Biological Behavior Of Tumor Cells Research Articles

Dual roles of HK3 in regulating the network between tumor cells and tumor-associated macrophages in neuroblastoma

Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma.

Abstract PO5-06-11: RPL27A promotes the growth and metastasis of triple negative breast cancer by regulating Ribosome biogenesis

Abstract Background: Ribosome is a complex structure in cells for protein synthesis. It has been considered always have a constant composition. Recent studies have revealed that the Ribosome composition of tumor cells is heterogeneous. The Ribosome protein composition, post-translational modification, rRNA modification, and rRNA variants can lead to the existence of specialized "onco-ribosomes" in tumor cells, which regulates the rate of translation and protein synthesis, and can affect the occurrence and development of tumors significantly. The abnormal expression of multiple Ribosome proteins in triple-negative breast cancer may be the target of its diagnosis and treatment, also, an independent factor in prognosis evaluation. Methods: To learn the expression levels of Ribosome biogenesis related genes in normal breast cells and abnormal breast cells with different pathological subtypes of breast cancer, the following studies have been done: 1. Bioinformatics analysis on TCGA database and single-cell sequencing data; 2. IHC detection on TNBC tissue and adjacent tissues; 3. Determine the expression level of RPL27A in TNBC cells, and analyze the correlation between the expression of RPL27A and clinical information of patients. To explore the effect of RPL27A on Ribosome biogenesis, protein synthesis and other signaling pathways through Proteomics and molecular biology experiments have been designed and tested. The effects of RPL27A on malignant biological behaviors such as proliferation, migration, infiltration, and clonal formation of TNBC cells were studied through cell biology experiments and mouse experiments. Results: The analysis of TCGA database and single-cell sequencing data showed that the RPL27A was significantly increased in TNBC group. Immunohistochemical experiments showed that RPL27A was highly expressed in TNBC tissue and was impressively positively correlated with tumor size, lymph node metastasis, and bone metastasis. There was significantly negatively correlated with overall survival (OS) and disease free survival (DFS). It can be an independent factor for evaluating the prognosis of TNBC. By knocking out RPL27A in TNBC cell line, label free proteomics analysis showed that Ribosome biogenesis, protein synthesis, cell cycle regulation and other signaling pathways were obviously down regulated. Cell biology experiments have implied that the high expression of RPL27A in TNBC promotes cell proliferation, enhances cell migration, infiltration, and cloning ability, leads to more malignant biological behavior of tumor cells. Further research demonstrates that the high expression of RPL27A in TNBC significantly activated the EIF3C signal, cause changes in the composition of Ribosome in TNBC cells, promoted the formation of "onco-ribosomes", and distinctly increased the rate of protein synthesis. The study of PDX mice and Organoid showed that the knock out of RPL27A significantly reduced the growth rate and transfer ability of TNBC. Conclusion: The obvious over expressing of RPL27A in TNBC, which can significantly promote the growth and metastasis of tumor cells by influencing the Ribosome biogenesis process. Citation Format: Weipeng Zhao, Jingyi Zhang, Ye Zhu, Xin Yang, Xichuan Li. RPL27A promotes the growth and metastasis of triple negative breast cancer by regulating Ribosome biogenesis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-06-11.

The role of SWI/SNF complexes in digestive system neoplasms.

Chromatin remodeling is a critical step in the DNA damage response, and the ATP-dependent chromatin remodelers are a group of epigenetic regulators that alter nucleosome assembly and regulate transcription factor accessibility to DNA, preventing genomic instability and tumorigenesis caused by DNA damage. The SWI/SNF chromatin remodeling complex is one of them, and mutations in the gene encoding the SWI/SNF subunit are frequently found in digestive tumors. We review the most recent literature on the role of SWI/SNF complexes in digestive tumorigenesis, with different SWI/SNF subunits playing different roles. They regulate the biological behavior of tumor cells, participate in multiple signaling pathways, interact with multiple genes, and have some correlation with the prognosis of patients. Their carcinogenic properties may help discover new therapeutic targets. Understanding the mutations and defects of SWI/SNF complexes, as well as the underlying functional mechanisms, may lead to new strategies for treating the digestive system by targeting relevant genes or modulating the tumor microenvironment.

