Tumor Promoter Research Articles

Secreted insulin-like growth factor binding protein 5 functions as a tumor suppressor and chemosensitizer through inhibiting insulin-like growth factor 1 receptor/protein kinase B pathway in acute myeloid leukemia

BackgroundIn addition to being secreted into the intercellular spaces by exocytosis, insulin-like growth factor binding protein 5 (IGFBP5) may also remain in the cytosol or be transported to the nucleus. Depending on the different cellular context and subcellular distribution, IGFBP5 can act as a tumor suppressor or promoter through insulin-like growth factor -dependent or -independent mechanisms. Yet, little is known about the impacts of IGFBP5 on acute myeloid leukemia (AML) and its underlying mechanism. MethodsHere we investigated the roles of IGFBP5 in human AML by using recombinant human IGFBP5 (rhIGFBP5) protein and U937 and THP1 cell lines which stably and ectopically expressed IGFBP5 or mutant IGFBP5 (mtIGFBP5) with the lack of secretory signal peptide. Cell counting kit-8 and flow cytometry assay were conducted to assess the cell viability, cell apoptosis and cell cycle distribution. Cytotoxicity assay was used to detect the chemosensitivity. Leukemia xenograft model and hematoxylin-eosin staining were performed to evaluate AML progression and extramedullary infiltration in vivo. ResultsIn silico analysis demonstrated a positive association between IGFBP5 expression and overall survival of the AML patients. Both IGFBP5 overexpression and extrinsic rhIGFBP5 suppressed the growth of THP1 and U937 cells by inducing cell apoptosis and arresting G1/S transition and promoted the chemosensitivity of U937 and THP1 cells to daunorubicin and cytarabine. However, overexpression of mtIGFBP5 failed to demonstrate these properties. An in vivo xenograft mouse model of U937 cells also indicated that overexpression of IGFBP5 rather than mtIGFBP5 alleviated AML progression and extramedullary infiltration. Mechanistically, these biological consequences depended on the inactivation of insulin-like growth factor 1 receptor -mediated phosphatidylinositol-3-kinase/protein kinase B pathway. ConclusionsOur findings revealed secreted rather than intracellular IGFBP5 as a tumor-suppressor and chemosensitizer in AML. Upregulation of serum IGFBP5 by overexpression or addition of extrinsic rhIGFBP5 may serve as a suitable therapeutic approach for AML.

Clinical and therapeutical significances of the cluster and signature based on oxidative stress for osteosarcoma.

It is of great clinical significance to find out the ideal tumor biomarkers and therapeutic targets to improve the prognosis of patients with osteosarcoma (OS). Oxidative stress (OXS) can directly target intracellular macromolecules and exhibit dual effects of tumor promotion and suppression. OXS-related genes (OXRGs) were extracted from public databases, including TARGET and GEO. Univariate Cox regression analysis, Random Survival Forest algorithm, and LASSO regression were performed to identify prognostic genes and establish the OXS-signature. The efficacy of the OXS-signature was further evaluated by Kaplan-Meier curves and timeROC package. Evaluation of immunological characteristics was achieved based on ESTIMATE algorithm and ssGSEA. Submap algorithm was used to explore the response to anti-PD1 and anti-CTLA4 therapy for OS. Drug response prediction was conducted by using pRRophetic package. The expression values of related genes in the OXS-signature were detected with PCR assays. Two OXS-clusters were identified for OS, with remarkable differences of clusters presented in prognosis. Kyoto Encyclopedia of Genes Genomes (KEGG) analysis showed that differentially expressed genes (DEGs) between the OXS-clusters were significantly enriched in several immune-related pathways. Patients with lower OS-scores attained better clinical outcomes, and presented more sensitivity to ICB therapy. By contrast, OS patients with higher OS-scores revealed more sensitivity to certain drugs. Furthermore, critical genes, RHBDL2 and CGREF1 from the model, were significantly higher expressed in OS cell lines. Our study identified the clusters and signature based on OXS, which would lay the foundation for molecular experimental research, disease prevention and treatment of OS.

Gut microbiome as a tumor promoter and tumor suppressor

The human microbiome is the aggregate of all the microbiota that reside on and within the human body. They have the ability to affect the homeostasis of the host body and change its pathology by the production of various metabolites. There is complex crosstalk occurring between the gut microbiome and the host through the gut-brain axis. Gut microbiome plays a dual role in cancer by promoting as well as by inhibiting tumor formation. Tumor formation may be initiated by the release of certain metabolites which cause degradation and DNA breaks. However, a number of probiotic microbiota, residing in the gut can help prevent cancer initiation by provoking apoptosis in cancer cells, as well as increasing the efficiency of anticancer therapy and reducing its toxicity outcomes. Any imbalance in the microbiome composition leads to the alteration of the non-pathogenic potential of the microbiome and an increased risk of diseases in the host. Establishing a robust understanding of this interplay can be instrumental for understanding the factors leading to tumor formation. This review highlights the interplay between the host and gut microbiome, as well as the role of the gut microbiome in cancer prevention, tumor formation, and anticancer therapy.

