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Finding effective treatments for cancer remains a challenge. Recent studies have found that the mechanisms of tumor evasion are becoming increasingly diverse, including abnormal expression of immune checkpoint molecules on different immune cells, in particular T cells, natural killer cells, macrophages and others. In this review, we discuss the checkpoint molecules with enhanced expression on these lymphocytes and their consequences on immune effector functions. Dissecting the diverse roles of immune checkpoints in different immune cells is crucial for a full understanding of immunotherapy using checkpoint inhibitors.
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Imunoterapia , Neoplasias , Humanos , Neoplasias/patologia , Linfócitos T/metabolismo , Células Matadoras Naturais , Terapia de Alvo MolecularRESUMO
VIMAS1, a cancerspecific long noncoding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIMAS1 in the proliferation and resistance to antiandrogen therapy of LNCaP and C42 prostate cancer cells remains to be determined. In the current study, gainandloss experiments were used to investigate the effects of VIMAS on the proliferation and antiandrogen therapy of LNCaP and C42 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIMAS1 driving prostate progression. It was demonstrated that VIMAS1 was upregulated in C42 cells, an established castrationresistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormonesensitive prostate cancer cell line. The present study further demonstrated that VIMAS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIMAS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIMAS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C42 cells in vitro and in vivo. Mechanistically, 3hydroxy3methylglutarylCoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIMAS1, and VIMAS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIMAS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNAprotein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIMAS1 overexpression. Overall, the present study determined the roles and mechanism of the VIMAS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIMAS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.
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Resistencia a Medicamentos Antineoplásicos , Neoplasias de Próstata Resistentes à Castração , RNA Longo não Codificante , Humanos , Masculino , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Hidroximetilglutaril-CoA Sintase/metabolismo , Nitrilas/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , RNA Longo não Codificante/genética , Estabilidade de RNARESUMO
BACKGROUND: Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. METHODS: CD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. RESULTS: CD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. CONCLUSIONS: Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors.
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Imunoconjugados , Miofibroblastos , Animais , Antígenos CD/metabolismo , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/metabolismo , Fibrose , Células Estreladas do Fígado/metabolismo , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/metabolismo , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Camundongos , Miofibroblastos/metabolismoRESUMO
Human leukocyte antigen (HLA)-G is a nonclassical MHC Class I molecule, which was initially reported as a mediator of immune tolerance when expressed in extravillous trophoblast cells at the maternal-fetal interface. HLA-G is the only known ligand of killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), an atypical family molecule that is widely expressed on the surface of NK cells. Unlike other KIR receptors, KIR2DL4 contains both an arginine-tyrosine activation motif in its transmembrane region and an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail, suggesting that KIR2DL4 may function as an activating or inhibitory receptor. The immunosuppressive microenvironment exemplified by a rewired cytokine network and upregulated immune checkpoint proteins is a hallmark of advanced and therapy-refractory tumors. Accumulating evidence has shown that HLA-G is an immune checkpoint molecule with specific relevance in cancer immune escape, although the role of HLA-G/KIR2DL4 in antitumor immunity is still uncharacterized. Our previous study had shown that HLA-G was a pivotal mediator of breast cancer resistance to trastuzumab, and blockade of the HLA-G/KIR2DL4 interaction can resensitize breast cancer to trastuzumab treatment. In this review, we aim to summarize and discuss the role of HLA-G/KIR2DL4 in the immune microenvironment of breast cancer. A better understanding of HLA-G is beneficial to identifying novel biomarker(s) for breast cancer, which is important for precision diagnosis and prognostic assessment. In addition, it is also necessary to unravel the mechanisms underlying HLA-G/KIR2DL4 regulation of the immune microenvironment in breast cancer, hopefully providing a rationale for combined HLA-G and immune checkpoints targeting for the effective treatment of breast cancer.