Association of the pathomics-collagen signature with lymph node metastasis in colorectal cancer: a retrospective multicenter study

BackgroundLymph node metastasis (LNM) is a prognostic biomarker and affects therapeutic selection in colorectal cancer (CRC). Current evaluation methods are not adequate for estimating LNM in CRC. H&E images contain much pathological information, and collagen also affects the biological behavior of tumor cells. Hence, the objective of the study is to investigate whether a fully quantitative pathomics-collagen signature (PCS) in the tumor microenvironment can be used to predict LNM.MethodsPatients with histologically confirmed stage I-III CRC who underwent radical surgery were included in the training cohort (n = 329), the internal validation cohort (n = 329), and the external validation cohort (n = 315). Fully quantitative pathomics features and collagen features were extracted from digital H&E images and multiphoton images of specimens, respectively. LASSO regression was utilized to develop the PCS. Then, a PCS-nomogram was constructed incorporating the PCS and clinicopathological predictors for estimating LNM in the training cohort. The performance of the PCS-nomogram was evaluated via calibration, discrimination, and clinical usefulness. Furthermore, the PCS-nomogram was tested in internal and external validation cohorts.ResultsBy LASSO regression, the PCS was developed based on 11 pathomics and 9 collagen features. A significant association was found between the PCS and LNM in the three cohorts (P < 0.001). Then, the PCS-nomogram based on PCS, preoperative CEA level, lymphadenectasis on CT, venous emboli and/or lymphatic invasion and/or perineural invasion (VELIPI), and pT stage achieved AUROCs of 0.939, 0.895, and 0.893 in the three cohorts. The calibration curves identified good agreement between the nomogram-predicted and actual outcomes. Decision curve analysis indicated that the PCS-nomogram was clinically useful. Moreover, the PCS was still an independent predictor of LNM at station Nos. 1, 2, and 3. The PCS nomogram displayed AUROCs of 0.849–0.939 for the training cohort, 0.837–0.902 for the internal validation cohort, and 0.851–0.895 for the external validation cohorts in the three nodal stations.ConclusionsThis study proposed that PCS integrating pathomics and collagen features was significantly associated with LNM, and the PCS-nomogram has the potential to be a useful tool for predicting individual LNM in CRC patients.

Hepatocellular Carcinoma-Derived Exosomes: Key Players in Intercellular Communication Within the Tumor Microenvironment

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Due to the insidious onset and rapid progression and a lack of effective treatments, the prognosis of patients with HCC is extremely poor, with the average 5-year survival rate being less than 10%. The tumor microenvironment (TME), the internal environment in which HCC develops, can regulate the oncogenesis, development, invasion, and metastasis of HCC. During the process of cancer progression, HCC cells can regulate the biological behaviors of tumor cells, cancer-associated fibroblasts, cancer-associated immune cells, and other cells in the TME by releasing exosomes containing specific signals, thereby promoting cancer progression. However, the exact molecular mechanisms and the roles of exosomes in the specific cellular regulation of these processes are not fully understood. Herein, we summarized the TME components of HCC, the sources and the biological traits of exosomes in the TME, and the impact of mechanical factors on exosomes. In addition, special attention was given to the discussion of the effects of HCC-exosomes on different types of cells in the microenvironment. There are still many difficulties to be overcome before exosomes can be applied as carriers in clinical cancer treatment. First of all, the homogeneity of exosomes is difficult to ensure. Secondly, exosomes are mainly administered through subcutaneous injection. Although this method is simple and easy to implement, the absorption efficiency is not ideal. Thirdly, exosome extraction methods are limited in number and inefficient, making it difficult to prepare exosomes in large quantities. It is important to ensure that exosomes are used in sufficient quantities to trigger an effective tumor immune response, especially for exosome-mediated tumor immunotherapy. With the improvement in identification, isolation, and purification technology, exosomes are expected to be successfully used in the clinical diagnosis of early-stage HCC and the clinical treatment of liver cancer.