Targeting the cGAS-STING Pathway Inhibits Peripheral T-cell Lymphoma Progression and Enhances the Chemotherapeutic Efficacy.

Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous group of mature T-cell malignancies. The efficacy of current first-line treatment is dismal, and novel agents are urgently needed to improve patient outcomes. A close association between the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and tumor promotion exists, revealing prospective therapeutic targets. This study, investigates the role of the cGAS-STING pathway and its underlying mechanisms in PTCL progression. Single-cell RNA sequencing showes that the cGAS-STING pathway is highly expressed and closely associated with PTCL proliferation. cGAS inhibition suppresses tumor growth and impaires DNA damage repair. Moreover, Cdc2-like kinase 1 (CLK1) is critical for residual tumor cell survival after treatment with cGAS inhibitors, and CLK1 suppression enhances sensitivity to cGAS inhibitors. Single-cell dynamic transcriptomic analysis indicates reduced proliferation-associated nascent RNAs as the underlying mechanism. In first-line therapy, chemotherapy-triggered DNA damage activates the cGAS-STING pathway, and cGAS inhibitors can synergize with chemotherapeutic agents to kill tumors. The cGAS-STING pathway is oncogenic in PTCL, whereas targeting cGAS suppresses tumor growth, and CLK1 may be a sensitivity indicator for cGAS inhibitors. These findings provide a theoretical foundation for optimizing therapeutic strategies for PTCL, especially in patients with relapsed/refractory disease.

METTL3/YTHDF1 m6A axis promotes tumorigenesis by enhancing DDR2 expression in ovarian cancer

Ovarian cancer has the highest mortality among all gynecological malignancies. Therefore, it is urgent to determine the molecular mechanism of ovarian cancer progression. As the most prevalent modification of messenger RNA (mRNA), N6-Methyladenosine (m6A) modification is recognized as a key regulatory role in the progression of various tumors. However, the specific role of m6A and its related regulatory pathways in ovarian cancer (OV) remains unclear. In this study, we demonstrated that the METTL3/YTHDF1 m6A axis plays an important role in the progression of ovarian cancer. Depletion of METTL3/YTHDF1 impaired cancer proliferation and metastasis in vitro and in vivo. Mechanistically, The METTL3/YTHDF1 m6A axis directly binds to the mRNA of DDR2, thereby promoting the expression levels of the tumor promoter DDR2 and thus contributing to the progression of ovarian cancer. Collectively, our findings on the METTL3/YTHDF1/DDR2 m6A axis provide the insight into the underlying mechanism of ovarian carcinogenesis and highlight potential therapeutic targets for cancer treatment.

B Vitamins, Glucoronolactone and the Immune System: Bioavailability, Doses and Efficiency.

The present review deals with two main ingredients of energy/power drinks: B vitamins and glucuronolactone and their possible effect on the immune system. There is a strong relationship between the recommended daily dose of selected B vitamins and a functional immune system. Regarding specific B vitamins: (1) Riboflavin is necessary for the optimization of reactive oxygen species (ROS) in the fight against bacterial infections caused by Staphylococcus aureus and Listeria monocytogenes. (2) Niacin administered within normal doses to obese rats can change the phenotype of skeletal fibers, and thereby affect muscle metabolism. This metabolic phenotype induced by niacin treatment is also confirmed by stimulation of the expression of genes involved in the metabolism of free fatty acids (FFAs) and oxidative phosphorylation at this level. (3) Vitamin B5 effects depend primarily on the dose, thus large doses can cause diarrhea or functional disorders of the digestive tract whereas normal levels are effective in wound healing, liver detoxification, and joint health support. (4) High vitamin B6 concentrations (>2000 mg per day) have been shown to exert a significant negative impact on the dorsal root ganglia. Whereas, at doses of approximately 70 ng/mL, sensory symptoms were reported in 80% of cases. (5) Chronic increases in vitamin B12 have been associated with the increased incidence of solid cancers. Additionally, glucuronolactone, whose effects are not well known, represents a controversial compound. (6) Supplementing with D-glucarates, such as glucuronolactone, may help the body's natural defense system function better to inhibit different tumor promoters and carcinogens and their consequences. Cumulatively, the present review aims to evaluate the relationship between the selected B vitamins group, glucuronolactone, and the immune system and their associations to bioavailability, doses, and efficiency.

Disruption of LPA-LPAR1 pathway results in lung tumor growth inhibition by downregulating B7-H3 expression in fibroblasts.

