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Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP+ CAFs and FAP- CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP+ CAFs and FAP- CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP+ CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP- CAFs. Importantly, FAP+ CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP+ CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.
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BACKGROUND: WeChat (Tencent) is one of the most important information sources for Chinese people. Relevantly, various health-related data are constantly transmitted among WeChat users. WeChat public accounts (WPAs) for health are rapidly emerging. Health-related WeChat public accounts have a significant impact on public health. Because of the rise in web-based health-seeking behavior, the general public has grown accustomed to obtaining cancer information from WPAs. Although WPAs make it easy for people to obtain health information, the quality of the information is questionable. OBJECTIVE: This study aims to assess the quality and suitability of cancer-related WeChat public accounts (CWPAs). METHODS: The survey was conducted from February 1 to 28, 2023. Based on the WPA monthly list provided by Qingbo Big Data, 28 CWPAs in the WeChat communication index were selected as the survey sample. Quality assessment of the included CWPAs was performed using the HONcode instrument. Furthermore, suitability was measured by using the Suitability Assessment of Materials. A total of 2 researchers conducted the evaluations independently. RESULTS: Of the 28 CWPAs, 12 (43%) were academic and 16 (57%) were commercial. No statistical difference was found regarding the HONcode scores between the 2 groups (P=.96). The quality of the academic and commercial CWPAs evaluated using the HONcode instrument demonstrated mean scores of 5.58 (SD 2.02) and 5.63 (SD 2.16), respectively, corresponding to a moderate class. All CWPAs' compliance with the HONcode principles was unsatisfactory. A statistically significant difference between the 2 groups was observed in the Suitability Assessment of Materials scores (P=.04). The commercial WPAs reached an overall 55.1% (SD 5.5%) score versus the 50.2% (SD 6.4%) score reached by academic WPAs. The suitability of academic and commercial CWPAs was considered adequate. CONCLUSIONS: This study revealed that CWPAs are not sufficiently credible. WPA owners must endeavor to create reliable health websites using approved tools such as the HONcode criteria. However, it is necessary to educate the public about the evaluation tools of health websites to assess their credibility before using the provided content. In addition, improving readability will allow the public to read and understand the content.
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Cells are a fundamental unit of biological organization, and identifying them in imaging data - cell segmentation - is a critical task for various cellular imaging experiments. While deep learning methods have led to substantial progress on this problem, most models in use are specialist models that work well for specific domains. Methods that have learned the general notion of "what is a cell" and can identify them across different domains of cellular imaging data have proven elusive. In this work, we present CellSAM, a foundation model for cell segmentation that generalizes across diverse cellular imaging data. CellSAM builds on top of the Segment Anything Model (SAM) by developing a prompt engineering approach for mask generation. We train an object detector, CellFinder, to automatically detect cells and prompt SAM to generate segmentations. We show that this approach allows a single model to achieve human-level performance for segmenting images of mammalian cells (in tissues and cell culture), yeast, and bacteria collected across various imaging modalities. We show that CellSAM has strong zero-shot performance and can be improved with a few examples via few-shot learning. We also show that CellSAM can unify bioimaging analysis workflows such as spatial transcriptomics and cell tracking. A deployed version of CellSAM is available at https://cellsam.deepcell.org/.
