This study aimed to investigate the role of a circular RNA (circRNF10) in BC progression and regulating NF-κB signaling pathway. METHODS: Bioinformatics analysis, RT-qPCR, subcellular fractionation, FISH, RNase R treatment, and actinomycin D assay were used to explore the expression and characteristics of circRNF10 in BC. The biological functions of circRNF10 in BC were analyzed by MTT assay, colony formation assay, wound healing assay, and Transwell assay. RNA pulldown and RIP assay were used to identify the interaction between circRNF10 and DEAH (Asp-Glu-Ala-His) box helicase 15 (DHX15). The impact of circRNF10-DHX15 interaction on NF-κB signaling pathway was explored by western blot, IF, and co-IP. Furthermore, dual-luciferase reporter assay, ChIP, and EMSA were performed to assess the effect of NF-κB p65 on DHX15 transcription. RESULTS: CircRNF10 was downregulated in BC, and lower expression of circRNF10 was related to poor prognosis of patients with BC. CircRNF10 inhibited the proliferation and migration of BC. Mechanically, circRNF10-DHX15 interaction sequestered DHX15 from NF-κB p65, thereby inhibiting the activation of NF-κB signaling pathway. On the other hand, NF-κB p65 enhanced DHX15 transcription by binding to the promoter of DHX15. Altogether, circRNF10 impaired the DHX15-NF-κB p65 positive feedback loop and suppressed the progression of BC. CONCLUSION: CircRNF10-DHX15 interaction suppressed the DHX15-NF-κB p65 positive feedback loop, thereby inhibiting BC progression. These findings provide new insights in the continuous activation of NF-κB signaling pathway and raised potential therapeutic approach for BC treatment.

CircXPO1 Promotes Glioblastoma Malignancy by Sponging miR-7-5p.

Mounting evidence suggests that circular RNAs play important roles in the development and progression of cancers. However, their function in glioblastomas (GBM) is still unclear. By circRNA array analysis, we found that circXPO1 (hsa_circ_102737) was significantly upregulated in GBM, and qPCR analysis verified that the circXPO1 expression level was increased in both GBM tissues and cell lines. Functional studies demonstrated that the knockdown of circXPO1 in GBM cell lines repressed cell proliferation and migration; conversely, the overexpression of circXPO1 promoted the malignancy of GBM cells. In line with these findings, circXPO1 inhibition effectively suppressed gliomagenesis in the in situ transplantation model of nude mice. Through bioinformatic analyses and dual-luciferase reporter assays, we showed that circXPO1 directly bound to miR-7-5p, which acted as a tumor suppressor through the negative regulation of RAF1. In conclusion, our studies suggest that the circXPO1/miR-7-5p/RAF1 axis promotes brain tumor formation and may be a potential therapeutic target for GBM treatment.

DNMT3a-dermatopontin axis suppresses breast cancer malignancy via inactivating YAP.

Breast cancer (BC) is the most common malignant tumor in women worldwide, and its recurrence and metastasis negatively affect patient prognosis. However, the mechanisms underlying its tumorigenesis and progression remain unclear. Recently, the influence of dermatopontin (DPT), which is an extracellular matrix protein, has been proposed in the development of cancer. Here we found that DNMT3a-mediated DPT, promoter hypermethylation results in the downregulation of DPT expression in breast cancer and its low expression correlated with poor prognosis. Notably, DPT directly interacted with YAP to promote YAP Ser127 phosphorylation, and restricted the translocation of endogenous YAP from the cytoplasm to the nucleus, thereby suppressing malignant phenotypes in BC cells. In addition, Ectopic YAP overexpression reversed the inhibitory effects of DPT on BC growth and metastasis. Our study showed the critical role of DPT in regulating BC progression, making it easier to explore the clinical potential of modulating DPT/YAP activity in BC targeted therapies.

E2F1-mediated ectopic expression of PP1A promotes breast cancer progression via activation of YAP1.

