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N-methyladenosine (m6A) represents a prevalent RNA modification observed in colorectal cancer. Despite its abundance, the biological implications of m6A methylation on the lncRNA CARMN remain elusive in colorectal cancer, especially for mutant p53 gain-of-function. Here, we elucidate that CARMN exhibits diminished expression levels in colorectal cancer patients with mutant p53, attributed to its rich m6A methylation, which promotes cancer proliferation, invasion and metastasis in vitro and in vivo. Further investigation illustrates that ALKBH5 acts as a direct demethylase of CARMN, targeting 477 methylation sites, thereby preserving CARMN expression. However, the interaction of mutant p53 with the ALKBH5 promoter impedes its transcription, enhancing m6A methylation levels on CARMN. Subsequently, YTHDF2/YTHDF3 recognise and degrade m6A-modified CARMN. Concurrently, overexpressing CARMN significantly suppressed colorectal cancer progression in vitro and in vivo. Additionally, miR-5683 was identified as a direct downstream target of lncRNA CARMN, exerting an antitumour effect by cooperatively downregulating FGF2 expression. Our findings revealed the regulator and functional mechanism of CARMN in colorectal cancer with mutant p53, potentially offering insights into demethylation-based strategies for cancer diagnosis and therapy. The m6A methylation of CARMN that is prime for mutant p53 gain-of-function-induced malignant progression of colorectal cancer, identifying a promising approach for cancer therapy.
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Homólogo AlkB 5 da RNA Desmetilase , Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Proteína Supressora de Tumor p53 , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Camundongos , Progressão da Doença , Desmetilação , Linhagem Celular Tumoral , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Camundongos Nus , Regulação Neoplásica da Expressão GênicaRESUMO
Epigenetic changes are heritable changes in gene expression without changes in the nucleotide sequence of genes. Epigenetic changes play an important role in the development of cancer and in the process of malignancy metastasis. Previous studies have shown that abnormal epigenetic changes can be used as biomarkers for disease status and disease prediction. The reversibility and controllability of epigenetic modification changes also provide new strategies for early disease prevention and treatment. In addition, corresponding drug development has also reached the clinical stage. In this paper, we will discuss the recent progress and application status of tumor epigenetic biomarkers from three perspectives: DNA methylation, non-coding RNA, and histone modification, in order to provide new opportunities for additional tumor research and applications.
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a notably poor prognosis. A large number of patients with PDAC develop metastases before they are diagnosed with metastatic pancreatic cancer (mPDAC). For mPDAC, FOLFIRINOX or gemcitabine plus nab-paclitaxel are the current first-line treatments. It is important to note, however, that many patients will fail chemotherapy because of drug resistance. âHeterogeneous tumors and complex tumor microenvironments are key factors. As a result, clinical researchers are exploring a variety of alternative treatment modalities. Current understanding of the molecular signature and immune landscape of PDAC has motivated the emergence of different targeted and immune-based therapeutic approaches, some of which have shown promising results. The purpose of this review is to discuss the new targets and new drugs for mPDAC in terms of specific pathogenic factors such as metabolic vulnerability, DNA damage repair system, tumor microenvironment and immune system, in order to identify potential vulnerabilities in mPDAC patients and hopefully improve the prognosis of mPDAC patients.
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Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD. Approach & Results: We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD. Conclusions: Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.