Implication of Amyloid Precursor-like Protein 2 Expression in Cutaneous Squamous Cell Carcinoma Pathogenesis.

Regulatory functions of amyloid precursor-like protein 2 (APLP2) expression in intracellular trafficking of major histocompatibility complex class I (MHC-I) and biological behavior of tumor cells have been reported in various types of malignancies but not in cutaneous squamous cell carcinoma (CSCC). This study aimed to investigate the role of APLP2 expression in the pathogenesis of CSCC. The expression of APLP2 and a key modulator of cancer immune escape, MHC-I, were determined in CSCC tissue samples obtained from 141 patients using immunohistochemistry. The regulatory effects of APLP2 expression on the biological behavior and surface expression of MHC-I in CSCC cells were investigated by trypan blue assay, Matrigel invasion assay, and in vivo xenograft analysis. APLP2 immunoreactivity was high in 73 (51.8%) tissue samples from patients with CSCC and was significantly related to subcutaneous fat invasion and poor prognosis in our cohort. Moreover, proliferation of and invasion by CSCC cells were significantly reduced after APLP2 knockdown in CSCC cells both in vitro and in vivo. A significant association was found between APLP2 and membrane MHC-I expression in patients with CSCC. In vivo xenograft analysis showed that APLP2 knockdown increased membrane MHC-I expression in CSCC cells. APLP2 not only acts as an oncogene in CSCC progression but also as a possible modulator of cancer immune escape by influencing MHC-I expression on the cell surface. APLP2 may serve as a novel molecular biomarker and therapeutic target for patients with CSCC.

MiRNA/epithelial-mesenchymal axis (EMT) axis as a key player in cancer progression and metastasis: A focus on gastric and bladder cancers

The metastasis a major hallmark of tumors that its significant is not only related to the basic research, but clinical investigations have revealed that majority of cancer deaths are due to the metastasis. The metastasis of tumor cells is significantly increased due to EMT mechanism and therefore, inhibition of EMT can reduce biological behaviors of tumor cells and improve the survival rate of patients. One of the gaps related to cancer metastasis is lack of specific focus on the EMT regulation in certain types of tumor cells. The gastric and bladder cancers are considered as two main reasons of death among patients in clinical level. Herein, the role of EMT in regulation of their progression is evaluated with a focus on the function of miRNAs. The inhibition/induction of EMT in these cancers and their ability in modulation of EMT-related factors including ZEB1/2 proteins, TGF-β, Snail and cadherin proteins are discussed. Moreover, lncRNAs and circRNAs in crosstalk of miRNA/EMT regulation in these tumors are discussed and final impact on cancer metastasis and response of tumor cells to the chemotherapy is evaluated. Moreover, the impact of miRNAs transferred by exosomes in regulation of EMT in these cancers are discussed.

GLIS3, a novel prognostic indicator of gastric adenocarcinoma, contributes to the malignant biological behaviors of tumor cells via modulating TGF-β1/TGFβR1/Smad1/5 signaling pathway