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OBJECTIVES: Radiation therapy in the treatment of brain tumors also leads to the occurrence of radiation brain injury (RBI). Anlotinib is a small-molecule inhibitor of multi-receptor tyrosine kinase with high selectivity for vascular endothelial growth factor receptor-2. In this study, we constructed a rat model of RBI and investigated the effect of anlotinib on RBI and its mechanism of action through drug intervention during the acute phase of RBI. METHODS: Six-week-old male (Sprague-Dawley) rats were used to construct an animal model of RBI to evaluate the protective effect of anlotinib on acute RBI by histopathological staining, brain edema determination, blood-brain barrier integrity evaluation and quick real time-polymerase chain reaction , ELISA detection of inflammation-related indexes, and western-blot detection of related gene protein expression. RESULTS: Anlotinib reduced the degree of edema in the hippocampal region of rats, improved the pathological morphology of neural cells and vascular endothelial cells, and decreased blood-brain barrier permeability. Anlotinib reduced glial fibrillary acidic protein protein expression in the hippocampal region of rat brain tissue and inhibited astrocyte activation. It inhibited the release of inflammatory factors (interleukin [IL]-6, IL-8 and vascular endothelial growth factor) and down-regulated the expression of janus kinase-2/signal transducer and activator of transcription-3 (JAK2/STAT3) signaling pathway-related proteins. CONCLUSION: This study found that anlotinib has a protective effect against RBI in rats and anlotinib may be a new candidate for the treatment of RBI.
Subject(s)
Brain Injuries , Endothelial Cells , Rats , Male , Animals , Rats, Sprague-Dawley , Endothelial Cells/metabolism , Vascular Endothelial Growth Factor A/metabolism , Brain/metabolism , Brain Injuries/drug therapy , Brain Injuries/etiology , Brain Injuries/metabolism , Interleukin-6/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
BACKGROUND: The aberrant expression of serpin family E member 1 (SERPINE1) is associated with carcinogenesis. This study assessed the alteration of SERPINE1 expression for an association with gastric adenocarcinoma prognosis. METHODS: The Cancer Genome Atlas (TCGA) dataset was applied to investigate the impact of SERPINE1 expression on the survival of patients afflicted with gastric cancer. Subsequently, 136 samples from the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University were subjected to qRT-PCR and Western blot to validate the expression level of SERPINE1 between tumor and adjacent normal tissues. The correlation between the expression of SERPINE1 with the clinicopathological features in TCGA patients was analyzed using Wilcoxon signed-rank and logistic regression tests. The potential molecular mechanism associated with SERPINE1 expression in gastric cancer were confirmed using gene set enrichment analysis (GSEA). RESULTS: The TCGA data showed that SERPINE1 was overexpressed in tumor tissues compared to normal mucosae and associated with the tumor T stage and pathological grade. SERPINE1 overexpression was associated with the poor overall survival (OS) of patients. The findings were confirmed with 136 patients, that is, SERPINE1 expression was associated with poor OS (hazard ratio (HR): 1.82; 95% confidence interval (CI): 0.84-1.83; p = 0.012)) as an independent predictor (HR: 2.11, 95% CI: 0.81-2.34; p = 0.009). The resulting data were further processed by GSEA showed that SERPINE1 overexpression was associated with the activation of EPITHELIAL_MESENCHYMAL_TRANSITION, TNFA_SIGNALING_VIA_NFKB, INFLAMMATORY_RESPONSE, ANGIOGENESIS, and HYPOXIA. CONCLUSIONS: SERPINE1 overexpression is associated with a poor gastric cancer prognosis.
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Oesophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumours with high morbidity and mortality. Although surgery, radiotherapy and chemotherapy are common treatment options available for oesophageal cancer, the 5-year survival rate remains low after treatment. On the one hand, many oesophageal cancers are are discovered at an advanced stage and, on the other hand, treatment resistance is a major obstacle to treating locally advanced ESCC. Cancer-associated fibroblasts (CAFs), the main type of stromal cell in the tumour microenvironment, enhance tumour progression and treatment resistance and have emerged as a major focus of study on targeted therapy of oesophageal cancer.With the aim of providing potential, prospective targets for improving therapeutic efficacy, this review summarises the origin and activation of CAFs and their specific role in regulating tumour progression and treatment resistance in ESCC. We also emphasize the clinical potential and emerging trends of ESCC CAFs-targeted treatments.
