Heat shock cognate protein 70 (HSC70) functions as a molecular chaperone and plays a crucial role in the regulation of intracellular protein modifications that are involved in tumor autophagy. However, its expression and mechanism in breast cancer have not been studied. The expression of HSC70 was verified by TCGA database and breast cancer patient tissue. We established breast cancer cell models and mouse models using knockdown HSC70. The expression and mechanism of HSC70 in breast cancer were investigated by immunocoprecipitation, protein stability, RNA stability, flow cytometry and biogenic analysis. In this study, we found that HSC70 is highly expressed in breast cancer and that high HSC70 expression positive correlated with poor prognosis using TCGA database and patient tissue verification. Subsequent experimental verification demonstrated that HSC70 drives cell cycle progression and promotes proliferation in breast cancer. Further studies revealed that HSC70 significantly promoted the phosphorylation of PI3K, AKT and mTOR but did not affect the total protein levels. Additionally, the AKT agonist SC79 reversed the effects of HSC70 knockdown on proliferation and cell cycle progression of breast cancer cells. Mechanistically, HSC70 reduces the protein stability of PTEN but does not change its mRNA level, suggesting that HSC70 binds to PTEN and promotes its autophagic degradation. More importantly, in vivo experiments demonstrated that HSC70 knockdown results in slower tumor proliferation and growth. In conclusion, HSC70 can bind to PTEN and promote its autophagic degradation, thereby activating the PI3K/AKT/mTOR signaling pathway to promote cell cycle progression and proliferation in breast cancer. These findings suggest that HSC70 may be a feasible target for breast cancer treatment.

This research details the synthesis of biogenic silver nanoparticles utilizing Origanum majorana as a supporting material. The leaves of the plant served as a natural reducing agent and a proficient stabilizer for the generated silver nanoparticles (Ag NPs). The formulated NPs were analyzed through the analysis of their physicochemical properties utilizing UV-Vis, FT-IR, and FE-SEM techniques. The investigation of the antioxidant characteristics of the Ag NPs was followed using the DPPH assay. The results revealed that the silver nanoparticles exhibited considerable antioxidant activity, as evidenced by the IC50 value. Recent findings suggest that the effectiveness of nanoparticles in treating human breast cancer can be linked to their antioxidant characteristics. An evaluation was followed on the ability of biologically synthesized Ag NPs to combat breast cancer in various cell lines. The silver nanoparticles exhibited significant anti-breast cancer properties, successfully eradicating the MCF10 cancer cell line in a manner that was influenced by both time and concentration, as assessed through the MTT assay. Ag NPs facilitate cell apoptosis, a process linked to elevated levels of pro-apoptotic markers, including Bax and cleaved caspase-8, while concurrently reducing the concentration of the anti-apoptotic marker Bcl-2. Furthermore, silver nanoparticles exhibit a decrease in colony formation in comparison to the respective control group. The examination of molecular pathways in cells exposed to Ag NPs revealed a significant elevation in p53 expression, coupled with a decrease in both total and phosphorylated levels of Signal Transducer and Activator of Transcription 3 (STAT3) in the studied cell lines. This suggests that p53 and STAT3 play essential roles in the biological responses triggered by the extract in human breast cancer cells.

Secondary central nervous system (SCNS) involvement is an infrequent but universally fatal event in diffused large B‐cell lymphoma. The occurrence rate of SCNS involvement is approximately 5% but comes with a poor prognosis ever after. However, existing risk models to predict the incidence and prognosis of these patients with SCNS involvement lack both efficiency and accuracy. Controversy has also been reported regarding which risk factor may best identify the population with a high CNS relapse rate. In this study, we retrospectively analyzed 831 patients with diffused large B‐cell lymphoma, diagnosed between March 2008 and June 2018 in Tianjin Medical University Cancer Institute and Hospital, Beijing Cancer Hospital, and Cancer Hospital of The University of Chinese Academy of Science. Risk factors and nomogram were identified and established based on Fine and Gray's competing risk analysis. Among these patients, 55 (6.6%) of them eventually developed SCNS involvement. The 1‐ and 2‐year incidence for SCNS involvement were 3.9% and 4.7%, respectively. The median time from de novo diagnosis to CNS relapse was 8 months, and the median overall survival of these patients was 28 months. Considering the competing mortality before SCNS involvement, Fine and Gray's competing risk model was performed to analyze the characteristics related to SCNS involvement, and identified risk factors as the multiple extranodal involvements, elevated LDH and AMC level, and the involvement of breast, adrenal gland/kidney, pulmonary and bone. Corresponding factors were integrated into the competing nomogram for SCNS involvement ( c ‐index = 0.778). In conclusion, we present the first predictive nomogram to evaluate the risk to develop SCNS involvement in de novo DLBCL patients, which may help in both prognostic evaluation and clinical decision for this subgroup.