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Neoplasias da Mama/genética , Antígenos HLA-G/genética , Receptores KIR2DL4/genética , Microambiente Tumoral/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Antígenos HLA-G/imunologia , Humanos , Células Matadoras Naturais/imunologia , Receptores KIR2DL4/imunologia , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVES: The aim of this study was to explore the expression of Galectin-9 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), evaluate its clinicopathological significance, and investigate whether Galecin-9 expression has prognostic value in HBV-associated HCC. METHODS: Immunohistochemistry staining was performed to examine the expression of Galectin-9 in paraffin-embedded tissues from 140 cases of HBV-associated HCC specimens. The association between Gal-9 expression, clinicopathological features and prognosis was analyzed by Kaplan-Meier method, log-rank test and Cox regression analysis. Dual immunofluorescence (IF) staining was performed to identify the cell types that have positive Gal-9 expression. RESULTS: Among the 140 cases of HBV-associated HCC, 39 (27.9%) cases showed high Gal-9 expression (score≥6), 21 (15%) cases showed moderate Gal-9 expression (6>score≥3), 33 (23.6%) cases showed weak Gal-9 expression (3>score>0), and 47 (33.6%) cases had no detectable Gal-9 expression (score=0). Positive Gal-9 expression (score>0) was associated with lymph node metastasis (P=0.029), Ki-67 proliferation index (P=0.009) and poor prognosis. Univariate and multivariate analyses showed that Gal-9 expression could be used as an independent prognostic marker for HBV-associated HCC. Dual IF staining indicated that Gal-9 was mainly expressed in CD68+CD163+ Kupffer cells (KCs) in HBV-associated HCC. CONCLUSIONS: Gal-9 was specifically expressed in certain HBV-associated HCC. Positive Gal-9 expression was significantly associated with poor prognosis, and Gal-9 could be used as a prognostic marker in HBV-associated HCC. Specific expression of Gal-9 on KCs indicated it may have immunosuppressive function in HBV-associated HCC.
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Carcinoma Hepatocelular , Galectinas/metabolismo , Hepatite B , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Hepatite B/complicações , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/patologia , PrognósticoRESUMO
Bladder cancer (BLCA) is the most common malignancy whose early diagnosis can ensure a better prognosis. However, the predictive accuracy of commonly used predictors, including patients' general condition, histological grade, and pathological stage, is insufficient to identify the patients who need invasive treatment. Autophagy is regarded as a vital factor in maintaining mitochondrial function and energy homeostasis in cancer cells. Whether autophagy-related genes (ARGs) can predict the prognosis of BLCA patients deserves to be investigated. Based on BLCA data retrieved from the Cancer Genome Atlas and ARGs list obtained from the Human Autophagy Database website, we identified prognosis-related differentially expressed ARGs (PDEARGs) through Wilcox text and constructed a PDEARGs-based prognostic model through multivariate Cox regression analysis. The predictive accuracy, independent forecasting capability, and the correlation between present model and clinical variables or tumor microenvironment were evaluated through R software. Enrichment analysis of PDEARGs was performed to explore the underlying mechanism, and a systematic prognostic signature with nomogram was constructed by integrating clinical variables and the aforementioned PDEARGs-based model. We found that the risk score generated by PDEARGs-based model could effectively reflect deteriorated clinical variables and tumor-promoting microenvironment. Additionally, several immune-related gene ontology terms were significantly enriched by PDEARGs, which might provide insights for present model and propose potential therapeutic targets for BLCA patients. Finally, a systematic prognostic signature with promoted clinical utility and predictive accuracy was constructed to assist clinician decision. PDEARGs are valuable prognostic predictors and potential therapeutic targets for BLCA patients.
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Autofagia/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Biomarcadores Tumorais/genética , Correlação de Dados , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Nomogramas , Prognóstico , Fatores de Risco , Microambiente Tumoral/genéticaRESUMO
Head and neck cancers are a heterogeneous collection of malignancies of the upper aerodigestive tract, salivary glands, and thyroid. However, the molecular mechanisms underlying the carcinogenesis of head and neck squamous cell carcinomas (HNSCCs) remain poorly understood. Over the past decades, overwhelming evidence has demonstrated the regulatory roles of long non-coding RNAs (lncRNAs) in tumorigenesis, including HNSCC. Notably, these lncRNAs have vital roles in gene regulation and affect various aspects of cellular homeostasis, including proliferation, survival, and metastasis. They exert regulating functions by interacting with nucleic acids or proteins and affecting cancer cell signaling. LncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of lncRNAs in HNSCC. In this review, we summarize the deregulation and function of lncRNAs in human HNSCC. We also review the working mechanism of lncRNAs in HNSCC pathogenesis and discuss the potential application of lncRNAs as diagnostic/prognostic tools and therapeutic targets in human HNSCC.
