High Expression Of CD147 Research Articles

Relationships between tumor CD147 expression, tumor-infiltrating lymphocytes, and oncostatin M in hepatocellular carcinoma.

In hepatocellular carcinoma (HCC), CD147 expression contributes to tumor malignancy; however, its relationship with the tumor-immune microenvironment (TIME) remains unclear. This study aimed to elucidate the clinicopathological characteristics associated with CD147 expression in HCC and investigate its association with the TIME, specifically its association with tumor-infiltrating lymphocytes (TILs) and oncostatin M (OSM). Using 397 HCC specimens from patients undergoing curative-intent resection, we assessed CD147 expression in tumor cells and quantified OSM-positive cells and various TILs (CD8+, CD4+, FOXP3+, and CD20+ cells) in the TIME. Using tissue microarrays, these assessments were performed through immunohistochemical analysis. We investigated the associations between CD147 expression status, the density of OSM-positive cells, and the densities of various TILs. High CD147 expression, found in 332 specimens (83.6%), was associated with advanced clinical stage (P = 0.029), fibrosis (P = 0.036), and higher densities of FOXP3+ cells (P = 0.0039), CD4+ cells (P = 0.0012), and OSM-positive cells (P = 0.0017). In CD147-high tumors, OSM-positive cell density was associated with all assessed TIL subsets (CD8+, CD4+, FOXP3+, and CD20+ cells; all Ps < 0.001), whereas in CD147-low tumors, OSM-positive cell density was associated only with FOXP3+ cells (P = 0.0004). In HCC, CD147 expression is associated with an immunosuppressive TIME, characterized by increased FOXP3+ regulatory T cells and a correlation with OSM-positive cells. These results elucidate the potential mechanisms through which CD147 facilitates tumor-immune evasion, suggesting the CD147 - OSM axis as a promising target for therapeutic intervention in HCC.

Abstract A138: Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody

Abstract Background: CD147 is a member of the immunoglobulin superfamily that is highly expressed in various cancers and is involved in growth, metastasis, and activation of inflammatory signals in cancer cells. DS-1471a is a novel humanized anti-human CD147 monoclonal antibody under development as an anticancer agent. In this study, pharmacokinetic (PK)-pharmacodynamic (PD) analysis of DS-1471a was conducted to set the dose and dosing regimen for first-in-human (FIH) study. The safety profile of DS-1471a was also assessed in cynomolgus monkeys. Methods: Preclinical pharmacological study was conducted in xenograft model mice transplanted with MIA PaCa-2 cells by intravenous (IV) administration of DS-1471a, and receptor occupancy (RO) of CD147 in tumor was measured. Monkey PK and RO in blood were measured after the IV administration of DS-1471a. The expression levels of CD147 in hepatocytes and erythrocytes in monkeys and humans were measured to estimate the species differences. Using monkey PK, RO, and CD147 expression data, a minimal physiologically based pharmacokinetic (PBPK) model was constructed. Subsequently, PK and RO profiles in humans were predicted by replacing physiological parameters and CD147 expression levels with human values. For the safety assessment, DS-1471a was intravenously administered to monkeys every 2 weeks for 1 month. Results: In xenograft model mice, DS-1471a exhibited partial and potent antitumor activity at 1 and 3 mg/kg, respectively. At those doses, RO in tumor the day after dosing was 18% (1 mg/kg) and 89% (3 mg/kg). In monkeys, non-linear PK was observed, owing to high expression of CD147 in erythrocytes, resulting in target-mediated drug disposition. Compared to the findings in monkeys, the human expression level of CD147 was lower in erythrocytes and higher in hepatocytes. PBPK modeling, incorporating species differences in CD147 expression levels, projected that RO in tumor after the IV administration of DS-1471a to humans would reach 20%, 50%, and 90% at 2 day after injection at 0.3, 1, and 3 mg/kg, respectively. In the monkey toxicity study, DS-1471a was well tolerated at up to 158.4 mg/kg (human equivalent dose of 51 mg/kg). Conclusions: Based on preclinical PK-PD analysis and safety study of DS-1471a, the starting dose in FIH study was set to 1 mg/kg as a safe and efficacious dose. Citation Format: Miki Yokoyama, Masataka Oitate, Ken Sakurai, Takuma Iguchi, Katja Damme, Kayoko Nanai, Keisuke Fukuchi. Preclinical pharmacokinetic-pharmacodynamic modeling guides setting of the human starting dose of DS-1471a, a novel anti-CD147 antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A138.