Thyroid cancer (TC) is the most common endocrine tumor, amongst which anaplastic thyroid carcinoma (ATC) is the most deadly. Aurora-A usually functions as oncogenes, and its inhibitor Alisertib exerts a powerful antitumor effect in various tumors. However, the mechanism of Aurora-A in regulating TC cell energy supply remains unclear. In the present study, we demonstrated the antitumor effect of Alisertib and an association between high Aurora-A expression and shorter survival. Multi-omics data and in vitro validation data suggested that Aurora-A induced PFKFB3-mediated glycolysis to increase ATP supply, which significantly upregulated the phosphorylation of ERK and AKT. Furthermore, the combination of Alisertib and Sorafenib had a synergistic effect, further confirmed in xenograft models and in vitro. Collectively, our study provides compelling evidence of the prognostic value of Aurora-A expression and suggests that Aurora-A upregulates PFKFB3-mediated glycolysis to enhance ATP supply and promote TC progression. Combining Alisertib with Sorafenib has huge prospects for application in treating advanced thyroid carcinoma.

目的:探索免疫化疗时代基于多种肿瘤浸润免疫细胞建立弥漫性大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)预后模型并进行初步评价.方法:采用ImmuCellAI算法计算DLBCL肿瘤微环境中24种免疫细胞的丰度,通过(least absolute shrinkage and selection operator,LASSO)回归和Cox回归筛选预测变量并构建基于免疫细胞的风险评分模型(immune cells-based risk scores,IRS)模型.同时将IRS模型与患者临床因素相结合,构建IRSC模型.采用Kaplan-Meier法和ROC曲线评估该模型,采用列线图计算不同时间点的生存率.结果:IRS模型高风险组患者总生存时间(OS)明显低于低风险组[P=1e-15,HR=0.298(0.2176～0.4082)],基于患者1、3、5年生存情况的ROC曲线AUC值分别为0.728、0.711和0.615,且该模型风险评分与免疫检查点抑制剂(immune checkpoint inhibitors,ICPIs)疗效呈负相关.IRSC模型较IRS模型预测效果更佳:高风险组预后显著差于低风险组P<2e-16,HR=0.170(0.1143～0.253)],基于患者1、3、5年生存情况的ROC曲线AUC值分别为0.797、0.809和0.792.结论:IRS模型能很好的预测DLBCL患者的预后及对ICPIs的疗效,而IRSC模型预后价值更高.

Objective: The oncoprotein, hepatitis B X-interacting protein (HBXIP), has been reported to play an important role in human malignancies. However, its functions in non-small cell lung cancer (NSCLC) are poorly understood. The goal of the present study was to identify the role of HBXIP in the regulation of NSCLC development. Methods: The level of HBXIP expression in NSCLC tissue was assessed by immunohistochemical and Western blot analyses, and its relationships with clinicopathological features and outcomes were statistically evaluated. The effects of HBXIP on NSCLC cell progression were assessed through cell viability, colony formation, and flow cytometry analyses in vitro. The mechanism by which HBXIP regulated the MAPK pathway was studied by Western blot, immunofluorescence, and immunoprecipitation assays. In addition, in vivo experiments were performed to evaluate the progression of NSCLC and ERK signaling pathway activation after HBXIP knockdown. Results: HBXIP was overexpressed in human NSCLC and was correlated with the invasiveness of NSCLC. The high expression of HBXIP in NSCLC was significantly correlated with gender (P = 0.033), N stage (P = 0.002), and tumor-node-metastasis stage (P = 0.008). In vitro experiments using an NSCLC cell line revealed that HBXIP knockdown resulted in the suppression of cell proliferation and colony formation, which was consistent with the enhanced cell cycle arrest in G1 phase. The results of a mechanistic investigation suggested that binding of HBXIP to MEK1 protein promoted MAPK/ERK signaling pathway activation in NSCLC by preventing the proteasome-mediated degradation of MEK1. In addition, the results obtained using in vivo subcutaneous tumor xenografts confirmed that HBXIP deficiency decreased MEK1 protein levels and NSCLC tumor growth. Conclusions: Taken together, our results showed that the HBXIP-MEK interaction promoted oncogenesis via the MAPK/ERK pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.