Hormone receptor-positive breast cancer is the most common subtype of breast cancer. The protein phosphatase PP1A gene is described as an oncogene in several tumor types; however, the biological function of PP1A in hormone receptor-positive breast cancer remains unclear. The Cancer Genome Atlas data indicates PP1A expression is upregulated in hormone receptor-positive breast cancer tissues than in normal breast tissues. We explored the biological function of PP1A in hormone receptor-positive breast cancer using MTT assays, colony formation assays, and a xenograft mouse model. The results indicated that PP1A promoted hormone receptor-positive breast cancer proliferation, both in vitro and in vivo. Mechanistically, LINC02754 recruited the binding of the transcription factor E2F1 to the PP1A promotor, thereby increasing PP1A expression. The PP1A then interacted with and dephosphorylated YAP1, resulting in YAP1 activation. The dephosphorylated YAP1 moved to the nucleus and increased the expression of the downstream oncogene CTGF, promoting hormone receptor-positive breast cancer progression. Our findings reveal the function of the LINC02754/E2F1/PP1A/YAP1 axis in hormone receptor-positive breast cancer and provide new insight into hormone receptor-positive breast cancer progression.

lncRNA HCG11 suppresses cell proliferation in hormone receptor-positive breast cancer via SRSF1/ß-catenin.

Hormone receptor positive (HR-positive) breast cancer (BC) is the most common subtype of breast cancer. Despite adjuvant endocrine therapy and chemotherapy-based treatment, the therapeutic response is often not satisfactory in HR-positive BC patients. Therefore, elucidating the mechanisms that regulate the progression of HR-positive BC is urgently required to identify new therapeutic targets. Previously, HLA Complex Group 11 (HCG11), located on the major histocompatibility complex (MHC) region, was found to be abnormally expressed in a variety of tumor cells. However, the role of HCG11 in HR-positive BC cells has not been explored to date. In the current study, we found that HCG11 is downregulated in HR-positive BC tissues and cell lines. Both in vitro and in vivo, HCG11 acts as a tumor suppressor in HR-positive BC cells. Furthermore, the mechanistic details unraveled that HCG11 recruits Serine/arginine-rich splicing factor 1 (SRSF1) to target ß-catenin mRNA for promoting the translation of ß-catenin. Our study emphasizes the potential of HCG11 as a novel intervention target for HR-positive BC treatment.

Regulation of SIRT1-TLR2/TLR4 pathway in cell communication from macrophages to hepatic stellate cells contribute to alleviates hepatic fibrosis by Luteoloside.

Regulating macrophage-hepatic stellate cells (HSCs) crosstalk through SIRT1-TLR2/TLR4 has contributed to the essence of new pharmacologic strategies to improve hepatic fibrosis. We investigated how Luteoloside (LUT), one of the flavonoid monomers isolated from Eclipta prostrata (L.) L., modulates macrophage-HSCs crosstalk during hepatic fibrosis. HSC-T6 or rat peritoneal macrophages were activated by TGF-ß or LPS/ATP, and then treated with LUT or Sirtinol (SIRT1 inhibitor) for 6 h. Further, HSCs were cultured with the conditioned medium from the LPS/ATP activated peritoneal macrophages. In HSC-T6 or peritoneal macrophages, LUT could decrease the expressions of α-SMA, Collagen-I, the ratio of TIMP-1/MMP-13. LUT also significantly increased the expressions of SIRT1 and ERRα. And LUT significantly suppressed the releases of pro-inflammatory cytokines, including NLRP3, ASC, caspase-1, IL-1ß, and regulated signaling TLR2/TLR4-MyD88 activation. The expressions of TLR2, TLR4, NLRP3, caspase-1, IL-1ß, α-SMA were increased and the expression of ERRα was decreased by Sirtinol, indicated that LUT might mediate SIRT1 to regulate TLR4 expression and further alleviate inflammation and fibrosis. LUT could regulate SIRT1-mediated TLR4 and ECM in HSCs was reduced, when HSCs were cultured with conditioned medium. Hence, LUT could decrease the expressions of fibrosis markers, reduce the releases of inflammatory cytokines in activated HSCs or macrophages. In conclusion, LUT might be a promising candidate that regulating SIRT1-TLR2/TLR4 signaling in macrophages interacting with HSCs during hepatic fibrosis.