Abstract B127: Novel anti-CD147 antibody DS-1471a exerts antitumor effect in hepatocellular carcinoma Patient Derived Xenograft models and its efficacy correlates with the expression of CD147

Abstract Background: CD147 is an immunoglobulin-like receptor that is highly expressed in various cancers and involved in the growth, metastasis, and activation of inflammatory pathways via interactions with various functional molecules, such as integrins, CD44, and monocarboxylate transporters. Through screening of CD147-targeting antibodies with antitumor efficacy, we developed a novel humanized IgG4-formatted monoclonal anti-CD147 antibody, DS-1471a. Our previous studies revealed this antibody showed potent antitumor efficacy superior to standard of care drugs in various cell line xenograft mouse models such as hepatocellular carcinoma (HCC), pancreatic invasive ductal adenocarcinoma, and chronic myelogenous leukemia. In this study, we further examined antitumor efficacy and biomarker expression in 18 patient derived xenograft (PDX) models established from HCC patients. Methods: DS-1471a or vehicle was administered intravenously once per week at 10 mg/kg doses in HCC-PDX models and tumor volumes were measured every 2 or 3 days. After tumors were harvested, samples were analyzed by simple western blotting (sWB, capillary based western blotting system) and immunohistochemistry (IHC). H-scores were calculated from IHC results and correlation between H-score, protein expression by sWB, and tumor growth inhibition (TGI) ratio were examined. Results: Seven out of 18 PDX models showed over 50% TGI with DS-1471a treatment in comparison to vehicle, regardless of gender, tumor grade, and hepatitis virus type. Protein expression analysis by sWB showed good correlation of several biomarker candidates with efficacy of DS-1471a. Among the biomarker candidates tested, CD147, the DS-1471a target molecule, showed the strongest correlation with efficacy (r = 0.78). SMAD4, which regulates the downstream signaling of the CD147 complex, and FBXO22, reported to contribute to CD147 degradation, also showed good correlation with DS-1471a efficacy (r = 0.66 and r = 0.77, respectively). By both sWB and IHC analysis, all PDX models showed negative or weak KLF5 expression, another biomarker candidate for DS-1471a that is known to be a suppressor for SMAD signaling pathway. A clear correlation between CD147 H-score and TGI was observed (r= 0.74) in these patient derived PDX models. Correlation between CD147 H-score and protein expression levels by sWB was also observed (r = 0.71). Of note, all PDX models showed moderate to high expression of CD147. Conclusion: These pre-clinical study results suggest DS-1471a may be potentially beneficial for HCC treatment. In addition, our results show correlation of DS-1471a efficacy with expression of CD147. Further studies are needed to further understand the full potential benefit of DS-1471a in clinical trials. Citation Format: Hiroshi Yuita, Ryuichi Nakamura, Jun Tsukada, Hideo Yukinaga, Huynh The Hung, Keisuke Fukuchi. Novel anti-CD147 antibody DS-1471a exerts antitumor effect in hepatocellular carcinoma Patient Derived Xenograft models and its efficacy correlates with the expression of CD147 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B127.

124I-labeled anti-CD147 antibody for noninvasive detection of CD147-positive pan-cancers: construction and preclinical studies.