GLIS3 is highly expressed in multiple cancers, but it has not been studied in gastric adenocarcinoma (GAC). Based on bioinformatics analysis, the prognostic significance of GLIS3 in GAC was analyzed. GAC cells were transfected with small interfering (si)-GLIS3 and GLIS3 overexpression plasmid as well as treated with SB505124 [an inhibitor for transforming growth factor beta receptor 1 (TGFβR1)] and dorsomorphin [an inhibitor for bone morphogenetic protein receptor 1 (BMPR1)]. The GLIS3 expression was detected using qRT-PCR. The impacts of GLIS3 on the proliferation, invasion and migration of GAC cells were measured using cell function assays. The activation of phosphor (p)-Smad1/5 was tested by immunofluorescence. Western blot was utilized to measure the level of transforming growth factor (TGF)-β1/Smad1/5 signaling pathway-related proteins (TGF-β1, p-Smad1, Smad1, p-Smad5, Smad5). GLIS3 was expressed at high levels in GAC tissues and cell lines and its high expression could indicate the poor prognosis of GAC patients. GLIS3 inhibition declined the proliferative, invasive and migratory capabilities as well as TGF-β1 expression and phosphorylation of Smad1/5 in GAC cells. Overexpressed GLIS3 promoted proliferation, migration, invasion, TGF-β1 expression and Smad1/5 phosphorylation in GAC cells, with SB505124 reversing the effects of overexpressed GLIS3 on proliferation, migration, invasion and Smad1/5 phosphorylation whereas dorsomorphin exhibiting no influence on GLIS3-induced effects. GLIS3 facilitated the malignant phenotype of GAC cells via regulating TGF-β1/TGFβR1/Smad1/5 pathway, which may be a novel prognostic indicator of GAC and provided a target for GAC treatment.

MOB kinase activator 1A acts as an oncogene by targeting PI3K/AKT/mTOR in ovarian cancer

BackgroundTo illuminate the precise roles of MOB Kinase Activator 1 A (MOB1A) in the development of ovarian cancer (OC).MethodsMOB1A expression and clinical data of OC were obtained from the public database on gene expression and proteomics. Meanwhile, verification of expression was carried out in Gene Expression Omnibus, the Human Protein Atlas, and OC cell lines. The prognosis of MOB1A was explored in the Kaplan-Meier plotter. RNA interference and lentivirus vectors were applied to construct knockdown and overexpressed cell models. Changes in the malignant behaviors of OC cells were detected by cholecystokinin octopeptide cell counting kit, wound healing, colony formation assay, transwell, flow cytometry assays, and in vivo experiments. Changes in proteins in the PI3K and autophagy-related makers were detected by western blot analysis.ResultsThe expression of MOB1A was significantly upregulated and accompanied by an inferior survival rate in OC. Knockdown of MOB1A inhibited the proliferation, invasion, migration, and cell cycle of OC cells, whereas induced cell autophagy. MOB1A upregulation had the opposite effects. In addition, bioinformatics analysis and western blot experiments showed that MOB1A plays an important role in the PI3K/AKT/mTOR pathway.ConclusionsOur findings indicated that MOB1A is highly expressed and related to poor prognosis in OC. MOB1A plays a role in promoting the malignant biological behavior of tumor cells through PI3K/AKT/mTOR signaling pathway.

Long Noncoding RNA LINC00578 Inhibits Ferroptosis in Pancreatic Cancer via Regulating SLC7A11 Ubiquitination.

Pancreatic cancer is a highly aggressive malignancy worldwide with rapid development and an exceedingly poor prognosis. lncRNAs play crucial roles in regulating the biological behaviors of tumor cells. In this study, we discovered that LINC00578 acted as a regulator of ferroptosis in pancreatic cancer. A series of loss- and gain-of-function experiments in vitro and in vivo were performed to explore the oncogenic role of LINC00578 in pancreatic cancer development and progression. Label-free proteomic analysis was performed to select LINC00578-related differentially expressed proteins. Pull-down and RNA immunoprecipitation assays were carried out to determine and validate the binding protein of LINC00578. Coimmunoprecipitation assays were used to investigate the association of LINC00578 with SLC7A11 in ubiquitination and to confirm the interaction between ubiquitin-conjugating enzyme E2 K (UBE2K) and SLC7A11. An immunohistochemical assay was used to confirm the correlation between LINC00578 and SLC7A11 in the clinic. LINC00578 positively regulated cell proliferation and invasion in vitro and tumorigenesis in vivo in pancreatic cancer. LINC00578 can obviously inhibit ferroptosis events, including cell proliferation, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP) depolarization. In addition, the LINC00578-induced inhibitory effect on ferroptosis events was rescued by SLC7A11 knockdown. Mechanistically, LINC00578 directly binds UBE2K to decrease the ubiquitination of SLC7A11, thus accelerating SLC7A11 expression. In the clinic, LINC00578 is closely associated with clinicopathologic factors and poor prognosis and correlated with SLC7A11 expression in pancreatic cancer. This study elucidated that LINC00578 acts as an oncogene to promote pancreatic cancer cell progression and suppress ferroptosis by directly combining with UBE2K to inhibit the ubiquitination of SLC7A11, which provides a promising option for the diagnosis and treatment of pancreatic cancer.