CircSEMA4B inhibits the progression of breast cancer by encoding a novel protein SEMA4B-211aa and regulating AKT phosphorylation.

PI3K/AKT signaling pathway plays an important role in regulating the tumorigenesis, recurrence, and metastasis of breast cancer (BC). In this study, we discovered a circRNA with protein-coding potential, which we named circSEMA4B. CircSEMA4B could encode a novel protein, SEMA4B-211aa. Both circSEMA4B and SEMA4B-211aa were remarkably downregulated in BC tissues and cell lines. Low expression of circSEMA4B was positively associated with TNM stage, tumor size, lymph node metastasis, and distant metastasis of BC patients. The functional investigation showed that circSEMA4B and SEMA4B-211aa could significantly inhibit the proliferation and migration of BC in vivo and in vitro. Of note, SEMA4B-211aa inhibited the generation of PIP3 by binding to p85, thereby inhibiting the phosphorylation of AKT (Thr308). CircSEMA4B inhibited the phosphorylation of AKT (Ser473) through miR-330-3p/PDCD4 axis. Taken together, circSEMA4B is a novel negative regulator of PI3K/AKT signaling pathway, providing novel mechanistic insights into the underlying mechanisms of BC.

Aging induces severe SIV infection accompanied by an increase in follicular CD8+ T cells with overactive STAT3 signaling.

The number of elderly people living with HIV is increasing globally, and the condition of this population is relatively complicated due to the dual effects of aging and HIV infection. However, the impact of HIV infection combined with aging on the immune homeostasis of secondary lymphoid organs remains unclear. Here, we used the simian immunodeficiency virus mac239 (SIVmac239) strain to infect six young and six old Chinese rhesus macaques (ChRMs) and compared the infection characteristics of the two groups in the chronic stage through multiplex immunofluorescence staining of lymph nodes. The results showed that the SIV production and CD4/CD8 ratio inversion in old ChRMs were more severe than those in young ChRMs in both the peripheral blood and the lymph nodes, especially when a large number of CD8+ T cells infiltrated the follicles and germinal centers. STAT3 in these follicular CXCR5+CD8+ T cells was highly activated, with high expression of granzyme B, which might be caused by the severe inflammatory milieu in the follicles of old ChRMs. This study indicates that aging may be a cofactor involved in SIV-induced immune disorders in secondary lymphoid tissues, affecting the effective antiviral activity of highly enriched follicular CXCR5+CD8+ cells.

Circular RNA_0006014 promotes breast cancer progression through sponging miR-885-3p to regulate NTRK2 and PIK3/AKT pathway.

Breast cancer is the most common cancer in women worldwide. Numerous reports have demonstrated that circRNAs play an essential role in regulating the biological characteristics of breast cancer. However, there are currently no reports regarding the role of hsa_circ_0006014 in breast cancer. In this study, qRT-PCR was used to detect the expression of hsa_circ_0006014 and related genes. MTT, colony formation and Transwell assays were used to explore the potential biological functions of hsa_circ_0006014 in breast cancer cells. Western blotting was used to explore the potential molecular mechanisms involving hsa_circ_0006014. In vivo experiments were used to evaluate the influence of hsa_circ_0006014 on animal tumors. In this study, we found higher expression of hsa_circ_0006014 in breast tumor samples than in matched adjacent normal samples, and its expression was positively correlated with histological grade (grade iii). Phenotypically, hsa_circ_0006014 promoted the proliferation of MDA-MB-231 and MCF-7 breast cancer cells. Mechanistically, there were confirmed binding sites between hsa_circ_0006014 and miR-885-3p, and hsa_circ_0006014 promoted breast cancer cell proliferation partially by sponging miR-885-3p and influenced CDK2/CCNE1 and CDK4/6/CCND1. Furthermore, we found that hsa_circ_0006014 regulated NTRK2 through miR-885-3p to modulate the PIK3/AKT signaling pathway. Our results demonstrated that hsa_circ_0006014 promotes breast cancer progression by sponging miR-885-3p to regulate the NTRK2/PIK3CA/AKT axis.