Extracellular matrix metalloproteinase inducer CD147 is a glycoprotein on the cell surface. There is minimal expression of CD147 in normal epithelial and fetal tissues, but it is highly expressed in a number of aggressive tumors. CD147 has been implicated in pan-cancer immunity and progression. With the development of CD147-targeting therapeutic strategy, accurate detection of CD147 expression in tumors and its changes during the therapy is necessary. In this study we constructed a novel radiotracer by labeling the anti-CD147 mAb with radionuclide 124/125I (124/125I-anti-CD147) for noninvasive detection of CD147 expression in pan-cancers, and characterized its physicochemical properties, affinity, metabolic characteristics, biodistribution and immunoPET imaging with 124I-IgG and 18F-FDG as controls. By examining the expression of CD147 in cancer cell lines, we found high CD147 expression in colon cancer cells LS174T, FADU human pharyngeal squamous cancer cells and 22RV1 human prostate cancer cells, and low expression of CD147 in human pancreatic cancer cells ASPC1 and human gastric cancer cells BGC823. 124/125I-anti-CD147 was prepared using N-bromine succinimide (NBS) as oxidant and purified by PD-10 column. Its radiochemical purity (RCP) was over 99% and maintained over 85% in saline or 5% human serum albumin (HSA) for more than 7 d; the RCP of 125I-anti-CD147 in blood was over 90% at 3 h post injection (p.i.) in healthy mice. The Kd value of 125I-anti-CD147 to CD147 protein was 6.344 nM, while that of 125I-IgG was over 100 nM. 125I-anti-CD147 showed much greater uptake in CD147 high-expression cancer cells compared to CD147 low-expression cancer cells. After intravenous injection in healthy mice, 125I-anti-CD147 showed high initial uptake in blood pool and liver, the uptake was decreased with time. The biological half-life of distribution and clearance phases in healthy mice were 0.63 h and 19.60 h, respectively. The effective dose of 124I-anti-CD147 was estimated as 0.104 mSv/MBq. We conducted immunoPET imaging in tumor-bearing mice, and demonstrated a significantly higher tumor-to-muscle ratio of 124I-anti-CD147 compared to that of 124I-IgG and 18F-FDG in CD147 (+) tumors. The expression levels of CD147 in cells and tumors were positively correlated with the maximum standardized uptake value (SUVmax) (P < 0.01). In conclusion, 124/125I-anti-CD147 displays high affinity to CD147, and represents potential for the imaging of CD147-positive tumors. The development of 124I-anti-CD147 may provide new insights into the regulation of tumor microenvironment and formulation of precision diagnosis and treatment programs for tumors.

Estrogen-responsive cancer-associated fibroblasts promote invasive property of gastric cancer in a paracrine manner via CD147 production.

Estrogen signaling has been extensively studied, especially in cancers that express estrogen receptor alpha (ERα). However, little is known regarding the effect of estrogen on cancer-associated fibroblasts (CAFs). Here, we explored the role of estrogen signaling of CAFs in gastric cancer (GC) progression. We investigated the phenotypic changes in CAFs upon 17β-estradiol (E2) treatment using ERα-negative/positive CAFs, and the conditioned media (CM) collected from these were compared with regard to cancer cell proliferation, migration, and invasion. A paracrine factor was found using a cytokine array and was confirmed using qRT-PCR, western blotting, and enzyme-linked immunosorbent assays. ERα-CD147-matrix metalloproteinase (MMP) axis was confirmed by knockdown experiments using specific siRNAs. We found that a subset of CAFs expressed ERα. ERα-positive CAFs were responsive to E2, inducing ERα expression in a dose-dependent manner. Although E2 did not induce the proliferation of ERα-positive CAFs, the CM from E2-bound ERα-positive CAFs significantly promoted cancer cell migration and invasion. Cytokine array revealed that CD147 was induced in ERα-positive CAFs upon E2 treatment; this was mediated via ERα. Increased CD147 upregulated MMP2 and MMP9 in CAFs, and also influenced cancer cells in a paracrine manner to increase MMPs and CD147 in cancer cells. High CD147 expression in tumor tissue was associated with a worse prognosis in GC patients. Our data suggest that estrogen signaling activation in CAFs and the byproduct CD147 are among the critical mediators between the interplay of CAFs and cancer cells to facilitate cancer progression.

The Expression of Glutaminases and their Association with Clinicopathological Parameters in the Head and Neck Cancers.

The increased glutamine metabolism is a characteristic feature of cancer cells. The interconversion between glutamine and glutamate is catalyzed by two glutaminase isoforms, GLS1 and GLS2, which appear to have different roles in different types of cancer. We investigated for the first time the protein expression of GLS1 and GLS2, and their correlation with advanced clinicopathological parameters in head and neck cancers. Consecutive slides from a tissue microarray comprised of 80 samples ranging from normal to metastatic were stained immunohistochemically for GLS1, GLS2, HIF-1α or CD147. Following analysis by two expert pathologists, we carried out a statistical analysis of the scores. GLS1 and GLS2 were found to be upregulated at the protein level in head and neck tumours compared to normal tissues, and this increased expression correlated positively (GLS1) and negatively (GLS2) with tumor grade, indicating a shift of expression between GLS enzyme isoforms based on tumor differentiation. Increased expression of GLS1 was associated with high CD147 expression, and elevated GLS2 expression was associated with both high CD147 and high HIF-1α expressions. The correlation of the GLS1 and GLS2 with HIF-1α or CD147 was strongly associated with more advanced clinicopathological parameters. The increased expression of GLS1 and GLS2 may be explored as a new treatment for head and neck cancers.