A novel five-gene metabolism-related risk signature for predicting prognosis and immune infiltration in endometrial cancer: A TCGA data mining

BackgroundMetabolism dysfunction can affect the biological behavior of tumor cells and result in carcinogenesis and the development of various cancers. However, few thoughtful studies focus on the predictive value and efficacy of immunotherapy of metabolism-related gene signatures in endometrial cancer (EC). This research aims to construct a predictive metabolism-related gene signature in EC with prognostic and therapeutic implications. MethodsWe downloaded the RNA profile and clinical data of 503 EC patients and screened out different expressions of metabolism-related genes with prognosis influence of EC from The Cancer Genome Atlas (TCGA) database. We first established a metabolism-related genes model using univariate and multivariate Cox regression and Lasso regression analysis. To internally validate the predictive model, 503 samples (entire set) were randomly assigned into the test set and the train set. Then, we applied the receiver operating characteristic (ROC) curve to confirm our previous predictive model and depicted a nomogram integrating the risk score and the clinicopathological feature. We employed a gene set enrichment analysis (GSEA) to explore the biological processes and pathways of the model. Afterward, we used ESTIMATE to evaluate the TME. Also, we adopted CIBERSORT and ssGSEA to estimate the fraction of immune infiltrating cells and immune function. At last, we investigated the relationship between the predictive model and immune checkpoint genes. ResultsWe first constructed a predictive model based on five metabolism-related genes (INPP5K, PLPP2, MBOAT2, DDC, and ITPKA). This model showed the ability to predict EC patients' prognosis accurately and performed well in the train set, test set, and entire set. Then we confirmed the predictive signature was a novel independent prognostic factor in EC patients. In addition, we drew and validated a nomogram to precisely predict the survival rate of EC patients at 1-, 3-, and 5-years (ROC1-year = 0.714, ROC3-year = 0.750, ROC5-year = 0.767). Furthermore, GSEA unveiled that the cell cycle, certain malignant tumors, and cell metabolism were the main biological functions enriched in this identified model. We found the five metabolism-related genes signature was associated with the immune infiltrating cells and immune functions. Most importantly, it was linked with specific immune checkpoints (PD-1, CTLA4, and CD40) that could predict immunotherapy's clinical response. ConclusionThe metabolism-related genes signature (INPP5K, PLPP2, MBOAT2, DDC, and ITPKA) is a valuable index for predicting the survival outcomes and efficacy of immunotherapy for EC in clinical settings.

Development and validation of a combined metabolism and immune prognostic model in lung adenocarcinoma.