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Breast cancer (BC), characterized by high heterogeneity, is the most commonly reported malignancy among females across the globe. Every year, many BC patients die owing to delayed diagnosis and treatment. Increasing researches have indicated that aberrantly expressed circular RNAs (circRNAs) are implicated in the tumorigenesis and progression of various tumors, including BC. Hence, this article provides a summary of the biogenesis and functions of circRNAs, as well as an examination of how circRNAs regulate the progression of BC. Moreover, circRNAs have aroused incremental attention as potential diagnostic and prognostic biomarkers for BC. Exosomes enriched with circRNAs can be secreted into the tumor microenvironment to mediate intercellular communication, affecting the progression of BC. Detecting the expression levels of exosomal circRNAs may provide reference for BC diagnosis and prognosis prediction. Illuminating insights into the earlier diagnosis and better treatment regimens of BC will be potentially available following elucidation of deeper regulatory mechanisms of circRNAs in this malignancy.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/genética , RNA Circular/genética , Transporte Biológico , Carcinogênese , Comunicação Celular , Microambiente TumoralRESUMO
Pancreatic cancer (PC), typically diagnosed at relatively advanced stages with poor prognosis, is a dominant cause of cancer-related deaths worldwide. Accumulating evidence demonstrates that circular RNAs (circRNAs) are abnormally expressed in diverse tumors and affect tumorigenesis and progression. In this article, we examine the roles of circRNAs in regulation of PC progression. Additionally, circRNAs enriched in exosomes could be transferred among PC cells to modulate malignancy. Characterization of regulatory mechanisms involving circRNAs in general and PC specifically will enable earlier detection and potential development of therapeutic strategies.
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Neoplasias Pancreáticas , RNA Circular , Humanos , RNA Circular/genética , RNA/genética , RNA Mensageiro , Neoplasias Pancreáticas/genéticaRESUMO
Ferroptosis is a new type of iron-dependent programmed cell death induced by lipid peroxidation. However, the underlying mechanisms and function in tumor therapy still remain undisclosed especially in post-transcription regulation. Here, we found that targeting AKT significantly induced GPX4 dependent ferroptosis and suppressed colorectal cancer growth both in vitro and in vivo. During this process, demethylase FTO was downregulated, which increased the m6A methylation level of GPX4, subsequently recognized by YTHDF2 and degraded. Prediction results showed that there are three potential methylated sites (193/647/766), and 193 site was identified as the right one, which was demethylated by FTO and read by YTHDF2. In parallel, AKT inhibition caused the accumulation of ROS which had a negative feedback on GPX4 expression. In addition, protective autophagy was initiated by MK2206 stimulation, while blocking autophagy further increased ferroptosis and markedly enhanced the anti-tumor activity of MK2206. In a word, inhibiting AKT activated ferroptosis through FTO/YTHDF2/GPX4 axis to suppress colon cancer progression, which raised FTO/GPX4 as potential biomarkers and targets in colorectal cancer therapy.
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Cholangiocarcinoma (CCA) is one of the most common tumors with high malignancy. Its incidence is increasing year by year, and it is insidious and easily metastasized, and most patients are already in advanced stages when they are diagnosed. Surgery is an essential treatment for CCA, but the 5-year survival rate is still unsatisfactory due to the low early diagnosis rate and high malignancy of CCA. Therefore, exploring the molecular mechanisms of CCA to find reliable biomarkers and effective therapeutic targets is essential to improve the early diagnosis and survival rate of CCA. Non-coding RNA (ncRNA) is a class of RNA without protein-coding ability, mainly including microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). In recent years, numerous pieces of evidence have shown that aberrantly expressed ncRNAs can regulate the occurrence and development of CCA through various mechanisms such as mediating epigenetic, sponge miRNAs regulating the expression of target genes and participating in regulating cancer-related signaling pathways, which provides new approaches and ideas for early diagnosis, prognosis assessment and therapeutic targeting of CCA. In this paper, we review the molecular mechanisms of lncRNAs and circRNAs regulating the progression of CCA in recent years and discuss their potential clinical value in CCA.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , MicroRNAs , RNA Longo não Codificante , Humanos , RNA não Traduzido/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Circular/genética , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-HepáticosRESUMO
CROP-Seq combines gene silencing using CRISPR interference with single-cell RNA sequencing. Here, we applied CROP-Seq to study adipogenesis and adipocyte biology. Human preadipocyte SGBS cell line expressing KRAB-dCas9 was transduced with a sgRNA library. Following selection, individual cells were captured using microfluidics at different timepoints during adipogenesis. Bioinformatic analysis of transcriptomic data was used to determine the knockdown effects, the dysregulated pathways, and to predict cellular phenotypes. Single-cell transcriptomes recapitulated adipogenesis states. For all targets, over 400 differentially expressed genes were identified at least at one timepoint. As a validation of our approach, the knockdown of PPARG and CEBPB (which encode key proadipogenic transcription factors) resulted in the inhibition of adipogenesis. Gene set enrichment analysis generated hypotheses regarding the molecular function of novel genes. MAFF knockdown led to downregulation of transcriptional response to proinflammatory cytokine TNF-α in preadipocytes and to decreased CXCL-16 and IL-6 secretion. TIPARP knockdown resulted in increased expression of adipogenesis markers. In summary, this powerful, hypothesis-free tool can identify novel regulators of adipogenesis, preadipocyte, and adipocyte function associated with metabolic disease.NEW & NOTEWORTHY Genomics efforts led to the identification of many genomic loci that are associated with metabolic traits, many of which are tied to adipose tissue function. However, determination of the causal genes, and their mechanism of action in metabolism, is a time-consuming process. Here, we use an approach to determine the transcriptional outcome of candidate gene knockdown for multiple genes at the same time in a human cell model of adipogenesis.