CD98-induced CD147 signaling stabilizes the Foxp3 protein to maintain tissue homeostasis

Regulatory T cell (Treg) stability is necessary for the proper control of immune activity and tissue homeostasis. However, it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions. Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability. Here, we demonstrate that to maintain Foxp3 protein expression, Tregs require cell-to-cell contact, which is mediated by the CD147-CD98 interaction. As Tregs are produced, CD147, which is expressed on their surface, is stimulated by CD98, which is widely expressed in the physiological environment. As a result, CD147’s intracellular domain binds to CDK2 and retains it near the membrane, leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation. In addition, the optimal distribution of Foxp3+ Tregs under both pathological and physiological conditions depends on CD98 expression. Thus, our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment. More importantly, Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability, which has guiding significance for the application of Tregs in immunotherapy.

CD147 Promotes Tumor Lymphangiogenesis in Melanoma via PROX-1.

Simple SummaryMelanoma is one of the most aggressive skin cancers, characterized by metastasis to the lymph nodes and a high capacity to develop drug resistance. There is a lack of knowledge on the mechanisms contributing to lymphatic vessel formation and metastasis regulation in malignant melanoma. We previously reported the involvement of CD147, a transmembrane glycoprotein overexpressed in melanoma, in the regulation of the tumor microenvironment and angiogenesis. The aim of our study was to further determine how CD147 is involved in lymphangiogenesis regulation. Our results revealed that high CD147 expression is correlated with the number of lymphatic vessels in the human melanoma lymph nodes and that paracrine CD147 upregulates lymphangiogenesis through lymphangiogenic mediators in vitro and in vivo, suggesting that CD147 could be a promising target for melanoma-associated lymphangiogenesis inhibition.Malignant melanoma is one of the most aggressive skin cancers and is characterized by early lymph node metastasis and the capacity to develop resistance to therapies. Hence, understanding the regulation of lymphangiogenesis through mechanisms contributing to lymphatic vessel formation represents a treatment strategy for metastatic cancer. We have previously shown that CD147, a transmembrane glycoprotein overexpressed in melanoma, regulates the angiogenic process in endothelial cells. In this study, we show a correlation between high CD147 expression levels and the number of lymphatic vessels expressing LYVE-1, Podoplanin, and VEGFR-3 in human melanoma lymph nodes. CD147 upregulates in vitro lymphangiogenesis and its related mediators through the PROX-1 transcription factor. In vivo studies in a melanoma model confirmed that CD147 is involved in metastasis through a similar mechanism as in vitro. This study, demonstrating the paracrine role of CD147 in the lymphangiogenesis process, suggests that CD147 could be a promising target for the inhibition of melanoma-associated lymphangiogenesis.

Impact of Epithelial-Mesenchymal Immunophenotype on Local Aggressiveness in Papillary Thyroid Carcinoma Invading the Airway.

Primary thyroid tumours show different levels of aggressiveness, from indolent to rapidly growing infiltrating malignancies. The most effective therapeutic option is surgery when radical resection is feasible. Biomarkers of aggressiveness may help in scheduling extended resections such as airway infiltration, avoiding a non-radical approach. The aim of the study is to evaluate the prognostic role of E-cadherin, N-cadherin, Aryl hydrocarbon receptor (AhR), and CD147 in different biological behaviours. Fifty-five samples from three groups of thyroid carcinomas were stained: papillary thyroid carcinomas (PTCs) infiltrating the airway (PTC-A), papillary intra-thyroid carcinomas (PTC-B) and poorly differentiated or anaplastic thyroid carcinomas (PDTC/ATC). High expressions of N-cadherin and AhR were associated with higher locoregional tumour aggressiveness (p = 0.005 and p < 0.001 respectively); PDTC/ATC more frequently showed a high expression of CD147 (p = 0.011), and a trend of lower expression of E-cadherin was registered in more aggressive neoplasms. Moreover, high levels of AhR were found with recurrent/persistent diseases (p = 0.031), particularly when tumours showed a concomitant high N-cadherin expression (p = 0.043). The study suggests that knowing in advance onco-biological factors with a potential role to discriminate between different subsets of patients could help the decision-making process, providing a more solid therapeutic indication and an increased expectation for radical surgery.