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AIMS: This study aimed to investigate the correlation between gene expression and immune cell infiltration and the overall survival rate in tumor tissues, which may contribute to the therapy and prognosis of small cell lung cancer (SCLC) patients. BACKGROUND: SCLC is the most aggressive type of lung neoplasm. There is no proper marker for the treatment and prediction of prognosis in SCLC. OBJECTIVES: Three gene expression profiles of SCLC patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified between normal lung samples and SCLC lung samples. METHODS: Functional enrichment analysis of all DEGs was performed to explore the linkage among DEGs, the tumor immune microenvironment, and SCLC tumorigenesis. The common genes among the 3 groups in the Venn diagram and hub genes in protein-protein interaction (PPI) networks were considered potential key genes in SCLC patients. The TIMER (tumor immune estimation resource) database calculation and Kaplan-Meier survival curves were used to investigate the association between potential key genes and immune infiltrate prognosis of SCLC patients. RESULTS: A total of 750 (top 250 from each study) differentially expressed genes (DEGs) were identified. CLDN18 and BRIP1 were significantly related to immune infiltration in the tumor microenvironment. SHCBP1 and KIF23 were related mostly to prognosis in SCLC patients. CONCLUSION: The present study may provide some potential biomarkers for the therapy and prognosis of SCLC.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/diagnosis , Small Cell Lung Carcinoma/genetics , Gene Expression Profiling/methods , Prognosis , Gene Regulatory Networks , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Computational Biology/methods , Tumor Microenvironment/genetics , Claudins/genetics , Claudins/metabolism , Shc Signaling Adaptor Proteins/genetics , Shc Signaling Adaptor Proteins/metabolismABSTRACT
Background: Acute myeloid leukemia (AML) is a type of heterogenous malignant hematological disorder. Recently developed immunotherapies such as chimeric antigen receptor T cell (CAR-T) do not demonstrated promising therapeutic results due to the off-target effect. The Dendritic cell-cytotoxic T lymphocyte adoptive immunotherapy (DC-CTL) is one of the recently developed immunotherapies. One of the reasons that DC-CTL does not work well in AML is the lack of antigens with high binding affinity, high antigen presentation potency, and the specificity to AML cells. Methods: DAC was used to treat AML cells to find overexpressed CTAs upon DAC treatment. The overexpression was confirmed at both mRNA and protein level by realtime PCR and western blotting. Peptides was designed by using the NetMHCpan database and EPIP based on the out-screened protein sequences. The peptides were then used to pulse DC-CTL coculture in vitro and tested the cytotoxicity of CTLs in vitro and their cancer inhibition potency in vivo. Results: Two cancer testis antigen (CTA) proteins, MAGEA1 and hTERT, was up-regulated in DAC treated AML cells. DC cells pulsed by the antigen peptides designed based on the sequence of these two proteins demonstrated increased potency to stimulate CTL cells in terms of cytokines secretion. These cytokines included IFN-γ, IL-6, and TNF-α. Moreover, enhanced in vitro cytotoxicity was found in CTL cells treated with peptide pulsed DC cells. AML progress was inhibited by CTA peptides pulsed DC-CTL in a mouse AML model. Conclusions: MAGEA1 and hTERT could possibly serve as specific tumor antigens upon DAC treatment, providing potential targets for the development of immunotherapies for AML in the future.
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The Structural Classification of Proteins-extended (SCOPe, https://scop.berkeley.edu) knowledgebase aims to provide an accurate, detailed, and comprehensive description of the structural and evolutionary relationships amongst the majority of proteins of known structure, along with resources for analyzing the protein structures and their sequences. Structures from the PDB are divided into domains and classified using a combination of manual curation and highly precise automated methods. In the current release of SCOPe, 2.08, we have developed search and display tools for analysis of genetic variants we mapped to structures classified in SCOPe. In order to improve the utility of SCOPe to automated methods such as deep learning classifiers that rely on multiple alignment of sequences of homologous proteins, we have introduced new machine-parseable annotations that indicate aberrant structures as well as domains that are distinguished by a smaller repeat unit. We also classified structures from 74 of the largest Pfam families not previously classified in SCOPe, and we improved our algorithm to remove N- and C-terminal cloning, expression and purification sequences from SCOPe domains. SCOPe 2.08-stable classifies 106 976 PDB entries (about 60% of PDB entries).