Tumor metabolism and immune response can affect the biological behavior of tumor cells. There is an obvious relationship between glycolysis and immune response. However, the association between metabolism and immune response and prognosis in lung adenocarcinoma (LUAD) has not yet been examined in a comprehensive and detailed manner. The establishment of reliable models for predicting the prognosis of LUAD based on glycolysis ability and immune status is still highly anticipated. The expression of genes were obtained from online databases, and the differentially expressed genes in LUAD tissues and adjacent tissues were identified. We used LUAD samples in The Cancer Genome Atlas (TCGA) database as training set and the Gene Expression Omnibus (GEO) databases as validation sets. The best predictive model was constructed using least absolute selection and shrinkage operator (LASSO) regression and Cox regression. The receiver operator characteristic (ROC) curve is used to verify the accuracy of the model. The expression status of the Glycolysis-related genes (GRGs) and the status of the immune cells in LUCD patients were further analyzed. The protein levels of the 3 identified genes were then tested in LUAD patients. We identified 3 GRGs and immune-related genes (i.e., fibroblast growth factor 2, hyaluronan-mediated motor receptor, and nuclear receptor 0B2) and constructed a stable comprehensive index of glycolysis and immunity (CIGI) prediction model. The validation results for this CIGI model were quite stable across different datasets and patient subgroups and the CIGI score can be included as an independent prognostic factor for LUAD patients. The area under the curve (AUC) values of 1-, 3- and 5-year of the finally established nomogram model are 0.767, 0.735 and 0.769. Further analysis showed that LUAD patients in the low-risk group had lower levels of glycolytic gene expression than those in the high-risk group and exhibited an immunosuppressed state. Finally, hyaluronan-mediated motor receptor may play a role in inhibiting cancer, while fibroblast growth factor 2 and nuclear receptor 0B2 may play roles in promoting cancer. In this study, we established a new prognostic prediction model for LUAD patients that combines glycolysis ability and immune status.

LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

A SERPINE1-Based Immune Gene Signature Predicts Prognosis and Immunotherapy Response in Gastric Cancer.

Immune checkpoint inhibitors (ICIs) therapy has been successfully utilized in the treatment of multiple tumors, but only a fraction of patients with gastric cancer (GC) could greatly benefit from it. A recent study has shown that the tumor microenvironment (TME) can greatly affect the effect of immunotherapy in GC. In this study, we established a novel immune risk signature (IRS) for prognosis and predicting response to ICIs in GC based on the TCGA-STAD dataset. Characterization of the TME was explored and further validated to reveal the underlying survival mechanisms and the potential therapeutic targets of GC. The GC patients were stratified into high- and low-risk groups based on the IRS. Patients in the high-risk group, associated with poorer outcomes, were characterized by significantly higher immune function. Further analysis showed higher T cell immune dysfunction and probability of potential immune escape. In vivo, we detected the expressions of SERPINE1 by the quantitative real-time polymerase chain reaction (qPCR)in tumor tissues and adjacent normal tissues. In vitro, knockdown of SERPINE1 significantly attenuated malignant biological behaviors of tumor cells in GC. Our signature can effectively predict the prognosis and response to immunotherapy in patients with GC.

Role of hypoxia in the tumor microenvironment and targeted therapy.

Tumor microenvironment (TME), which is characterized by hypoxia, widely exists in solid tumors. As a current research hotspot in the TME, hypoxia is expected to become a key element to break through the bottleneck of tumor treatment. More and more research results show that a variety of biological behaviors of tumor cells are affected by many factors in TME which are closely related to hypoxia. In order to inhibiting the immune response in TME, hypoxia plays an important role in tumor cell metabolism and anti-apoptosis. Therefore, exploring the molecular mechanism of hypoxia mediated malignant tumor behavior and therapeutic targets is expected to provide new ideas for anti-tumor therapy. In this review, we discussed the effects of hypoxia on tumor behavior and its interaction with TME from the perspectives of immune cells, cell metabolism, oxidative stress and hypoxia inducible factor (HIF), and listed the therapeutic targets or signal pathways found so far. Finally, we summarize the current therapies targeting hypoxia, such as glycolysis inhibitors, anti-angiogenesis drugs, HIF inhibitors, hypoxia-activated prodrugs, and hyperbaric medicine.

Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target

Simple SummaryGlioma is one of the most common intracranial malignancies and is incurable due to strong aggressiveness and resistance to radiotherapy and chemotherapy. The lack of effective therapeutic targets is a major problem in current treatment. In the present study, we found that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the occurrence and development of glioma. High NNMT expression in glioma is a predictor of short overall survival and poor patient outcome. NNMT knockdown reduced the volume of mice xenograft glioma and the viability of glioma cells. Additionally, overexpression of NNMT epigenetically silenced GAP43 through DNA methylation, histone methylation, and deacetylation modification processes. GAP43 can inhibit the formation of microtubules in tumor and intertumor cell network connections and induce apoptosis through the SIRT1 signaling pathway. Therefore, NNMT could be a potential candidate for the clinical diagnosis and treatment of glioma.Purpose: Increasing evidence has revealed that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the prognosis of tumors. The present study aimed to investigate the role of NNMT in glioma and to elucidate the associated functional mechanisms. Methods: Clinical samples were analyzed by immunohistochemical staining and Western blotting to evaluate NNMT expression in glioma and normal brain tissues. The correlation between NNMT expression and glioma was analyzed using the Cancer Genome Atlas (TCGA) database. Additionally, NNMT was knocked down in two types of glioma cells, U87 and U251, to evaluate the invasive ability of these cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate NNMT knockdown in the cells. Furthermore, ELISA was used to determine the balance between nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogen (NAD/NADH ratio), which verified the altered methylation patterns in the cells. The glioma xenograft mouse models were used to verify the regulatory role of NNMT, GAP43, and SIRT1. Results: Analysis based on our clinical glioma samples and TCGA database revealed that overexpression of NNMT was associated with poor prognosis of patients. Knockdown of NNMT reduced the invasive ability of glioma cells, and downregulation of its downstream protein GAP43 occurred due to altered cellular methylation caused by NNMT overexpression. Gene Set Enrichment Analysis confirmed that NNMT modulated the NAD-related signaling pathway and showed a negative association between NNMT and SIRT1. Moreover, the regulatory roles of NNMT, GAP43, and SIRT1 were confirmed in glioma xenograft mouse models. Conclusion: Overexpression of NNMT causes abnormal DNA methylation through regulation of the NAD/NADH ratio, which in turn leads to the downregulation of GAP43 and SIRT1, eventually altering the biological behavior of tumor cells.

FRA-1: A key factor regulating signal transduction of tumor cells and a potential target molecule for tumor therapy.

Fos-related antigen-1 (FRA-1) is a member of activator protein-1 (AP-1) transcription factor superfamily, and FRA-1 is highly expressed in colon cancer, breast cancer, gastric cancer, lung cancer, bladder cancer, and other tumors. The expression level of FRA-1 is closely related to the processes of tumor cell proliferation, apoptosis, transformation, migration, and invasion, which is a potential therapeutic target and prognostic factor for many tumors. Clarifying the detailed mechanism of action of FRA-1 could provide the theoretical basis for tumor diagnosis, treatment, and prognosis, and is of great significance for the study of tumor etiology and pathogenesis. In this paper, the expression levels and influencing factors of FRA-1 in various tumor tissues and cells are summarized, as well as the effect of FRA-1 expression level on the biological behavior of tumor cells and the signal transduction mechanism. At the same time, the signal transduction mechanism of FRA-1 in inflammation was expounded. In addition, the related metabolites, drugs and non-coding RNA that affect the expression and function of FRA-1 were summarized. Finally, it illustrates that FRA-1 may be taken as a key factor for tumor prognosis and a potential therapeutic target. This review provides a theoretical basis for the systematic understanding of the relationship between FRA-1 and tumors, its function, and possible mechanism.

Identifying biomarkers associated with tumor growth rate: a longitudinal preoperative magnetic resonance imaging follow-up of low-grade gliomas.