Purpose: To investigate the prognostic significance of programmed cell death ligand-1 (PD-L1) and phosphorylated ERK (p-ERK) and their interactions in T-cell lymphoma (TCL). Methods: The mRNA levels of PD-L1 and ERK in TCL samples were analyzed. Formalin-fixed paraffin-embedded tissues from 69 TCL patients were collected to detect the expression of PD-L1 and p-ERK by multiplexed immunofluorescence staining. The total PD-L1 and p-ERK was measured by western blotting, and membrane PD-L1 was determined using flow cytometry. Results: PD-L1 and ERK mRNA levels were significantly upregulated in TCL. The expression rates of PD-L1 and p-ERK were 52.2% and 27.5%, respectively. PD-L1 expression correlated with stage (R=0.304, P=0.011) and IPI score (R=0.313, P=0.009), and p-ERK expression correlated with stage (R=0.330, P=0.006) and IPI score (R=0.376, P=0.002). PD-L1 expression positively correlated with p-ERK expression (R=0.355, P=0.003). Patients with co-expression of PD-L1 and p-ERK had the worst overall survival (P=0.007). In three TCL cell lines with PD-L1 expression, we demonstrated that the expression of p-ERK was upregulated after stimulation with PD-1, suggesting that ERK signaling was activated. Conclusions: The PD-1/PD-L1 axis activates intracellular ERK signaling in tumor cells and that PD-L1, p-ERK or their combination are potential biomarkers for predicting the prognosis in TCL patients.

Background: Patients with metastatic radioiodine-refractory papillary thyroid carcinoma (PTC) have limited treatment options and a poor prognosis. There is an urgent need to develop new drugs targeting PTC for clinical application. Apatinib, a novel small-molecule tyrosine kinase inhibitor (TKI), is highly selective for vascular endothelial growth factor receptor-2 (VEGFR2) and exhibits antitumor effects in a variety of solid tumors. Although apatinib has been shown to be safe and efficacious in radioiodine-refractory differentiated thyroid cancer, the mechanism underlying its antitumor effect is unclear. In this report, we explored the effects of apatinib on PTC in vitro and in vivo. Methods: VEGFR2 expression levels were evaluated by immunohistochemistry (IHC), qPCR, and western blotting (WB). The effects of apatinib on cell viability, colony formation, and migration in the Transwell assay were assessed in vitro, and its effect on tumor growth rate was assessed in vivo. In addition, the levels of proteins in signaling pathways were determined by WB. Finally, the autophagy level was assessed by WB, immunofluorescence (IF), and transmission electron microscopy. Results: We found that high VEGFR2 expression is associated with tumor size, T stage, and lymph node metastasis in patients with PTC and that apatinib inhibits PTC cell growth, promotes apoptosis, and induces cell cycle arrest through the PI3K/Akt/mTOR signaling pathway. Moreover, apatinib induces autophagy, and pharmacological inhibition of autophagy or small interfering RNA (siRNA)-mediated targeting of autophagy-associated gene 5 (ATG5) can further increase PTC cell apoptosis. Conclusion: Our data suggest that apatinib can induce apoptosis and autophagy via the PI3K/Akt/mTOR signaling pathway for the treatment of PTC and that autophagy is a potential novel target for future therapy in resistant PTC.