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Myofibroblasts, or activated fibroblasts, play a critical role in the process of renal fibrosis. Targeting myofibroblasts to inhibit their activation or induce specific cell death has been considered to be an effective strategy to attenuate renal fibrosis. However, specific biomarkers for myofibroblasts are needed to ensure the efficacy of these strategies. Here, we verified that CD248 was mainly expressed in myofibroblasts in patients with chronic kidney disease, which was inversely correlated with renal function. The same result was also confirmed in renal fibrotic mice induced by unilateral ureteral obstruction and aristolochic acid nephropathy. By using an antibody-drug conjugate (ADC) named IgG78-DM1, in which maytansinoid (DM1) was linked to a fully human antibody IgG78 through an uncleavable SMCC linker, we demonstrated that it could effectively bind with and kill CD248+ fibroblasts in vitro and alleviate renal fibrosis in mice models. Besides, we confirmed that IgG78-DM1 had qualified biosafety in vivo. Our results confirmed that CD248 can be used as a specific marker for myofibroblasts, and specific killing of CD248+ myofibroblasts by IgG78-DM1 has excellent anti-fibrotic effect in renal fibrotic mice. Our study expanded the application of ADC and provided a novel strategy for the treatment of renal fibrosis.
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Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Sistemas de Liberação de Medicamentos , Imunoconjugados/farmacologia , Maitansina/farmacologia , Miofibroblastos/metabolismo , Insuficiência Renal Crônica , Animais , Fibrose , Masculino , Camundongos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismoRESUMO
Despite the successful use of the humanized monoclonal antibody trastuzumab (Herceptin) in the clinical treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, the frequently occurring drug resistance remains to be overcome. The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized. Here, we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer (NK) cell receptor KIR2DL4. Unless engaged by HLA-G, KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ (IFN-γ) production pathway, in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the Fcγ receptor to increase IFN-γ secretion by NK cells. Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-ß (TGF-ß) and IFN-γ, which subsequently reinforce HLA-G/KIR2DL4 signaling. In addition, TGF-ß and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells. Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo. These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.
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Neoplasias da Mama/tratamento farmacológico , Antígenos HLA-G/genética , Receptor ErbB-2/genética , Receptores KIR2DL4/genética , Trastuzumab/farmacologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/genética , Anticorpos Monoclonais Humanizados/imunologia , Citotoxicidade Celular Dependente de Anticorpos/genética , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Humanos , Interferon gama/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Pessoa de Meia-Idade , Receptores de Células Matadoras Naturais/genética , Receptores de Células Matadoras Naturais/imunologia , Trastuzumab/efeitos adversos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
e23sFv is a HER2-targeted single-chain variable fragment (scFV) that was characterized as the targeting portion of a HER2-targeted tumour proapoptotic molecule in our previous study. In vitro antibody affinity maturation is a method to enhance antibody affinity either by complementarity-determining region (CDR) mutagenesis or by framework region (FR) engraftment. In the present study, the affinity of e23sFv was enhanced using two strategies. In one approach, site-directed mutations were introduced into the FRs of e23sFv (designated EMEY), and in the other approach e23sFv FRs were substituted with FRs from the most homologous screened antibodies (designated EX1 and EX2). Notably, EX1 derived from the FR engraftment strategy demonstrated a 4-fold higher affinity for HER2 compared with e23sFv and was internalized into HER2-overexpressing cells; however, EMEY and EX2 exhibited reduced affinity for HER2 and decreased internalization potential compared with EX1. The 3D structure of EX1 and the HER2-EX1 complex was acquired using molecular homology modelling and docking and the HER2 epitopes of EX1 and the molecular interaction energy of the EX1-HER2 complex were predicted. In the present study, it was demonstrated that scFv affinity improvement based on sequence alignment was feasible and effective. Moreover, the FR grafting strategy was indicated to be more effective and simple compared with site-directed mutagenesis to improve e23sFv affinity. In conclusion, it was indicated that the affinity-improved candidate EX1 may present a great potential for the diagnosis and treatment of HER2-overexpressing tumours.