BackgroundAlthough the influence of molecular biomarkers on the biological behavior of tumor cells has been investigated, their quantitative influence on the velocity of tumor growth remains unclear. This study aimed to identify the molecular biomarkers associated with tumor growth rates in World Health Organization (WHO) grade II gliomas, or low-grade gliomas (LGGs).MethodsPreoperative magnetic resonance imaging (MRI) data of patients with LGGs were retrospectively reviewed. Patients with at least 2 preoperative MRIs taken more than 90 days apart were enrolled. Patients with isocitrate dehydrogenase (IDH) wild-type tumors or with no recorded IDH status were excluded. A linear mixed-effects model was used to assess the velocity of tumor diameter expansion. The effect of biomarker expression on tumor growth rate was assessed using a multivariate linear mixed-effects regression model.ResultsData from 56 patients were used in our study. The overall velocity of diameter expansion (VDE) for LGGs was 2.1 mm/year. Higher expression level of mutant p53 were significantly associated with a higher tumor growth rate (+1.9 mm/year, P<0.01), while higher expression level of alpha-thalassemia/mental retardation syndrome X-linked protein (ATRX) were significantly associated with a lower tumor growth rate (−1.3 mm/year, P<0.01). Tumors with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation were found to grow significantly more slowly than those with no methylation (−3.1 mm/year, P<0.01). The telomerase reverse transcriptase (TERT) promoter type and expressions levels of Ki-67 and epidermal growth factor receptor (EGFR) showed no significant independent impact on tumor growth rates.ConclusionsThe status of biomarkers is significantly associated with the tumor growth rate in LGGs.

Epigenetics Regulates Antitumor Immunity in Melanoma

Melanoma is the most malignant skin cancer, which originates from epidermal melanocytes, with increasing worldwide incidence. The escape of immune surveillance is a hallmark of the tumor, which is manifested by the imbalance between the enhanced immune evasion of tumor cells and the impaired antitumor capacity of infiltrating immune cells. According to this notion, the invigoration of the exhausted immune cells by immune checkpoint blockades has gained encouraging outcomes in eliminating tumor cells and significantly prolonged the survival of patients, particularly in melanoma. Epigenetics is a pivotal non-genomic modulatory paradigm referring to heritable changes in gene expression without altering genome sequence, including DNA methylation, histone modification, non-coding RNAs, and m6A RNA methylation. Accumulating evidence has demonstrated how the dysregulation of epigenetics regulates multiple biological behaviors of tumor cells and contributes to carcinogenesis and tumor progression in melanoma. Nevertheless, the linkage between epigenetics and antitumor immunity, as well as its implication in melanoma immunotherapy, remains elusive. In this review, we first introduce the epidemiology, clinical characteristics, and therapeutic innovations of melanoma. Then, the tumor microenvironment and the functions of different types of infiltrating immune cells are discussed, with an emphasis on their involvement in antitumor immunity in melanoma. Subsequently, we systemically summarize the linkage between epigenetics and antitumor immunity in melanoma, from the perspective of distinct paradigms of epigenetics. Ultimately, the progression of the clinical trials regarding epigenetics-based melanoma immunotherapy is introduced.

RIG-I acts as a tumor suppressor in melanoma via regulating the activation of the MKK/p38MAPK signaling pathway

Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. To investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma, we constructed RIG-I knockout, RIG-I-overexpressing B16-F10 and RIG-I knockdown A375 melanoma cell lines, and analyzed the RIG-I-mediated change in the biological behavior of tumor cells in spontaneous and poly (I:C)-induced RIG-I activation. Cell proliferation, cell cycling, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation assay, Annexin V–PI staining assay and Transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently by Ki67 staining and TUNEL assays. Furthermore, Western blotting was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Our data showed that RIG-I promotes apoptosis and inhibits proliferation by G1 phase cell cycle arrest in the melanoma cell lines. Mechanistically, RIG-I induced the phosphorylation of p38 MAPK and MAPK kinases MKK3 and MKK4. In conclusion, the current study demonstrated that RIG-I suppressed the development of melanoma by regulating the activity of the MKK/p38 MAPK signaling pathway, which is relevant to research on novel therapeutic targets for this malignant disease.