Cluster of differentiation 147 (CD147) expression is linked with thiram induced chondrocyte’s apoptosis via Bcl-2/Bax/Caspase-3 signalling in tibial growth plate under chlorogenic acid repercussion

Tibial dyschondroplasia (TD) is a metabolic disease of young poultry that affects bone andcartilage's growth. It mostly occurs in broilers due to thiram toxicity in the feed. In this disease, tibial cartilage is not yet ripe for ossification, but it also results in lameness, death, and moral convictions of commercial poultry due to numerous apoptotic changes on cell level. These changes serve a cardinal role in this situation. Many potential problems indicate that chlorogenic acid (CGA) performs an extensive role in controlling apoptosis's perception. However, the actual role of CGA in TD affected chondrocytes in-vitro is still unidentified. The current study investigates the imperceptible insight of CGA on chondrocyte’s apoptosis via B-cell lymphoma 2 (Bcl-2), Bcl-2 associated x-protein (Bax), and Caspase-3 with CD147 signalling. The expression of these markers was investigated by Immunofluorescence, western blot analysis, and reverse transcription-quantitative polymerase chain (RT-qPCR). Chondrocytes from the growth plate of tibia were isolated, cultured, and processed. A sub-lethal thiram (2.5 μg/mL) was used to induce cytotoxicity and then treated with an optimum dose (40 μg/ mL) of CGA. According to the results, thiram distorted chondrocyte cells with enhanced apoptotic rate. But, in case of CGA, high expression of CD147 enhanced cell viability of chondrocytes, accompanied by downregulation of Bax/Caspase-3 signalling with the upregulation of Bcl-2. The first possibility has ruled out in the present study by the observation that the cells apoptosis marker, Caspase-3 showed a significant change in CD147 overexpressing cells. Conversely, immunodepletion of CD147 with enhanced cleavage of Caspase-3, indicating the activation of apoptosis in chondrocytes cells. Therefore, these findings suggest a novel insight about CD147 in thiram induced TD about the regulation of Bcl-2/Bax/Caspase-3 apoptosis-signalling axis.

Vigilance on New-Onset Atherosclerosis Following SARS-CoV-2 Infection.

The pandemic of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has become a global challenge to public health. While its typical clinical manifestations are respiratory disorders, emerging evidence of cardiovascular complications indicates the adverse interaction between SARS-CoV-2 infection and cardiovascular outcomes. Given that viral infection has emerged as an additional risk factor for atherosclerosis, in this paper, we attempt to clarify the susceptibility to new-onset atherosclerosis in individuals infected with SARS-CoV-2. Mechanistically, serving as functional receptors for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) mediates SARS-CoV-2 infection of endothelial cells (ECs) directly, leading to endothelial dysfunction and dysregulation of the renin-angiotensin system (RAS). In addition, high expression of CD147, an alternative receptor, and activation of the NLRP3 inflammasome may also contribute to atherosclerosis in the context of COVID-19. More importantly, SARS-CoV-2 attacks the immune system, which results in excessive inflammation and perpetuates a vicious cycle of deteriorated endothelial dysfunction that further promotes inflammation. The alterations in the blood lipid profile induced by COVID-19 should not be ignored in assessing the predisposition toward atherosclerosis in victims of COVID-19. A better understanding of the underlying mechanisms of SARS-CoV-2 infection and the long-term monitoring of inflammatory factors and endothelial function should be considered in the follow-up of patients who have recovered from COVID-19 for early detection and prevention of atherosclerosis.

Psychological Stress Up-Regulates CD147 Expression Through Beta-Arrestin1/ERK to Promote Proliferation and Invasiveness of Glioma Cells.

Psychological stress is closely related to the occurrence and prognosis of various malignant tumors, but the underlying mechanisms are not well studied. CD147 has been reported to be expressed in glioma and other malignant tumors. CD147 not only participates in lactic acid transport, but it also plays an important role in the invasion and metastasis of malignant tumor cells by stimulating the production of numerous matrix metalloproteinases (MMPs) and vascular endothelial growth factor by fibroblasts, and could also act as an autocrine factor stimulating MMPs production in metastatic tumor cells. Here, we found that silencing CD147 in chronically stressed nude mice not only inhibited the proliferation of xenografts but also decreased matrix metalloproteinase-2, 9 expression and lactic acid content in tumor tissues. Furthermore, norepinephrine (NE) was significantly increased in the serum of nude mice in glioma stress model. To determine the underlying cellular mechanism, we added exogenous NE into LN229 and U87 cells to simulate the stress environment in vitro. The invasiveness of the glioma cells was subsequently examined using a Matrigel invasion assay. We demonstrated that knockdown of CD147 inhibited glioma invasiveness and metastasis with norepinephrine stimulation. Luciferase reporter gene experiments further demonstrated that the expression of CD147 is up-regulated primarily by norepinephrine via the β-Adrenalin receptor (βAR)-β-arrestin1-ERK1/2-Sp1 pathway. High expression of CD147 promoted the secretion of MMP-2 and the increment of lactic acid, which accelerated the augmented invasion and metastasis of glioma induced by psychological stress. Taken together, these results suggest that psychological stress promotes glioma proliferation and invasiveness by up-regulating CD147 expression. Thus, CD147 might be a potential target site in the treatment of glioma progression induced by chronic psychological stress.

