Prognostic implications of combined high expression of CD47 and MCT1 in breast cancer: a retrospective study during a 10-year period.

Background: Clinical outcome after surgery of breast cancer needs more prognostic markers to predict currently. Cluster of differentiation 47 (CD47), due to its overexpression in various tumors and ability to inhibit phagocytosis, has been identified as a new immune checkpoint. Monocarboxylate transporter 1 (MCT1) is a protein involved in the immunomodulatory activities of the tumor microenvironment (TME) by maintaining the pH through aerobic glycolysis. Methods: We explored the expression of CD47 and MCT1 in breast invasive ductal carcinoma specimens to determine their association with prognosis. A total of 137 breast invasive ductal carcinoma tissues were collected for CD47 and MCT1 immunohistochemical staining. Results: Statistically analyzed, our study first indicated that in both univariate and multivariate analyses, the coexpression of CD47 and MCT1 was an independent prognostic factor for a poor 10-year overall survival rate (10-OS) and 10-year progression-free survival rate (10-DFS) (P<0.05). In addition, the combined high expression of these two markers also led to worse OS and PFS rates in the TNM (II + III), histologic grade (I + II), HER2 overexpression and basal-like subgroups. High expression of CD47 and MCT1 and combined high expression of CD47 and MCT1 were associated with clinicopathological parameters, such as histological grade, TNM stage, death status, and recurrence status in breast cancer patients. However, in the multivariate survival analysis, high expression of CD47 alone was not an independent prognostic factor for the 10-OS or the 10-DFS (P=0.104; P=0.153), and high expression of MCT1 alone was not an independent predictor for a poor 10-DFS (P=0.177) either. Conclusions: The coexpression of CD47 and MCT1 can serve as a prognostic biomarker leading to poor survival and an increased risk for recurrence, and this novel information could help guide the development of adjuvant therapy for breast cancer.

miR-128 Regulates Tumor Cell CD47 Expression and Promotes Anti-tumor Immunity in Pancreatic Cancer.

Pancreatic adenocarcinoma (PDAC) is a highly fatal disease worldwide. MicroRNAs (miRNAs) could regulate the protein-coding RNAs related to tumor growth, invasion, and immune evasion. Therefore, the investigation of novel miRNAs may be helpful in the development of more effective therapies for PDAC. In this study, we investigated the role and mechanism of action of miR-128 in PDAC. By using bioinformatics methods, we found that decreased expression of miR-128 was associated with poor overall survival of PDAC. miR-128 was inversely correlated with cluster of differentiation 47 (CD47), which was positively related to zinc finger E-box-binding homeobox 1 (ZEB1) in PDAC. Through in vivo experiments, we found that miR-128 could suppress the growth and metastasis of PDAC. Analysis of the immune microenvironment demonstrated that overexpression of miR-128 on tumor cells could increase the percentages of dendritic cells (DCs), CD8+ T lymphocytes, and natural killer T cells (NKT) in the tumor and spleen, consequently enhancing anti-tumor immunity. In vitro assays showed that miR-128 could inhibit cell proliferation, clonogenicity, migration, and invasion in Panc02 cells and could also enhance the phagocytosis of macrophages and the activity of DCs. Western blot and qRT-PCR confirmed that miR-128 could regulate ZEB1 and further inhibit CD47 in pancreatic cancer cells. Therefore, we identified a novel regulatory anti-tumor mechanism by miR-128 in PDAC, which may serve as a novel therapy for PDAC.

microRNA-222 Attenuates Mitochondrial Dysfunction During Transmissible Gastroenteritis Virus Infection.

Transmissible gastroenteritis virus (TGEV) is a member of Coronaviridae family. Our previous research showed that TGEV infection could induce mitochondrial dysfunction and upregulate miR-222 level. Therefore, we presumed that miR-222 might be implicated in regulating mitochondrial dysfunction induced by TGEV infection. To verify the hypothesis, the effect of miR-222 on mitochondrial dysfunction was tested and we showed that miR-222 attenuated TGEV-induced mitochondrial dysfunction. To investigate the underlying molecular mechanism of miR-222 in TGEV-induced mitochondrial dysfunction, a quantitative proteomic analysis of PK-15 cells that were transfected with miR-222 mimics and infected with TGEV was performed. In total, 4151 proteins were quantified and 100 differentially expressed proteins were obtained (57 upregulated, 43 downregulated), among which thrombospondin-1 (THBS1) and cluster of differentiation 47 (CD47) were downregulated. THBS1 was identified as the target of miR-222. Knockdown of THBS1 and CD47 decreased mitochondrial Ca2+ level and increased mitochondrial membrane potential (MMP) level. Reversely, overexpression of THBS1 and CD47 elevated mitochondrial Ca2+ level and reduced mitochondrial membrane potential (MMP) level. Together, our data establish a significant role of miR-222 in regulating mitochondrial dysfunction in response to TGEV infection.

Antibody drugs targeting CD47: research advances / 国际药学研究杂志

With the development and clinical application of immunological checkpoint drugs such as pro- grammed cell death protein-1(PD-1)/programmed cell death-ligand 1(PD-L1)and cytotoxic T lymphocyte-associated an- tigen-4(CTLA-4), immunotherapy has gradually become one of the most effective clinical treatment methods. Cluster of differentiation 47(CD47), as a natural immune checkpoint molecule, is highly expressed in almost all human cancers (solid tumors and hematological tumors), affecting tumor progression and metastasis, and is involved in the apoptosis, proliferation, adhesion, migration and other processes. Therefore, CD47 has become an important target for the study of human tumors. At present, a number of preclinical studies and clinical trials of the drugs targeting CD47 antibodies and Fc fusion protein are being actively carried out in various countries. This review briefly introduces the structure, function and related diseases of CD47 and focuses mainly on the development and clinical application strategy of CD47 therapeutic antibody drugs.