Downsstanley5405

Our results, therefore, provide evidence of the novel anti-tumour effect of FBP1 via its blockade of BRD4 function in pancreatic cancer cells. AJCR Copyright © 2020.Triple-negative breast cancer (TNBC) is one of the most aggressive cancers with a high rate of recurrence and metastasis. Trifluridine (TFT) is a thymidine analog to target thymidylate synthase (TS) and has potent ant-herpes simplex virus activity. However, little is known whether and how TFT treatment can modulate the growth of TNBC. In this study, we found that treatment with TFT selectively inhibited the proliferation of TNBC cells and triggered their apoptosis. TFT treatment significantly up-regulatd the expression of G1 phase inhibitor p21 and p27, and pro-apoptotic factor γ-H2AX, Bax and cleaved caspase-7 in TNBC cells. TFT treatment significantly down-regulated the expression of proliferating cell nuclear antigen (PCNA), minichromosome maintenance component 7 (MCM7) and anti-apoptotic Bcl-2 in TNBC cells. TFT treatment significantly mitigated the growth of implanted mouse TNBC in vivo, associated with increased expression of γ-H2AX and cleaved caspase-7 in mouse TNBC tumors. TS expression was up-regulated in breast cancer, particularly in TNBC tissues, and up-regulated TS expression was significantly associated with a shorter overall survival and disease free survival in TNBC patients. TS silencing selectively decreased the proliferation of TNBC cells, but did not trigger their apoptosis. Treatment with TFT induced DNA double strand break (DSB) and damages in TNBC cells. Collectively, TFT selectively inhibited the growth of TNBC by inducing chromosome instability and inhibiting thymidine synthase. Therefore, TFT may be valuable for the intervention of TNBC. AJCR Copyright © 2020.Tumor development is accompanied by high hypoxia and a dense network of immature vessels. The hypoxia-inducible factor/vascular endothelial growth factor (HIF/VEGF) signaling pathway is activated in various solid tumors. It is thought that HIF/VEGF signaling activation results from intratumoral hypoxia partly. Multiple studies have reported that VEGF is a common target gene for both transcription factors STAT3 and HIF1. KDM4C has also been reported to function as a co-activation factor for HIF-1β/VEGF signaling activation. In this manuscript. Our results demonstrate that KDM4C promotes NSCLC tumor angiogenesis by transcriptionally activating HIF1α/VEGFA signaling pathway. We also find that STAT3 functions as a costimulatory factor in this process. This pathway opens a potential therapeutic window for the treatment of NSCLC. AJCR Copyright © 2020.Recently, the combination of platinum chemotherapy with PD-1/PD-L1 pathway blockades has shown synergistic efficacy in a few clinical trials. However, the exact mechanisms and the optimized sequence of such combinations are not fully clear. In this study, we combined different doses of platinum agents (cisplatin or oxaliplatin) with sequential therapy of PD-1 blockade therapy (anti-PD-1 antibody or anti-PD-L1 antibody) to treat established MC38 murine colon tumors. Although 10 mg/kg platinum (cisplatin or oxaliplatin) showed no significant effect on tumor growth, its combination with sequential anti-PD-1 antibody administration caused complete tumor remission in 80-100% mice. The synergic therapeutic efficacy was found to be associated with more effector and less exhausted CD8 T cell infiltration in the tumor sites. Platinum chemotherapy is generally considered immunosuppressive, with lymphopenia and neutropenia being common side effects. However, our data showed that high-dose (20 mg/kg) platinum treatment iotherapy combined with PD-1 blockade and provide an indication for the improvement of combined therapies in clinical trials. AJCR Copyright © 2020.Epidermal growth factor receptor (EGFR) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and related to cancer progression. The resistance to anti-EGFR therapy remains a major clinical problem in HNSCC. In this study, we found that TOLL-like receptor 4 (TLR4) was highly expressed in 50% of EGFR overexpressed HNSCC biopsies, which correlated to worse prognosis in patients. In HNSCC cell lines, activation of TLR4 reversed cetuximab-induced the inhibition of proliferation, migration and invasion. LPS induced of TLR4 signaling was potentiated under cetuximab treatment, showing increased activation of downstream NF-κB and MAPK pathways. Accordingly, cetuximab treatment also increased expression of TNF-α, COX2, and other molecules involved in TLR4 induced tumor inflammation. Mechanistically, we found inhibition of EGFR by cetuximab led to decreased phosphorylation of Src and sequentially Src-medicated activation of Cbl-b. This inhibited Cbl-b-mediated degradation of the key TLR4 adaptor protein MyD88 and activated TLR4 signaling. TLR4 or MyD88 overexpressed CAL27 and SCC4 cells grew faster and were more resistant to cetuximab and gefitinib both in vitro and in vivo. Out study delineates a crosstalk between EGFR and TLR4 pathways and identified TLR4 as a potential biomarker as well as a therapeutic target in overcoming the resistance to anti-EGFR therapy of HNSCC. AJCR Copyright © 2020.Radiotherapy (RT) is the primary treatment for cancer. Ionizing radiation from RT induces tumor damage at the irradiated site, and, although clinically infrequent, may cause regression of tumors distant from the irradiated site-a phenomenon known as the abscopal effect. Recently, the abscopal effect has been related to prolongation of overall survival time in cancer patients, though the factors that influence the abscopal effect are not well understood. The aim of this study is to clarify the factors influencing on abscopal effect. Here, we established a mouse model in which we induced the abscopal effect. We injected MC38 (mouse colon adenocarcinoma) cells