Objectives To study the clinical characteristics,diagnosis,treatment and prognosis of cancer metastases to the thyroid gland.Methods At Tianjin Medical University Cancer Hospital,from 1980 to 2016 30 patients were identified with a metastatic malignant tumor of the thyroid gland.Results Primary tumor sites were in the esophagus (26.7％),lung (16.7％),and kidney (13.3％).The median age at discovery of thyroid metastasis was 56 years old.The time lapse ranged from 0 to 108 months.There were 18 patients with metachronous metastasis with median survival of 36 months,12 patients were with synchronous metastasis,and the median survival was 8 months (P ＜ 0.01).20 patients were treated with thyroid surgery,and of which 15 patients were given post-op radiotherapy and chemotherapy.Patients who underwent thyroid resection had a median survival of 15 months,while that was 8 months in those without thyoid surgery (P ＜ 0.01).Conclusions Metastases to the thyroid gland is a rare clinical phenomenon,the prognosis of patients is mainly related to the biological behavior of primary tumors,but surgical resection and combined treatment can increase the survival rate.

Anaplastic thyroid cancer (ATC), usually derived from well-differentiated thyroid cancers is one of the most lethal human endocrine malignancies. In the present study, we report that in human ATC tumor tissue samples exist undetectable Notch1 and the active Notch1 intracellular domain could not be detected in ATC-CAL-62 cells. Interesting, suberoyl bis-hydroxamic acid (SBHA) administration could induce Notch1 intracellular domain levels in a dose-dependent manner, coupled with the increase of p53 and p21. Furthermore, ectopic expression of Notch1 or deletion of p53 with small-interfering RNA was able to abolish the effects of SBHA to elevation of Notch1 and p53 in ATC cells. As a result, SBHA treatment efficiently induced ATC cell apoptosis. These results indicate that SBHA may play antitumor functions via regulating Notch1/p53 signals, and highlight that SBHA could have clinical potential to benefit the therapy of ATC patients.

BACKGROUND:miR-24 is one of the most significantly up-regulated miRNAs in tongue squamous cell carcinoma (TSCC). PTEN plays an important role in the cell survival and cisplatin resistance of multiple cancers. However, it remains unclear what role does function and mechanism of miR-24 and PTEN play in TSCC. METHODOLOGY/PRINCIPAL FINDINGS:In this study, miR-24 expression was detected in 79 cases of paired TSCC and normal tissues and 8 TSCC cell lines by real-time PCR and the relevance between miR-24 expression and clinicopathological parameters were analyzed. Further, we demonstrated that deregulation of miR-24 was found to associate with high grade and late stage tumor. In addition, miR-24 induces cell survival and cisplatin resistance through targeting 3'-UTR region of the PTEN, which leads to downregulation of PTEN protein and activation of Akt pro-survival pathway. CONCLUSIONS/SIGNIFICANCE:In conclusion, our results demonstrated that deregulation of miR-24 is a recurrent event in human tongue squamous cell carcinoma and associate with tumor progression and that miR-24 induces cell survival and cisplatin resistance primarily through targeting PTEN/Akt pathway. Thus, miR-24 could be important targets for intervention of this malignancy.

This study aims to observe the expression of HSV1-tk in mouse bone marrow mesenchymal stem cells (BMSCs-EGFP-tk) and detect the inhibition and killing effects of BMSCs as mediator of HSV1-tk/GCV on A549 cells in vitro, which can provide the experimental basis for gene therapy of lung cancer. We constructed the recombinant plasmid Vector pDON-AI-2 Neo-HSV1-tk-IRES2-EGFP with genetic engineering methods. Then we obtained the virus-like particles with infection ability after packaging the virus. The recombinant plasmid was transfected into mouse bone marrow mesenchymal stem cells in vitro. The expressions of EGFP in cells were observed by fluorescence microscopy and HSV1-tk gene was detected with RT-PCR. At last, the A549 cells and BMSCs-EGFP-tk cells were co-cultured with in vitro contact method, and the effect of BMSCs-EGFP-tk/GCV system was determined by MTT. Results indicated that the biological characteristics of BMSCs-EGFP-tk were consistent with those of BMSCs and fluorescent light expression and HSV1-tk gene expression can persist at least 15 days. The A549 cells and BMSCs-EGFP-tk cells were co-cultured and BMSCs-EGFP-tk:A549 = 2:1, adding 1 μg/mL GCV, the theory mortality is 58.44%, but actually the mortality is 90%. There is almost no difference between BMSCs-EGFP-tk and BMSCs cells in biological characteristics. The growth of A549 cells have an obviously inhibition and the bystander effect is outstanding in vitro after co-culture and this experiment lays solid foundation for the future research.