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Ring finger protein 2 (RNF2) is an important component of polycomb repressive complex 1. RNF2 is upregulated in many kinds of tumors, and elevated RNF2 expression is associated with a poor prognosis in certain cancers. To assess the function of RNF2 in colorectal cancer, we examined RNF2 protein levels in 313 paired colorectal cancer tissues and adjacent normal tissues. We then analyzed the association of RNF2 expression with the patients' clinicopathologic features and prognoses. RNF2 expression was upregulated in colorectal cancer tissues and was associated with the tumor differentiation status, tumor stage and prognosis. In colorectal cancer cell lines, downregulation of RNF2 inhibited cell proliferation and induced apoptosis. Gene microarray analysis revealed that early growth response 1 (EGR1) was upregulated in RNF2-knockdown cells. Knocking down EGR1 partially reversed the inhibition of cell proliferation and the induction of apoptosis in RNF2-knockdown cells. RNF2 was enriched at the EGR1 promoter, where it mono-ubiquitinated histone H2A, thereby inhibiting EGR1 expression. These results indicate that RNF2 is oncogenic in colorectal cancer and may promote disease progression by inhibiting EGR1 expression. RNF2 is thus a potential prognostic marker and therapeutic target in colorectal cancer.
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Apoptose/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Complexo Repressor Polycomb 1/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Código das Histonas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Complexo Repressor Polycomb 1/metabolismo , Prognóstico , Regiões Promotoras Genéticas , Ubiquitinação , Regulação para CimaRESUMO
MicroRNAs (miRNAs) are a group of non-coding RNAs that play a crucial role in post-transcriptional gene regulation and act as indispensable mediators in several critical biological processes, including tumorigenesis, tissue homeostasis, and regeneration. MiR-424 and miR-503 are intragenic miRNAs that are clustered on human chromosome Xq26.3. Previous studies have reported that both miRNAs are dysregulated and play crucial but paradoxical roles in tumor initiation and progression, involving different target genes and molecular pathways. Moreover, these two miRNAs are concomitantly expressed in several cancer cells, indicating a coordinating function as a cluster. In this review, the roles and regulatory mechanisms of miR-424, miR-503, and miR-424/503 cluster are summarized in different types of cancers.
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MicroRNAs/genética , Neoplasias/genética , Cromossomos Humanos X/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Família MultigênicaRESUMO
Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, cross-talk between these two kinds of cells has not been well studied. Endosialin (CD248/TEM1) is a transmembrane glycoprotein that is expressed in certain cancer cells, tumor stromal cells, and pericytes. In this study, we found that endosialin is mainly expressed in cancer-associated fibroblasts (CAF) in HCC and its expression inversely correlates with patient prognosis. Endosialin interacted with CD68 to recruit macrophages and regulated expression of GAS6 in CAFs to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAFs, thus weakening the cross-talk between CAFs and macrophages. In subcutaneous and orthotopic xenograft models of HCC in nude mice, treatment with IgG78 significantly inhibited tumor growth. These results indicate that endosialin-positive CAFs promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment. SIGNIFICANCE: These findings highlight CAF-expressed endosialin as a primary regulator of macrophage recruitment and polarization and demonstrate endosialin inhibition as a potential treatment strategy for HCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3892/F1.large.jpg.