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Doenças Metabólicas , RNA Guia de Sistemas CRISPR-Cas , Humanos , Adipogenia/genética , Adipócitos/metabolismo , Linhagem Celular , Doenças Metabólicas/metabolismo , Diferenciação Celular/genéticaRESUMO
Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on these widely used in vitro models of human and mouse adipogenesis, and on cell-to-cell variability during this process.
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Adipogenia , Análise da Expressão Gênica de Célula Única , Transcriptoma , Humanos , Adipócitos/metabolismo , Adipogenia/genética , Tecido Adiposo/metabolismo , Diferenciação Celular , Animais , CamundongosRESUMO
Hepatocellular carcinoma (HCC) has developed into one of the most lethal, aggressive, and malignant cancers worldwide. Although HCC treatment has improved in recent years, the incidence and lethality of HCC continue to increase yearly. Therefore, an in-depth study of the pathogenesis of HCC and the search for more reliable therapeutic targets are crucial to improving the survival quality of HCC patients. Currently, miRNAs have become one of the hotspots in life science research, which are widely present in living organisms and are non-coding RNAs involved in regulating gene expression. MiRNAs exert their biological roles by suppressing the expression of downstream genes and are engaged in various HCC-related processes, including proliferation, apoptosis, invasion, and metastasis. In addition, the expression status of miRNAs is related to the drug resistance mechanism of HCC, which has important implications for the systemic treatment of HCC. This paper reviews the regulatory role of miRNAs in the pathogenesis of HCC and the clinical applications of miRNAs in HCC in recent years.
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Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on human and mouse adipogenesis, as well as on cell-to-cell variability in gene expression during this process.
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Long non-coding RNAs (LncRNAs) are single-stranded RNAs over 200 nucleotides in length that have no protein-coding function and have long been considered non-functional by-products of transcription. Recent studies have shown that dysregulation of lncRNAs may be involved in the malignant biological behavior of tumors. Targeted regulation of lncRNAs has become a research focus of anti-tumor treatment. LncRNAs heart and neural crest derivatives expressed 2 antisense RNA 1 (HAND2-AS1) was down-regulated in various tumors and can be used as a critical tumor regulator to modulate tumor cells proliferation, apoptosis, metastasis, invasion, metabolism and drug resistance. Additionally, aberrantly expressed HAND2-AS1 was closely related to the clinical pathological characteristics of cancer patients and serve as a promising tumor diagnostic and prognostic biomarker. This article aims to review the roles of HAND2-AS1 in tumorigenesis and development, as well as the underlying molecular mechanisms and clinical significance.
