An emergence of the novel coronavirus designated as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019 has triggered an ongoing pandemic of coronavirus disease 2019 (COVID-19) globally. As of 22nd September 2020, more than 30,949,804 confirmed cases and 959,116 deaths have been reported worldwide (WHO, 2020). COVID-19 bears several pathological hallmarks including fever, breathing difficulty, bilateral lung infiltration, and death in the most extreme cases (Huang et al., 2020). Several anti-viral drugs have been used to target the SARS-CoV-2 infection. These drugs include remdesivir, ribavirin, penciclovir, lopinavir/ritonavir, chloroquine (Wang, Cao, et al., 2020). However, most of these medicines have limited efficacy to reduce
RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlights the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions of RNF126 remain largely unknown. Homologous recombination (HR)-mediated DNA double-strand break repair is important for tumor suppression and cancer therapy resistance. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 11 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression and HR by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Lastly, RNF126 depletion leads to the increased sensitivity to ionizing radiation (IR) and poly (ADP-ribose) polymerase (PARP) inhibition. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through positive regulation on BRCA1 expression by direct interaction with E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for cancer treatment.
Background Chemo-resistance is one of the major challenges in the therapy of small cell lung cancer (SCLC). Multiple mechanisms are thought to be involved in chemo-resistance during SCLC treatment, but unfortunately, these mechanisms have not been well elucidated. Herein, we investigated the role of miRNA in the resistance of SCLC cells to doxorubicin (Dox). Methods MiRNA microarray analysis revealed that several miRNAs, including miR-7-5p, were specifically decreased in Dox-resistant SCLC cells (H69AR) compared to parental cells (H69). The expression level of miR-7-5p was confirmed by qRT-PCR in Dox-resistant cells (H69AR and H446AR cells) and their parental cells. Bioinformatic analysis indicated that poly ADP-ribose polymerase 1 (PARP1) is a direct target of miR-7-5p. The binding sites of miR-7-5p in the PARP1 3′ UTR were verified by luciferase reporter and Western blot assays. To investigate the role of miR-7-5p in the chemo-resistance of SCLC cells to doxorubicin, mimic or inhibitor of miR-7-5p was transfected into SCLC cells, and the effect of miR-7-5p on homologous recombination (HR) repair was analyzed by HR reporter assays. Furthermore, the expression of HR repair factors (Rad51 and BRCA1) induced by doxorubicin was detected by Western blot and immunofluorescent staining in H446AR cells transfected with miR-7-5p mimic. Results The expression level of miR-7-5p was remarkably reduced ( -fold) in Dox-resistant SCLC cells (H69AR and H446AR cells) compared with that in parental cells (H69 and H446 cells). Poly ADP-ribose polymerase 1 (PARP1) is a direct target of miR-7-5p, and PARP1 expression was downregulated by miR-7-5p. MiR-7-5p impeded Dox-induced HR repair by inhibiting the expression of HR repair factors (Rad51 and BRCA1) that resulted in resensitizing SCLC cells to doxorubicin. Conclusions Our findings provide evidence that miR-7-5p targets PARP1 to exert its suppressive effects on HR repair, indicating that the alteration of the expression of miR-7-5p may be a promising strategy for overcoming chemo-resistance in SCLC therapy. Electronic supplementary material The online version of this article (10.1186/s12885-019-5798-7) contains supplementary material, which is available to authorized users.
Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells.
The successful generation of T cell-mediated immunity for the treatment of cancer has been a major focal point of research. One of the critical strategies of cancer immunotherapy is to efficiently activate antigen-specific CD8 T cells in the immunosuppressive tumor environment. Here, we used transgenic OT-I/CD45.2/Rag −/− mice as a source of effector CD8 T cells to determine whether irradiation combined with adoptive T cell transfer therapy could improve T cell proliferation and effector function in murine tumor models. Local irradiation combined with adoptive T cell therapy showed a synergistic effect on tumor growth inhibition in mice. Mechanistically, irradiation increased the release of tumor-associated antigens, which facilitated cross-presentation of tumor-associated antigens by dendritic cells and the priming of antigen-specific T lymphocytes. Additionally, irradiation enhanced the homing of the antigen-specific T cells to tumor tissues via the increased release of CCL5, CXCL9, and CXCL11 from tumor cells. Moreover, irradiation enhanced the proliferation and effector function of both adoptively transferred T cells and endogenous antigen-specific T cells. Our findings provide evidence to support that local irradiation enhanced the therapeutic efficacy of adoptive T cell therapy for cancer, indicating that the combination of radiotherapy and adoptive T cell therapy may be a promising strategy for tumor treatment.