CD147 Expression Is Associated with Tumor Proliferation in Bladder Cancer via GSDMD.

Purpose CD147, also known as BSG, is a type I transmembrane glycoprotein that belonged to immunoglobulin superfamily. Mature CD147 is an N-linked glycosylated protein and exists on the transmembrane and as soluble forms in tumors. However, the function of CD147 in cell proliferation of bladder cancer (BC) remains to be elucidated. Methods The study included 159 patients with BC and 68 healthy controls. The expression of CD147 and gasdermin D (GSDMD) was analyzed by immunohistochemistry (IHC). Western blotting was performed to detect the expression of proteins in BC cells. The relationship between CD147 and GSDMD was analyzed by the IHC score. Results The expression of CD147 was significantly increased in BC when compared to healthy controls, and the level of CD147 was correlated with tumor proliferation characterized by Ki-67, which is a cell proliferation antigen. In addition, CD147 treatment of BC cells increased the expression of GSDMD, leading to increased Ki-67 expression, while CD147 blockade with peptide in BC significantly reduced GSDMD expression, resulting in reduced cell proliferation. Furthermore, overexpression of GSDMD markedly overcame the inhibitory effect of CD147 peptide on tumor proliferation. BC patients with overexpression of CD147 showed correlation with GSDMD and demonstrated significantly poorer prognosis and overall survival rate. Conclusion These findings suggested that high expression of CD147 contributed to tumor proliferation in BC via GSDMD, which might in turn act as an unfavorable prognostic marker.

MiR-890 inhibits proliferation and invasion and induces apoptosis in triple-negative breast cancer cells by targeting CD147

BackgroundTriple-negative breast cancer (TNBC) is a type of breast cancer with a high degree of malignancy. Because of the remarkable biological characteristics of high invasion, metastasis and recurrence, TNBC is often accompanied by a poor prognosis. As a molecular characteristic of TNBC, high expression of CD147 has been confirmed by a large number of studies. However, the mechanism of CD147 expression regulation in TNBC remains elusive. In this study, we investigated the roles of miR-890 in inhibiting CD147.MethodsQuantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) was used to detect CD147 mRNA and miR-890 level, and western blotting was used to detect CD147 protein. Bioinformatics screening and 3′-Untranslated Region (3′-UTR) luciferase assays were used to analyze the microRNAs (miRNA) binding site. Cell proliferation, apoptosis and invasion were assessed by using CCK-8, flow cytometry and transwell assays.ResultsThe upregulation of miR-890 inhibited cell proliferation and invasion, induced apoptosis in MDA-MB-231 and HCC-70 TNBC cells by negatively regulating its target gene, CD147, and the upregulation of CD147 rescued the inhibitory effects of miR-890. miR-890 targeted CD147 by binding to its 3′-UTR. Further results showed that the upregulation of miR-890 also inhibited the expression of MMPs, the downstream genes of CD147, and promoted the cleavage of Caspase-3. The CD147 recovery experiment was further confirmed by the activity changes in the downstream MMPs of CD147. In addition, it was confirmed that the effect of CD147 in promoting TNBC cell proliferation and invasion, inhibiting apoptosis was related to the change in caspase-3 activity.ConclusionThe downregulation of miR-890 is the potential cause of high CD147 expression in TNBC, which can promote the malignant transformation of TNBC.

CD147-mediated glucose metabolic regulation contributes to the predictive role of 18 F-FDG PET/CT imaging for EGFR-TKI treatment sensitivity in NSCLC.