Subject(s)
Computational Biology , Databases, Protein , Proteins/classification , Algorithms , Databases, Chemical , Gene Expression Regulation/genetics , Machine Learning , Proteins/geneticsABSTRACT
OBJECTIVES: CAR-based immunotherapies represent a potentially curative strategy for hematological malignancies. However, there are a number of intracellular antigens that CAR-T cells are unable to target. Furthermore, CAR-T cells often suffer from insufficient expansion in part because of the immunosuppressive mechanisms. Lenalidomide (LEN), an immunomodulatory drug, can potentiate T cell functionality. Therefore, it is necessary to investigate combinatorial therapy using CAR-T cells and LEN for enhancing function. METHODS: We redirected T cells to express HLA-A*2402+-restricted-CAR capable of recognizing WT1235-243 peptide and adoptively transferred them into tumor-bearing mice to test their anti-tumor activity. Then we assessed the combinatorial efficacy using CAR-T cells and LEN in vitro and in vivo. RESULTS: Using an anti-WT1 CAR-T, we showed that LEN enhances CAR-T cell function in a concentration-dependent manner. Our data demonstrated that LEN improved the anti-tumor activity of CAR-T cells in vivo by increasing the infiltration of tumors with CD3+ and CD8+ T cells. Proteomics studies supported LEN enhanced the efficacy of CAR-T cells, including T-cell activation, mitochondrial activity and immune synapse formation. CONCLUSION: These results demonstrate that lenalidomide potentiates WT1 CAR-T activity and paves the way to evaluate the combination of LEN with CAR-T for a planned clinical trial.
Subject(s)
Hematologic Neoplasms/therapy , Immunologic Factors/therapeutic use , Immunotherapy, Adoptive/methods , Lenalidomide/therapeutic use , WT1 Proteins/immunology , Animals , Hematologic Neoplasms/immunology , Humans , K562 Cells , Lymphocyte Activation/drug effects , MiceABSTRACT
BACKGROUND: Sarcopenia has been associated with treatment-related toxicities and poor survival in cancer patients. Our aim was to investigate the prevalence of sarcopenia in postoperative recurrent esophageal squamous cell carcinoma (ESCC) patients receiving chemoradiotherapy (CRT) and evaluate associations with treatment-related toxicity and prognosis. METHODS: One hundred and eighty-four patients with postoperative locoregional recurrent ESCC receiving CRT between January 2014 and December 2016 were included. The skeletal muscle area (SMA) was measured at the third lumbar vertebra level. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) less than 47.24/cm2/m2 for men and 36.92/cm2/m2 for women. Association of sarcopenia with overall survival (OS) was analyzed using univariate and multivariate cox regression models. RESULTS: Sarcopenia was observed in 94 of 184 (51.1%) patients. Sarcopenic patients had significantly higher rates of grade 3-4 toxicities compared to those without sarcopenia (36.2% vs 21.1%, p = 0.034). The survival rate at 12 and 24 months was 36.2% and 3.2% in the sarcopenic patients and 57.8% and 17.8% in the non-sarcopenic patients (p < 0.001). Multivariate cox regression analysis showed that sarcopenia was significantly associated with decreased OS (HR = 1.729, 95% CI 1.231-2.428, p = 0.002). CONCLUSIONS: Sarcopenia is an independent indicator of poor survival in postoperative locoregional recurrent ESCC patients treated with CRT. Early nutritional interventions before treatment may improve the prognosis.