Although abscopal tumor regression remains a rare phenomenon, interest in exploiting how radiation stimulates the immune system to induce systemic abscopal response is increasing. Here, we tested the hypothesis that tumor immunogenicity determined the ability of radiotherapy to induce abscopal effects. We established highly (MC-38 and E.G7-OVA) or poorly (LL/2 and B16-F10) immunogenic tumor models in this study and treated them with sham radiation, a single dose of 15 Gy, or three fractions of 5 Gy on three consecutive days. Alterations in the tumor microenvironment after radiation were examined by flow cytometry and RNA sequencing. Our results demonstrated the positive correlation between tumor immunogenicity and the abscopal effect of radiotherapy. The single dose of 15 Gy radiation was an effective regimen for inducing abscopal effects in highly immunogenic tumors. Local radiation reshaped the tumor microenvironment of irradiated and non-irradiated distant tumors by increasing CD8 T-cell infiltration and reducing suppressive immune cell accumulation. However, radiation alone was insufficient to elicit abscopal effects in poorly immunogenic tumors. No significant alterations were detected in the non-irradiated distant tumor microenvironment after radiation of poorly immunogenic tumors. In addition, tumor immunogenic subtypes were associated with the radiological response and clinical outcome of patients receiving radiotherapy. These findings indicated that tumor immunogenicity was the dominant characteristic that could predict the abscopal effect of radiotherapy. Our study provides an in-depth understanding of the immunological mechanisms involved in abscopal effects and highlights the impact of tumor heterogeneity on the therapeutic efficacy of radiotherapy and their combination with immunotherapy in clinical trials.
Background Endometrial cancer (EC) is the most frequent malignancy of the female genital tract worldwide. Our study aimed to construct an effective protein prognostic signature to predict prognosis and immunotherapy responsiveness in patients with endometrial carcinoma. Methods Protein expression data, RNA expression profile data and mutation data were obtained from The Cancer Proteome Atlas (TCPA) and The Cancer Genome Atlas (TCGA). Prognosis-related proteins in EC patients were screened by univariate Cox regression analysis. Least absolute shrinkage and selection operator (LASSO) analysis and multivariate Cox regression analysis were performed to establish the protein-based prognostic signature. The CIBERSORT algorithm was used to quantify the proportions of immune cells in a mixed cell population. The Immune Cell Abundance Identifier (ImmuCellAI) and The Cancer Immunome Atlas (TCIA) web tools were used to predict the response to immunochemotherapy. The pRRophetic algorithm was used to estimate the sensitivity of chemotherapeutic and targeted agents. Results We constructed a prognostic signature based on 9 prognostic proteins, which could divide patients into high-risk and low-risk groups with distinct prognoses. A novel prognostic nomogram was established based on the prognostic signature and clinicopathological parameters to predict 1, 3 and 5-year overall survival for EC patients. The results obtained with Clinical Proteomic Tumor Analysis Consortium (CPTAC), Human Protein Atlas (HPA) and immunohistochemical (IHC) staining data from EC samples in our hospital supported the predictive ability of these proteins in EC tumors. Next, the CIBERSORT algorithm was used to estimate the proportions of 22 immune cell types. The proportions of CD8 T cells, T follicular helper cells and regulatory T cells were higher in the low-risk group. Moreover, we found that the prognostic signature was positively associated with high tumor mutation burden (TMB) and high microsatellite instability (MSI-H) status in EC patients. Finally, ImmuCellAI and TCIA analyses showed that patients in the low-risk group were more inclined to respond to immunotherapy than patients in the high-risk group. In addition, drug sensitivity analysis indicated that our signature had potential predictive value for chemotherapeutics and targeted therapy. Conclusion Our study constructed a novel prognostic protein signature with robust predictive ability for survival and efficiency in predicting the response to immunotherapy, chemotherapy and targeted therapy. This protein signature represents a promising predictor of prognosis and response to cancer treatment in EC patients.
Background Malignant mesothelioma (MM) is a relatively rare and highly lethal tumor with few treatment options. Thus, it is important to identify prognostic markers that can help clinicians diagnose mesothelioma earlier and assess disease activity more accurately. Alternative splicing (AS) events have been recognized as critical signatures for tumor diagnosis and treatment in multiple cancers, including MM. Methods We systematically examined the AS events and clinical information of 83 MM samples from TCGA database. Univariate Cox regression analysis was used to identify AS events associated with overall survival. LASSO analyses followed by multivariate Cox regression analyses were conducted to construct the prognostic signatures and assess the accuracy of these prognostic signatures by receiver operating characteristic (ROC) curve and Kaplan–Meier survival analyses. The ImmuCellAI and ssGSEA algorithms were used to assess the degrees of immune cell infiltration in MM samples. The survival-related splicing regulatory network was established based on the correlation between survival-related AS events and splicing factors (SFs). Results A total of 3976 AS events associated with overall survival were identified by univariate Cox regression analysis, and ES events accounted for the greatest proportion. We constructed prognostic signatures based on survival-related AS events. The prognostic signatures proved to be an efficient predictor with an area under the curve (AUC) greater than 0.9. Additionally, the risk score based on 6 key AS events proved to be an independent prognostic factor, and a nomogram composed of 6 key AS events was established. We found that the risk score was significantly decreased in patients with the epithelioid subtype. In addition, unsupervised clustering clearly showed that the risk score was associated with immune cell infiltration. The abundances of cytotoxic T (Tc) cells, natural killer (NK) cells and T-helper 17 (Th17) cells were higher in the high-risk group, whereas the abundances of induced regulatory T (iTreg) cells were lower in the high-risk group. Finally, we identified 3 SFs (HSPB1, INTS1 and LUC7L2) that were significantly associated with MM patient survival and then constructed a regulatory network between the 3 SFs and survival-related AS to reveal potential regulatory mechanisms in MM. Conclusion Our study provided a prognostic signature based on 6 key events, representing a better effective tumor-specific diagnostic and prognostic marker than the TNM staging system. AS events that are correlated with the immune system may be potential therapeutic targets for MM.
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