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Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígenos de Neoplasias/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Hepatocelular/metabolismo , Comunicação Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos Associados a Tumor/metabolismo , Animais , Especificidade de Anticorpos , Antígenos CD/efeitos dos fármacos , Antígenos CD/imunologia , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Fibroblastos Associados a Câncer/fisiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Movimento Celular , Polaridade Celular , Progressão da Doença , Glicosilação , Humanos , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/uso terapêutico , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos , Camundongos Nus , Macrófagos Associados a Tumor/fisiologiaRESUMO
In the past two decades, miRNAs have been demonstrated to play critical roles in development and progression of malignant diseases. To identify the role and mechanism of miRNA are urgent for the application of miRNA-based therapeutics in cancers. MiR-205 is a conserved miRNA from the invertebrate to mammalian species. Previous studies showed a large body of evidence to demonstrate the oncogenic or tumor suppressive role of it in different types of cancers. Our aim here is to clarify the role and novel mechanism of miR-205 in solid tumors. In the present study, we found that a high level of miR-205 is an independent biomarker for favorable prognosis in LIHC, HNSCC and LUSC. In the functional experiment, we stably expressed miR-205 in tumor cell lines derived from above mentioned cancers. The result showed that overexpression of miR-205 significantly inhibits cancer cell proliferation. Mechanistically, we identified that the lysophosphatidylcholine acyltransferase-1 (LPCAT1) is a novel target of miR-205 in multiple cancer cells. Furthermore, we found that LPCAT1 is required for sustained proliferation of cancer cells and a high level of it is closely associated with poor prognosis in clinical patients. Collectively, we revealed the important prognostic value of a miR-205-LPCAT1 axis in multiple cancers and highlighted an essential role of LPCAT1 in miR-205-regulated cancer cell proliferation. All these discoveries make a miR-205-LPCAT1 axis to shed light upon a potential therapeutic target in cancer treatment.
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1-Acilglicerofosfocolina O-Aciltransferase/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/genética , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Humanos , Neoplasias/diagnóstico , PrognósticoRESUMO
Pseudogenes were initially regarded as "nonfunctional" genomic elements that did not have protein-coding abilities due to several endogenous inactivating mutations. Although pseudogenes are widely expressed in prokaryotes and eukaryotes, for decades, they have been largely ignored and classified as gene "junk" or "relics". With the widespread availability of high-throughput sequencing analysis, especially omics technologies, knowledge concerning pseudogenes has substantially increased. Pseudogenes are evolutionarily conserved and derive primarily from a mutation or retrotransposon, conferring the pseudogene with a "gene repository" role to store and expand genetic information. In contrast to previous notions, pseudogenes have a variety of functions at the DNA, RNA and protein levels for broadly participating in gene regulation to influence the development and progression of certain diseases, especially cancer. Indeed, some pseudogenes have been proven to encode proteins, strongly contradicting their "trash" identification, and have been confirmed to have tissue-specific and disease subtype-specific expression, indicating their own value in disease diagnosis. Moreover, pseudogenes have been correlated with the life expectancy of patients and exhibit great potential for future use in disease treatment, suggesting that they are promising biomarkers and therapeutic targets for clinical applications. In this review, we summarize the natural properties, functions, disease involvement and clinical value of pseudogenes. Although our knowledge of pseudogenes remains nascent, this field deserves more attention and deeper exploration.
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Regulação da Expressão Gênica/genética , Neoplasias/genética , Pseudogenes/fisiologia , Biomarcadores , Técnicas e Procedimentos Diagnósticos , Evolução Molecular , Humanos , Expectativa de Vida , Mutação , Prognóstico , Pseudogenes/genética , Terapêutica/estatística & dados numéricosRESUMO
UHRF1 is an important epigenetic regulator that belongs to the UHRF family. Overexpression of UHRF1 has been found in many kinds of tumors and its overexpression is associated with poor prognosis and short survival in certain cancer types. However, its function in renal cell carcinoma (RCC) is not clear. Here we report that RCC tumor tissues had obviously higher UHRF1 expression than normal renal tissues. Downregulation of UHRF1 by siRNA or shRNA in RCC cell lines resulted in decreased cell viability, inhibited cell migration and invasion, and increased apoptosis. UHRF1 knockdown RCC xenografts also resulted in obviously inhibited tumor growth in vivo. After downregulation of UHRF1 in RCC cells, the expression of TXNIP was upregulated. In addition, after UHRF1 and TXNIP were simultaneously downregulated, cell viability and cell invasion increased, whereas cell apoptosis decreased compared with UHRF1 single downregulated cells. We also showed that UHRF1 could recruit HDAC1 to the TXNIP promoter and mediate the deacetylation of histone H3K9, resulting in the inhibition of TXNIP expression. Our results confirm that UHRF1 has oncogenic function in RCC and UHRF1 may promote tumor progression through epigenetic regulation of TXNIP. UHRF1 might be used as a therapeutic target for RCC treatment.