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BACKGROUND: This retrospective study was to assess and compare the toxicity and efficacy of concurrent chemoradiotherapy (CCRT) with S-1 or docetaxel and cisplatin in patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC who received CCRT with S-1 (70 mg/m2 twice daily on days 1-14, every 3 weeks for 2 cycles, S-1 group) or docetaxel (25 mg/m2) and cisplatin (25 mg/m2) on day 1 weekly (DP group) between 2014 and 2016 were retrospectively analyzed. Radiotherapy was delivered in 1.8-2.0 Gy per fraction to a total dose of 50-60 Gy. Treatment-related toxicities (Common Terminology Criteria for Adverse Events version 4.0), response rate, and survival outcomes were compared between groups. RESULTS: A total of 175 patients were included in this study (72 in the S-1 group and 103 in the DP group). Baseline characteristics were well balanced between the two groups. The incidence of grade 3-4 adverse events were significantly lower in the S-1 group than that of the DP group (22.2% vs. 45.6%, p = 0.002). In the DP group, elderly patients (> 60 years) had a significantly higher rate of grade 3-4 adverse events than younger patients (58.1% vs. 31.3%, p = 0.01). The objective overall response rate (complete response + partial response) was 68.1% in the S-1 group, and 73.8% the DP group (p = 0.497). The 3-year overall survival was 34.7% in the S-1 group, and 38.8% in the DP group (p = 0.422). The 3-year progression free survival in the DP group was higher than that in the S-1 group but without significant difference (33.0% vs. 25.0%, p = 0.275). CONCLUSION: CCRT with S-1 is not inferior to CCRT with docetaxel and cisplatin and is better tolerated in in elderly patients with locally advanced ESCC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy , Esophageal Neoplasms/therapy , Esophageal Squamous Cell Carcinoma/therapy , Aged , Chemoradiotherapy/adverse effects , Chemoradiotherapy/mortality , Cisplatin/administration & dosage , Cisplatin/adverse effects , Docetaxel/administration & dosage , Docetaxel/adverse effects , Dose Fractionation, Radiation , Drug Combinations , Drug-Related Side Effects and Adverse Reactions/diagnosis , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/mortality , Esophageal Squamous Cell Carcinoma/pathology , Female , Humans , Male , Middle Aged , Oxonic Acid/administration & dosage , Oxonic Acid/adverse effects , Retrospective Studies , Survival Rate , Tegafur/administration & dosage , Tegafur/adverse effects , Treatment OutcomeABSTRACT
Background: Acute myeloid leukemia (AML) is a malignant hematological disease with high refractory rate. Immune escape of AML cells is one of the underlying mechanisms mediating the relapse of the cancers. Various immunotherapies based on the 'patients' immune response to tumor cells have been developed to targeting the immune escape of AML cells, which lead to the minimal residual disease (MRD) after treatment. But the efficacy of those treatments or the combination of treatments remains unsatisfactory. Methods: A Toll-like receptor (TLR)-7 agonist SZU-106 was chemically synthesized. SZU-106 was conjugated to Decitabine (DAC), a demethylation agent, treated AML cells to construct tumor vaccine. The potency of the newly constructed AML cell vaccine, SZU-106-DAC-AML was tested in vitro and in vivo for the expression of tumor antigens and the activation level of immune responses. Results: Compared to the well characterized TLR7 agonist R848, SZU-106 has a comparable potency to activate TLR7 signaling pathway. SZU-106-DAC-AML, constructed by conjugating SZU-106 to DAC treated tumor cells, exhibited increased expression of tumor antigens, and enhanced the activation of DC cells and T cells in vitro and in vivo. The result of xenograft tumor model showed that SZU-106-DAC-AML tumor vaccine greatly inhibited tumor growth and prolonged animal survival. Conclusions: Conjugation of TLR7 agonist combined with up-regulation of tumor antigen expression improved the effectiveness of whole-cell tumor vaccine in AML.