The aim of this study is to investigate the role of CD147 in glucose metabolic regulation and its association with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment sensitivity prediction using 18 F-fluorodeoxyglucose (18 F-FDG) PET/CT imaging in non-small cell lung cancer (NSCLC). In this study, four human NSCLC cell lines with different EGFR-TKI responses were used to detect p-EGFR/EGFR and CD147 expression via Western blotting and flow cytometric analyses. Radioactive uptake of 18 F-FDG by established stable NSCLC cell lines (HCC827, H1975) with different levels of CD147 expression and the corresponding xenografts was assessed through γ-radioimmunoassays in vitro and micro-PET/CT imaging in vivo to study the role of CD147 in glucose metabolic reprogramming. Correlation analyses were performed to investigate the association between CD147 expression and PD-L1 expression in stable NSCLC cell lines. Higher CD147 expression was found in EGFR-TKI-sensitive NSCLC cell lines than in relatively resistant NSCLC cell lines (HCC827>PC9>A549>H1975). CD147 could promote 18 F-FDG uptake by HCC827 and H1975 cells in vitro and in vivo through an EGFR-initiated Akt/mTOR-dependent signaling pathway. Programmed cell death-ligand 1 (PD-L1) expression was positively correlated with CD147 expression in human NSCLC cell lines. EGFR-TKI treatment sensitivity prediction in NSCLC using 18 F-FDG PET/CT imaging significantly correlated with CD147-mediated glucose metabolic regulation via the Akt/mTOR-dependent pathway. Moreover, PD-L1 expression in NSCLC cell lines could be regulated by CD147, suggesting a potential immunosuppression induced by the upregulation of tumor glucose metabolism.

Efficacy Evaluation of Combination Treatment Using Gemcitabine and Radioimmunotherapy with 90Y-Labeled Fully Human Anti-CD147 Monoclonal Antibody 059-053 in a BxPC-3 Xenograft Mouse Model of Refractory Pancreatic Cancer.

The poor prognosis of pancreatic cancer requires the development of more effective therapy. CD147 expresses in pancreatic cancer with high incidence and has a crucial role in invasion and metastasis. We developed a fully human monoclonal antibody (059-053) with high affinity for CD147. Here we evaluated the efficacy of combined treatment using radioimmunotherapy (RIT) with 90Y-labeled 059-053 and gemcitabine in a BxPC-3 xenograft mouse model. Expression of CD147 and matrix metalloproteinase-2 (MMP2) in BxPC-3 tumors was evaluated. In vitro and in vivo properties of 059-053 were evaluated using 111In-labeled 059-053 and a pancreatic cancer model BxPC-3. Tumor volume and body weight were periodically measured in mice receiving gemcitabine, RIT, and both RIT and gemcitabine (one cycle and two cycles). High expression of CD147 and MMP2 was observed in BxPC-3 tumors and suppressed by 059-053 injection. Radiolabeled 059-053 bound specifically to BxPC-3 cells and accumulated highly in BxPC-3 tumors but low in major organs. Combined treatment using RIT with gemcitabine (one cycle) significantly suppressed tumor growth and prolonged survival with tolerable toxicity. The two-cycle regimen had the highest anti-tumor effect, but was not tolerable. Combined treatment with 90Y-labeled 059-053 and gemcitabine is a promising therapeutic option for pancreatic cancer.

RNA interference targeting CD147 inhibits metastasis and invasion of human breast cancer MCF-7 cells by downregulating MMP-9/VEGF expression.

Breast cancer is one of the most common malignancies. It is necessary to identify new markers for predicting tumor progression and therapeutic molecular targets. It has been reported that CD147 is one of the most commonly expressed proteins in primary tumors and in metastatic cells. In this study, we investigated the role of CD147 in human breast cancer metastasis and invasion, and examined its underlying molecular mechanisms. Immunohistochemistry results revealed high expression of CD147 in human breast tumor tissues, which was positively correlated with the malignancy of breast cancer. MCF-7 cells were transfected with CD147 siRNA eukaryotic expression vector, which resulted in significant knockdown of CD147. We found that CD147 siRNA dramatically inhibited cell proliferation, metastasis, and invasion. Furthermore, our results demonstrated that CD147 siRNA inhibited the synthesis of matrix metalloproteinase 9 (MMP-9) but had no significant effect on matrix metalloproteinase 2 (MMP-2). In addition, CD147 siRNA significantly inhibited the production of vascular endothelial growth factor (VEGF). Taken together, these data indicate that CD147 promotes breast cancer cell proliferation, metastasis, and invasion by modulating MMP-9 and VEGF expression. Thus, CD147 may be used as an important indicator for the judgment of malignant behavior of breast cancer, and may be a potential novel target for breast cancer therapy.