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Neoplasias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias/diagnóstico , Neoplasias/genética , Carcinogênese/genética , RNA Antissenso , Transformação Celular Neoplásica/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular TumoralRESUMO
Photodynamic therapy (PDT) is clinically promising in destructing primary tumors and immunotherapy awakes host immunity to control distant metastases. 5-aminolevulinic acid (5-ALA), a smart photosensitizer, converts into a physiological PDT agent with no dark toxicity in vivo. In this study, we found for the first time 5-ALA-PDT induced colorectal cancer (CRC) cells death by immunogenic cell death (ICD) upon AKT inhibition. Dying cancer cells induced by 5-ALA-PDT efficiently activated bone-marrow derived dendritic cells (BMDCs). Simultaneously, autophagy was observed after AKT inhibition by 5-ALA-PDT. Besides, we found cells died more remarkable by ICD under a circumstance of low occurrence of autophagy. To evaluate the effects of 5-ALA-PDT in vivo, we applied subcutaneous tumor mouse model and delightedly found 5-ALA-PDT induced a systemic antitumor immune response to control both primary tumors and distant metastases. Meanwhile, 5-ALA-PDT enhanced Th1 immunity, leading cytotoxic T lymphocyte response, and raised tumor-specific T cells. Combining with Chloroquine (CQ), 5-ALA-PDT further augmented tumor-specific immunity effects indicating protective role of autophagy. Together, the combination therapy of 5-ALA-PDT and autophagy inhibitor synergistically led to a novel clinical approach and potential ICD-based tumor vaccine for CRC patients.
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Neoplasias , Fotoquimioterapia , Animais , Camundongos , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Morte Celular Imunogênica , Proteínas Proto-Oncogênicas c-akt , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias/tratamento farmacológico , Imunoterapia , Linhagem Celular TumoralRESUMO
Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.
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Diabetes Mellitus Tipo 2 , Gluconeogênese , Humanos , Camundongos , Animais , Gluconeogênese/genética , Diabetes Mellitus Tipo 2/genética , Fígado , Ácido Pirúvico , Camundongos Knockout , GlucoseRESUMO
Myocardial regeneration is identified as a concept at histological level. The core content is to increase the number of cardiomyocytes (CMs), so as to maintain the steady state of CMs under pathological or physiological conditions and ensure the normal cardiac function. In this review, we discussed the relevant factors involved in the regeneration of CMs, generalized in mice, large mammals and human. During different development stages of mammalian hearts, CMs showed several controlling and growth modes on the physiological or pathological state: mitosis, hypertrophy, nuclear polyploidy and multinucleation, amitosis and etc. We also discussed the mechanisms of specific microRNAs implicated in the cardiac development, as well as disease-induced apoptosis in CMs and the process of re-entering cell cycle after injury. It is hoped that this review will contribute to a deeper understanding of therapeutic approaches for myocardial regeneration after injury.
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MicroRNAs , Miócitos Cardíacos , Camundongos , Humanos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Mamíferos/genética , Ciclo Celular/genética , Proliferação de CélulasRESUMO
BACKGROUND: Targeting AKT suppresses tumor growth through inducing apoptosis, however, during which whether other forms of cell death occurring is poorly understood. METHODS: The effects of increasing PARP1 dependent cell death (parthanatos) induced by inhibiting AKT on cell proliferation were determined by CCK-8 assay, colony formation assay, Hoechst 33,258 staining and analysis of apoptotic cells by flow cytometry. For the detailed mechanisms during this process, Western blot analysis, qRT-PCR analysis, immunofluorescence and co-immunoprecipitation were performed. Moreover, the inhibition of tumor growth by inducing p53/SIRT6/PARP1-dependent parthanatos was further verified in the xenograft mouse model. RESULTS: For the first time, we identified that inhibiting AKT triggered parthanatos, a new form of regulated cell death, leading to colon cancer growth suppression. For the mechanism investigation, we found that after pharmacological or genetic AKT inhibition, p53 interacted with SIRT6 and PARP1 directly to activate it, and promoted the formation of PAR polymer. Subsequently, PAR polymer transported to outer membrane of mitochondria and resulted in AIF releasing and translocating to nucleus thus promoting cell death. While, blocking PARP1 activity significantly rescued colon cancer from death. Furthermore, p53 deletion or mutation eliminated PAR polymer formation, AIF translocation, and PARP1 dependent cell death, which was promoted by overexpression of SIRT6. Meanwhile, reactive oxygen species production was elevated after inhibition of AKT, which might also play a role in the occurrence of parthanatos. In addition, inhibiting AKT initiated protective autophagy simultaneously, which advanced tumor survival and growth. CONCLUSION: Our findings demonstrated that AKT inhibition induced p53-SIRT6-PARP1 complex formation and the activation of parthanatos, which can be recognized as a novel potential therapeutic strategy for cancer. Video Abstract.