Subject(s)
Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Decitabine/pharmacology , Leukemia, Myeloid, Acute/therapy , Toll-Like Receptor 7/agonists , Animals , Antigens, Neoplasm/genetics , Cancer Vaccines/administration & dosage , Cancer Vaccines/genetics , Cell Line, Tumor , DNA Methylation/drug effects , DNA Methylation/immunology , Dendritic Cells , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/pathology , Mice , Primary Cell Culture , T-Lymphocytes , Toll-Like Receptor 7/immunology , Vaccine Potency , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Seeking health information on the internet is a popular trend. Xigua Video, a short video platform in China, ranks among the most accessed websites in the country and hosts an increasing number of videos with medical information. However, the nature of these videos is frequently unscientific, misleading, or even harmful. OBJECTIVE: Little is known about Xigua Video as a source of information on breast cancer. Thus, the study aimed to investigate the contents, quality, and reliability of breast cancer-related content on Xigua Video. METHODS: On February 4, 2020, a Xigua Video search was performed using the keyword "breast cancer." Videos were categorized by 2 doctors based on whether the video content provided useful or misleading information. Furthermore, the reliability and quality of the videos were assessed using the 5-point DISCERN tool and 5-point global quality score criteria. RESULTS: Out of the 170 videos selected for the study, 64 (37.6%) were classified as useful, whereas 106 (62.4%) provided misleading information. A total of 41.8% videos (71/170) were generated by individuals compared to 19.4% videos (33/170) contributed by health care professionals. The topics mainly covered etiology, anatomy, symptoms, preventions, treatments, and prognosis. The top topic was "treatments" (119/170, 70%). The reliability scores and global quality scores of the videos in the useful information group were high (P<.001). No differences were observed between the 2 groups in terms of video length, duration in months, and comments. The number of total views was higher for the misleading information group (819,478.5 vs 647,940) but did not reach a level of statistical significance (P=.112). The uploading sources of the videos were mainly health care professionals, health information websites, medical advertisements, and individuals. Statistical differences were found between the uploading source groups in terms of reliability scores and global quality scores (P<.001). In terms of total views, video length, duration, and comments, no statistical differences were indicated among the said groups. However, a statistical difference was noted between the useful and misleading information video groups with respect to the uploading sources (P<.001). CONCLUSIONS: A large number of Xigua videos pertaining to breast cancer contain misleading information. There is a need for accurate health information to be provided on Xigua Video and other social media; health care professionals should address this challenge.
Subject(s)
Breast Neoplasms/diagnosis , Social Media/standards , Videoconferencing/standards , China , Female , Humans , Reproducibility of ResultsABSTRACT
BACKGROUND Circular RNA UBE2D2 (circ_UBE2D2) has been found to be involved in the progression of breast cancer. Exosomes are critical mediators of intercellular communication, however, the function of exosomal circ_UBE2D2 in breast cancer remains vague. MATERIAL AND METHODS Cell viability was measured by Cell Counting Kit-8 assay. Western blot was used to detect the levels of estrogen receptor alpha (ERalpha), E-cadherin, vimentin, CD9, and CD63. Migrated and invaded cells were examined using Transwell assay. Circ_UBE2D2 and microRNA (miR)-200a-3p levels were detected using quantitative real-time polymerase chain reaction. Exosomes were isolated by ultracentrifugation method. The interaction between circ_UBE2D2 and miR-200a-3p was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Murine xenograft model was established to conduct in vivo experiments. RESULTS We found that circ_UBE2D2 was upregulated in breast cancer tamoxifen-resistant tissues and cell lines, and circ_UBE2D2 deletion mitigated tamoxifen resistance in breast cancer cells. Circ_UBE2D2 was also significantly loaded in exosomes isolated from resistant cells and could be transferred to parental cells. MiR-200a-3p was a target of circ_UBE2D2, and we demonstrated that exosomes mediated transfer of circ_UBE2D2 interacted with miR-200a-3p to enhance tamoxifen resistance of breast cancer cells by regulating cell viability, metastasis, and the level of ERalpha in vivo and in vitro. CONCLUSIONS Exosomes mediated transfer of circ_UBE2D2 reinforced tamoxifen resistance in breast cancer by binding to miR-200a-3p, providing new insights into the boost of the effectiveness of tamoxifen on breast cancer patients.