Ratio of CD147high/CD147low in CD4+CD25+ T cells: A potential biomarker for early diagnosis and prediction of response to therapy for autoimmune diseases

Regulatory T cell (Treg cell) is an important immunosuppressive T cell subset and plays a dominant role in maintaining the immune balance in vivo. The function defects in Treg cells have been involved in the pathogenesis of many autoimmune diseases. The detection of Treg cell suppressive function is important for early diagnosis and prediction of response to treatment for autoimmune diseases. The traditional detection of Treg cell suppressive function needs at least 20 mL peripheral blood sample of patients and the results would be got in sixth day, therefore, it could not be widely applied in clinical. However, to find fast and simple detection method is very important. CD147 is a transmembrane protein and its expression is related to Treg cell suppressive function. Recent research has shown that the Treg cells with high CD147 expression have stronger suppressive function than which with low CD147 expression. In this work, we detected the ratio of CD147high/CD147low in CD4+CD25+ T cells in patients with active AS using fluorescence-activated cell sorter (FACS). The results show the ratio of CD147high/CD147low decreased obviously in patients with active AS compared with healthy controls, which reflects the suppressive function deficit of Treg cell. In the same time, the detection of the ratio of CD147high/CD147low needs only 150 μL peripheral blood sample and the result would be got in 4 h. We therefore hypothesize that the ratio of CD147high/CD147low is a good indicator for the Treg cell function, and it is especially suitable for early diagnosis and prediction of response to therapy targeted recovering Treg cell function in autoimmune diseases.

CD147-mediated chemotaxis of CD4+CD161+ T cells may contribute to local inflammation in rheumatoid arthritis.

CD161 is used as a surrogate marker for Th17 cells, which are implicated in the pathogenesis of rheumatoid arthritis (RA). In this study, we evaluated the percentage, clinical significance, and CD98 and CD147 expression of CD4+CD161+ T cells. The potential role of CD147 and CD98 in cyclophilin A-induced chemotaxis of CD4+CD161+ T cells was analyzed. Thirty-seven RA patients, 15 paired synovial fluid (SF) of RA, and 22 healthy controls were recruited. The cell populations and surface expression of CD98 and CD147 were analyzed by flow cytometry. Spearman's rank correlation coefficient and multiple linear regression were applied to calculate the correlations. Chemotaxis assay was used to investigate CD4+CD161+ T cell migration. We found that the percentage of CD4+CD161+ T cells and their expression of CD147 and CD98 in SF were higher than in the peripheral blood of RA patients. Percentage of SF CD4+CD161+ T cells was positively correlated with 28-Joint Disease Activity Score (DAS28). CD147 monoclonal antibody (HAb18) attenuated the chemotactic ability of CD4+CD161+ T cells. An increased CD4+CD161+ T cell percentage and expression of CD147 and CD98 were shown in RA SF. Percentage of SF CD4+CD161+ T cells can be used as a predictive marker of disease activity in RA. CD147 block significantly decreased the chemotactic index of CD4+CD161+ cells induced by cyclophilin A (CypA). These results imply that the accumulation of CD4+CD161+ T cells in SF and their high expression of CD147 may be associated with CypA-mediated chemotaxis and contribute to local inflammation in RA.

CD147 blockade as a potential and novel treatment of graft rejection.

Cluster of differentiation (CD)147 is highly involved in the T cell activation process. High CD147 expression is observed on the surfaces of activated T cells, particularly CD4+ T cells. In organ transplantation, it is important to prevent graft rejection resulting from the excessive activation of T cells, particularly CD4+ T cells, which exhibit a key role in amplifying the immune response. The present study aimed to investigate the effects of CD147 blockade in vitro and in vivo and used a transplant rejection system to assess the feasibility of utilizing CD147 antibody-based immunosuppressant drugs for the treatment of graft rejection. The effects of CD147 antibodies were evaluated on lymphocyte proliferation stimulated by phytohemagglutinin or CD3/CD28 magnetic beads and in a one-way mixed lymphocyte reaction (MLR) system in vitro. For the in vivo analysis, an allogeneic skin transplantation mouse model was used. CD147 antibodies were effective against lymphocytes, particularly CD4+T lymphocytes, and were additionally effective in the one-way MLR system. In the allogeneic skin transplantation mouse model, the survival of transplanted skin was extended in the CD147 antibody-treated group. Furthermore, the level of inflammatory cell infiltration in transplanted skin was reduced. CD147 blockade decreased the serum levels of interleukin (IL)-17 and the proportions of peripheral blood CD4+ and CD8+ memory T cells. The data demonstrated that CD147 blockade suppressed skin graft rejection, primarily by suppressing CD4+T and memory T cell proliferation, indicating that CD147 exhibits great potential as a target of immunosuppressant drugs.