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Neoplasias do Colo , Parthanatos , Poli(ADP-Ribose) Polimerase-1 , Proteínas Proto-Oncogênicas c-akt , Sirtuínas , Proteína Supressora de Tumor p53 , Animais , Apoptose , Fator de Indução de Apoptose/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Xenoenxertos , Humanos , Camundongos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Polímeros/metabolismo , Polímeros/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sirtuínas/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
The most frequent genetic alterations of the TP53 gene in human cancer were reported. TP53 mutation gains new function as a target of genetic instability, which is associated with increased tumor progression and poor survival rate in patients. In this study, more than three hundred colorectal cancer patients' samples were firstly analyzed, and the results showed that patients with mutant p53 had higher levels of AKT phosphorylation and PD-L1 expression, which were next verified both in cell lines in vitro and patients' samples in vivo. Further studies demonstrated that the hotspot of mutant p53 directly binds to the promoter of PHLPP2 to inhibit its transcription, and resulting in down-regulating its protein expressional level. Subsequently, AKT was released and activated, promoting tumor proliferation and metastasis. In parallel, 4EBP1/eIF4E was identified as downstream executors of AKT to enhance the translational level of PD-L1, which decreased the activation of T cells. Besides, inhibiting AKT/mTOR pathway significantly suppressed PD-L1 expression, tumor growth, and immune escape in p53 mutated cells. In conclusion, mutant p53 achieved its Gain-of-Function by transcriptionally inhibiting PHLPP2 and activating AKT, which suppresses immune response and advances tumor growth. Thus, this study provides an excellent basis for a further understanding of the clinical treatment of neoplastic diseases for patients with mutant p53, with an emphasis on immunotherapy.
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Antígeno B7-H1 , Proteínas Proto-Oncogênicas c-akt , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Mutação com Ganho de Função , Genes p53 , Humanos , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Melanoma is a highly aggressive tumor located in the skin, with limited traditional therapies. In order to reduce the side effects caused by traditional administration method and amplify the killing effect of immune system against tumor cells, an in situ injectable hydrogel drug delivery system is developed for the first time which co-delivers doxorubicin (Dox) and imiquimod (R837) for the synergistic therapy of melanoma. The mechanical properties and stability of the hydrogel are characterized and the optimal doses of hydrogel and drugs are also identified. As a result, the co-delivery system effectively suppresses melanoma growth and metastatic progression both in vitro and in vivo. Further studies show that the co-delivery system causes immunogenic cell death, activation of antigen presenting cells, comprising dendritic cells and M1 macrophages, and secretion of related cytokines consisted of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), subsequently with the activation of T lymphocytes and natural killer cells in spleen and tumor area. The co-delivery system also decreases the suppressive immune responses, including infiltration of M2 macrophages and secretion of interleukin-10 (IL-10), in vivo. Besides, other death modes are induced by the co-delivery system, including apoptosis and non-apoptotic cell death. In a word, this co-delivery system induces melanoma cell death directly and activates immune system for further tumor killing simultaneously, which shows probability for precise targeted tumor therapy.
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Mesothelioma (MESO) is a mesothelial originate neoplasm with high morbidity and mortality. Despite advancement in technology, early diagnosis still lacks effectivity and is full of pitfalls. Approaches of cancer diagnosis and therapy utilizing immune biomarkers and transcription factors (TFs) have attracted more and more attention. But the molecular mechanism of these features in MESO bone metastasis has not been thoroughly studied. Utilizing high-throughput genome sequencing data and lists of specific gene subsets, we performed several data mining algorithm. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to identify downstream immune cells. Potential pathways involved in MESO bone metastasis were identified using Gene Oncology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Cox regression analysis. Ultimately, a model to help early diagnosis and to predict prognosis was constructed based on differentially expressed immune-related genes between bone metastatic and nonmetastatic MESO groups. In conclusion, immune-related gene SDC2, regulated by TFs TCF7L1 and POLR3D, had an important role on immune cell function and infiltration, providing novel biomarkers and therapeutic targets for metastatic MESO.