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Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Carcinoma de Células Renais/patologia , Proteínas de Transporte/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Renais/patologia , Ubiquitina-Proteína Ligases/fisiologia , Acetilação , Animais , Apoptose , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Xenoenxertos , Histonas/metabolismo , Humanos , Neoplasias Renais/genética , Camundongos , Camundongos Nus , Invasividade NeoplásicaRESUMO
INTRODUCTION: Prostate-specific membrane antigen (PSMA) was originally found to be specifically expressed in normal prostate, and its expression was upregulated in almost all stages of prostate cancer. In recent years, PSMA was also found to be expressed in tumor-associated vasculature in many nonprostatic solid tumors. However, the expression pattern of PSMA in hepatocellular carcinoma (HCC) is not well studied. METHODS: In this study, we examined PSMA expression in 103 HCC tissues using immunohistochemical staining and analyzed the association between PSMA expression and other clinicopathological features and prognosis. RESULTS: Among the 103 cases, 27 cases (26%) showed PSMA expression in more than 50% of tumor-associated vasculature, 49 cases (48%) showed PSMA expression in less than 50% of vasculature, and 27 cases (26%) did not have detectable PSMA expression. Vascular PSMA expression was associated with several clinicopathological features, such as tumor stage, tumor differentiation, lymph node metastasis, and Ki-67 index. Furthermore, high vascular PSMA expression was also associated with poor prognosis in patients with HCC. Univariate and multivariate analyses showed that high vascular PSMA expression can be used as an independent prognostic marker for HCC. DISCUSSION: Our study provides the evidence that PSMA is specifically expressed in tumor-associated vasculature of HCC, and vascular PSMA expression may be used as a novel prognostic marker and a vascular therapeutic target for HCC.
Assuntos
Antígenos de Superfície/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Glutamato Carboxipeptidase II/metabolismo , Neoplasias Hepáticas/mortalidade , Neovascularização Patológica/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/análise , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Feminino , Seguimentos , Glutamato Carboxipeptidase II/análise , Glutamato Carboxipeptidase II/antagonistas & inibidores , Hepatectomia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Fígado/irrigação sanguínea , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica/mortalidade , Neovascularização Patológica/terapia , Prognóstico , Fatores de Tempo , Adulto JovemRESUMO
Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related death. It is of vital importance to develop new strategies for prostate cancer therapy. PSMA (prostate-specific membrane antigen) is specifically expressed in prostate cancer and the neovasculature of certain cancer types, thus is considered to be an ideal target for cancer therapy. In our previous study, we have obtained a PSMA-specific single-chain variable fragment (scFv), named gy1, from a large yeast display naïve human scFv library. In this study, we reconstructed the PSMA scFv into a fully human antibody (named PSMAb) and evaluated its characterization both in vitro and in vivo We showed that PSMAb can specifically bind with and internalize into PSMA+ cells. The binding affinity of PSMAb is measured to be at nanomolar level, and PSMAb has very good thermostability. In vivo study showed that near IR dye-labeled PSMAb can specifically localize at PSMA+ tumors, and the application of PSMAb in vivo significantly inhibited the growth of PSMA+ tumors, but not PSMA- tumors. At the studied doses, no obvious toxicity was observed when applied in vivo, as shown by the relative normal liver and kidney function and normal structure of important organs, shown by hematoxylin and eosin staining. In addition, PSMAb may inhibit tumor growth through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity mechanisms. Our results indicated that the novel fully human antibody, PSMAb, deserve further study for PSMA-targeted diagnosis and therapy for prostate cancer and other cancer types with vascular PSMA expression.