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Drug Resistance, Neoplasm/genetics , Estrogen Antagonists/pharmacology , Exosomes/metabolism , MicroRNAs/metabolism , RNA, Circular/metabolism , Tamoxifen/pharmacology , Ubiquitin-Conjugating Enzymes/metabolism , Animals , Breast Neoplasms/pathology , Cell Movement/drug effects , Cell Movement/genetics , Cell Survival/drug effects , Cell Survival/genetics , Estrogen Receptor alpha/metabolism , Female , HEK293 Cells , Humans , MCF-7 Cells , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , RNA Interference , RNA, Circular/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Transfection , Tumor Burden/drug effects , Ubiquitin-Conjugating Enzymes/genetics , Up-Regulation , Xenograft Model Antitumor AssaysABSTRACT
Cancer-associated fibroblasts (CAFs), an activated subpopulation of fibroblasts, occupy a central position in the tumor microenvironment and have been shown to promote chemoresistance in multiple cancer types by secreting inflammatory cytokines. Herein, we report that tumor-secreted exosomal long non-coding RNAs (lncRNAs) can regulate cisplatin resistance in esophageal squamous cell carcinoma (ESCC) through transformation of normal fibroblasts (NFs) to CAFs. Primary CAFs and matched NFs were isolated from tumor tissues and matched normal esophageal epithelial tissues of ESCC patients. Fluorescence microscopy and qRT-PCR were used to investigate the transportation of exosomal lncRNAs from ESCC cells to NFs. To identify the specific lncRNAs involved, 14 ESCC-related lncRNAs were measured in NFs after incubation with exosomes from ESCC cells. We demonstrated that lncRNA POU3F3 can be transferred from ESCC cells to NFs via exosomes and that it mediated fibroblast activation. Activated fibroblasts further promoted proliferation and cisplatin resistance of ESCC cells through secreting interleukin 6 (IL-6). Moreover, our clinical data showed that high levels of plasma exosomal lncRNA POU3F3 correlated significantly with lack of complete response and poor survival in ESCC patients. Therefore, these data demonstrate that lncRNA POU3F3 is involved in cisplatin resistance in ESCC and that this effect is mediated through exosomal lncRNA POU3F3-induced transformation of NFs to CAFs.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Systems biology provides an opportunity to discover the role that gut microbiota play in almost all aspects of human health. Existing evidence supports the hypothesis that gut microbiota is closely related to the pharmacological effects of chemical therapy and novel targeted immunotherapy. Gut microbiota shapes the efficiency of drugs through several key mechanisms: metabolism, immunomodulation, translocation, enzymatic degradation, reduction of diversity, and ecological variability. Therefore, gut microbiota have emerged as a novel target to enhance the efficacy and reduce the toxicity and adverse effects of cancer therapy. There is growing evidence to show that cancer therapy perturbs the host immune response and results in dysbiosis of the immune system, which then influences the efficiency of the therapy. Studies suggest that gut microbes play a significant role in cancer therapy by modulating drug efficacy, abolishing the anticancer effect, and mediating toxicity. In this review, we outline the role of gut microbiota in modulating cancer therapy and the implications for improving the efficacy of chemotherapy and immunotherapy in clinical practice. We also summarize the current limitations of the safety and effectiveness of probiotics in cancer therapies such as personalized cancer therapy.
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Genome sequencing identifies vast number of genetic variants. Predicting these variants' molecular and clinical effects is one of the preeminent challenges in human genetics. Accurate prediction of the impact of genetic variants improves our understanding of how genetic information is conveyed to molecular and cellular functions, and is an essential step towards precision medicine. Over one hundred tools/resources have been developed specifically for this purpose. We summarize these tools as well as their characteristics, in the genetic Variant Impact Predictor Database (VIPdb). This database will help researchers and clinicians explore appropriate tools, and inform the development of improved methods. VIPdb can be browsed and downloaded at https://genomeinterpretation.org/vipdb.