subcutaneously into C57BL/6 mice at two sites. Only one tumor was irradiated and the sizes of both tumors were measured over time. The non-irradiated-site tumor showed regression, demonstrating the abscopal effect. This effect was enhanced by an increase in the irradiated-tumor volume and by administration of anti-PD1 antibody. When the abscopal effect was induced by a combination of RT and anti-PD1 antibody, it was also influenced by radiation dose and irradiated-tumor volume. These phenomena were also verified in other cell line, B16F10 cells (mouse melanoma cells). These findings provide further evidence of the mechanism for, and factors that influence, the abscopal effect in RT. AJCR Copyright © 2020.Programmed cell death 4 (PDCD4) suppresses tumorigenesis, tumor progression, and invasion by inhibiting transcription and translation of oncogenes. However, the role of PDCD4 in lung tumorigenesis is unclear. Sequestosome1/p62 mediates cell proliferation, survival, and death through multiple signaling pathways, including autophagy and cell metabolism. p62/SQSTM1 is transcriptional target of Nrf2 and an important regulator of tumor growth. The aim of this study was to clarify whether and how PDCD4 regulates the p62-Nrf2 pathway, and how this regulation relates to tumorigenesis in human lung cancer cells. We established two stable human lung cancer cell lines, A549 and H460 that each overexpressed PDCD4. We found that PDCD4 overexpression decreased p62 expression levels and inhibited cell proliferation, and also increased the expression levels of cleaved PARP and cleaved caspase 3. Knockdown of p62 markedly increased the apoptotic rate of A549 and H460 cells overexpressing PDCD4. Furthermore levels of the epithelial-mesenchymal transition-related markers Slug, Snail, Twist1 and Vimentin were decreased and expression level of E-cadherin was increased in PDCD4-overexpressing cells. We also found that PDCD4 suppressed transcriptional activation of Nrf2 (an upstream regulator of p62) and increased endogenous levels of Keap1 (a negative regulator of Nrf2). Upregulation of Keap1 induced apoptosis and inhibited cell proliferation by suppressing activity of the p62-Nrf2 pathway in PDCD4-overexpressing cells. As anticipated, results from a mouse xenograft model showed that PDCD4 overexpression in xenografts inhibited cell proliferation and tumorigenesis. Taken together, our results demonstrate that PDCD4 overexpression, which increased Keap1 expression, reduces the levels and activity of the p62-Nrf2 pathway, thereby inhibiting tumorigenesis. Our findings suggest that PDCD4 may be a potential target for lung cancer therapies. AJCR Copyright © 2020.Chemoresistance is a leading cause of tumor relapse and treatment failure in colorectal cancer (CRC) patients and is correlated with epithelial-mesenchymal transition (EMT). This study was aimed to explore the mechanism of EMT in chemoresistant CRC. Bioinformatic method was used to screen differentially expressed genes between 5-FU sensitive and resistant CRC cells. find more Immunohistochemistry staining was utilized to analyze the expression of FLNA in CRC tissues. The roles of FLNA in chemoresistance were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic CRC animal model. The regulation of c-Met signaling by FLNA was explored via Co-Immunoprecipitation and luciferase reporter assays. Our results suggested FLNA directly regulated the metastasis and EMT of chemoresistant CRC cells. Moreover, c-Met-AKT mediated ser2152 phosphorylation of FLNA was demonstrated to be correlated with EMT. In turn, FLNA enhanced c-Met promoter activity by its interaction with smad2. Clinically, the expression of FLNA was significantly associated with c-Met protein levels in CRC tissues. These data established that FLNA could be a novel and reliable CRC marker and a potential therapeutic target against CRC. AJCR Copyright © 2020.Recent studies have revealed that tRNAs are not always the terminal molecules and small RNA fragments can be mapped to precursor tRNA sequences or mature tRNA sequences. tRNA-derived fragments (tRFs) are a novel class of small RNAs in miRNA-size found in a diverse range of organisms and can be the source of small regulatory RNAs, a previously unanticipated concept. tRFs have a diverse range of effects on cells involving in cell differentiation and homeostasis. They play a critical role in pathological processes, particularly in cancer, and therefore can modulate complicated regulatory networks. Recent studies on the role of tRFs in tumorigenesis suggest that they are promising targets for diagnosis and therapeutics. Improvement in experimental and computational approaches permit a greater understanding of the regulatory networks and will have a significant impact on both basic and clinical research. AJCR Copyright © 2020.Currently, adipocytes and macrophages are considered to be key cell types of breast cancer (BC) tissues. With the emergence of crown-like structures (CLS), cancer-associated adipocytes (CAAs) and tumour-associated macrophages (TAMs) are formed respectively in tumor microenvironment (TME). Both of them affect the progress of breast cancer, while forming crosstalk in the tumour tissue. CAAs play an important role, which produces hypoxia and inflammation environment and aggravates this environment. The formation and secretion of TAMs with M2 phenotypic characteristics, such as HIF-1α, and TNF-α, affect the progress of cancer cells by interfering with the secretion of MCP-1 by CAAs. Therefore, the interaction between CAAs and TAMs may be an effective therapeutic target for breast cancer. In this review, we focus on the biological effects of two types of cells in breast cancer, in order to better explain the crosstalk between them and provide new ideas for the future treatment of breast cancer. AJCR Copyright © 2020.