Assuntos
Glutamato Carboxipeptidase II/genética , Glicoproteínas de Membrana/genética , Neoplasias da Próstata/genética , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/patologiaRESUMO
Background and Aims: Prostate specific membrane antigen (PSMA) is specifically expressed on prostate epithelial cells and markedly overexpressed in almost all prostate cancers. TRIM24 is also up-regulated from localized prostate cancer to metastatic castration-resistant prostate cancer (CRPC). Because of the high relevance of TRIM24 for cancer development and the universal expression of PSMA in CPRC, we investigated the efficacy of human monoclonal PSMA antibody (PSMAb)-based platform for the targeted TRIM24 siRNA delivery and its therapeutic efficacy in CRPC in vivo and in vitro. Methods: The therapeutic complexes were constructed by conjugating PSMAb and sulfo-SMCC-protamine, and encapsulating TRIM24 siRNA. Flow cytometry, immunofluorescence, and fluorescence imaging were performed to detect the receptor-binding, internalization, and targeted delivery of PSMAb-sulfo-SMCC-protamine (PSP)-FAM-siRNA complex (PSPS) in vitro and in vivo. CCK-8, plate-colony formation, apoptosis, cell cycle, and Transwell assays were performed to evaluate the therapeutic potential of the PSP-TRIM24 siRNA complex in vitro, whereas the in vivo therapeutic efficacy was monitored by small animal imaging, radiography, and micro CT. Results: We confirmed that PSP could efficiently protect siRNA from enzymatic digestion, enable targeted delivery of siRNA, and internalize and release siRNA into PSMA-positive (PSMA+) prostate cancer cells in vitro and in vivo. Silencing TRIM24 expression by the PSP-TRIM24 siRNA complex could dramatically suppress proliferation, colony-formation, and invasion of PSMA+ CRPC cells in vitro, and inhibit tumor growth of PSMA+ CRPC xenografts and bone loss in PSMA+ CRPC bone metastasis model without obvious toxicity at therapeutic doses in vivo. Conclusion: PSMAb mediated TRIM24 siRNA delivery platform could significantly inhibit cell proliferation, colony-formation, and invasion in PSMA+ CRPC in vitro and suppressed tumor growth and bone loss in PSMA+ CRPC xenograft and bone metastasis model.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos de Superfície/imunologia , Proteínas de Transporte/antagonistas & inibidores , Glutamato Carboxipeptidase II/imunologia , Terapia de Alvo Molecular/métodos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , RNA Interferente Pequeno/administração & dosagem , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Nus , Modelos Teóricos , Usos Terapêuticos , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Human colorectal cancer (CRC), characterized by its high morbidity and lethality, seriously threatens human health and lives. MicroRNA-487b (miR-487b) is currently reported to be aberrantly expressed in several tumors, but the detailed functions and underlying mechanisms of miR-487b in CRC remain unclear. Here, we found that miR-487b is downregulated in CRC cell lines and is markedly decreased in tumor specimens derived from CRC patients. MiR-487b inhibits cell proliferation, migration and invasion and promotes the apoptosis of CRC cells in vitro. Statistical analysis of clinical samples indicates that miR-487b may serve as a biomarker for early CRC diagnosis. Inverse correlations between the expression levels of MYC, SUZ12, and KRAS and that of miR-487b exist in vitro and in CRC patient tissue specimens. Further experiments demonstrated the regulatory effects of miR-487b on MYC, SUZ12, and KRAS, and the disruption of these genes partially restores the miR-487b inhibitor-induced phenotype. Additionally, miR-487b promoter region is in a DNA hypermethylated condition and the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza) increases the levels of miR-487b but suppresses the expression of MYC, SUZ12, and KRAS in a time- and concentration-dependent manner in CRC cells. Collectively, miR-487b is regulated by DNA methylation and it functions as a tumor suppressor in CRC mainly through targeting MYC, SUZ12, and KRAS. Our study provides insight into the regulatory network in CRC cells, offering a new target for treating CRC patients.