Lysophosphatidic acids (LPAs) belong to a class of bioactive lysophospholipids with multiple functions including immunomodulatory roles in tumor microenvironment (TME). LPA exerts its biological effects via its receptors that are highly expressed in fibroblasts among other cell types. As cancer-associated fibroblasts (CAFs) are a key component of the TME, it is important to understand LPA signaling and regulation of receptors in fibroblasts or CAFs and associated regulatory roles on immunomodulation-related molecules. Cluster analysis, immunoblotting, real-time quantitative-PCR, CRISPR-Cas9 gene editing system, immunohistochemical staining, coculture model, and in vivo xenograft model were used to investigate the effects of LPA-LPAR1 on B7-H3 in tumor promotion of CAFs. In this study, we found that LPAR1 and CD276 (B7-H3) were generally highly expressed in fibroblasts with good expression correlation. LPA induced B7-H3 up-expression through LPAR1, and stimulated fibroblasts proliferation that could be inhibited by silencing LPAR1 or B7-H3 as well as small molecule LPAR1 antagonist (Ki16425). Using engineered fibroblasts and non-small cell lung carcinoma (NSCLC) cell lines, subsequent investigations demonstrated that CAFs promoted the proliferation of NSCLC in vitro and in vivo, and such effect could be inhibited by knocking out LPAR1 or B7-H3. The present study provided new insights for roles of LPA in CAFs, which could lead to the development of innovative therapies targeting CAFs in the TME. It is also reasonable to postulate a combinatory approach to treat malignant fibrous tumors (such as NSCLC) with LPAR1 antagonists and B7-H3 targeting therapies.

ANP32B promotes colorectal cancer cell progression and reduces cell sensitivity to PRAP1 inhibitor through up-regulating HPF1

ANP32B, a member of the acidic leucine-rich nuclear phosphoprotein 32 family member B, is aberrantly expressed in various cancers, including colorectal cancer. However, the function and mechanism of action of ANP32B in colorectal cancer remain unclear. The present study therefore analyzed the expression of ANP32B and its activity in colorectal cancer patient samples and colorectal cancer cell lines. ANP32B expression was found to be significantly upregulated in colorectal cancer patient samples and cell lines. Upregulation of ANP32B enhanced colorectal cancer cell proliferation and migration, whereas downregulation of ANP32B suppressed colorectal cancer cell proliferation. RNA sequencing analysis of differentially expressed genes in ANP32B silenced colorectal cancer cells showed that histone PARylation factor 1 (HPF1), which protects against DNA damage by interacting with the anti-tumor target PARP1, was significantly downregulated. Luciferase promoter assays testing the regulatory association between ANP32B and HPF1 showed that ANP32B interacted with the HPF1 promoter. Analysis of colorectal cancer samples from The Cancer Genome Atlas showed that ANP32B and HPF1 expression were positively correlated, and recovery assays showed that ANP32B promoted colorectal cancer progression by up-regulating HPF1. Overexpression of ANP32B also reduced the sensitivity of colorectal cancer cells to PARP1 inhibitor, consistent with the oncogenic role of ANP32B. ANP32B may alter the sensitivity of colorectal cancer cells to PARP1 inhibitor via a mechanism associated with the HPF1 gene. In summary, these findings showed that ANP32B acted as a tumor promoter, potentiating both colorectal cancer malignancy and drug resistance. Targeting the ANP32B/HPF1 axis may have benefit for patients with colorectal cancer.

In silico approach reveals N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamides as promising selective SIRT2 inhibitors: the case of structural optimization of virtual screening-derived hits

Epigenetic modifications play an essential role in tumor suppression and promotion. Among the diverse range of epigenetic regulators, SIRT2, a member of NAD+-dependent protein deacetylates, has emerged as a crucial regulator of cellular processes, including cell cycle progression, DNA repair, and metabolism, impacting tumor growth and survival. In the present work, a series of N-(5-phenoxythiophen-2-yl)-2-(arylthio)acetamide derivatives were identified following a structural optimization of previously reported virtual screening hits, accompanied by enhanced SIRT2 inhibitory potency. Among the compounds, ST44 and ST45 selectively inhibited SIRT2 with IC50 values of 6.50 and 7.24 μM, respectively. The predicted binding modes of the two compounds revealed the success of the optimization run. Moreover, ST44 displayed antiproliferative effects on the MCF-7 human breast cancer cell line. Further, the contribution of SIRT2 inhibition in this effect of ST44 was supported by western blotting, affording an increased α-tubulin acetylation. Furthermore, molecular dynamics (MD) simulations and binding free energy calculations using molecular mechanics/generalized born surface area (MM-GBSA) method evaluated the accuracy of predicted binding poses and ligand affinities. The results revealed that ST44 exhibited a remarkable level of stability, with minimal deviations from its initial docking conformation. These findings represented a significant improvement over the virtual screening hits and may contribute substantially to our knowledge for further selective SIRT2 drug discovery. Communicated by Ramaswamy H. Sarma

KLF5 promotes esophageal squamous cell cancer through the transcriptional activation of FGFBP1

Krüpple-like factor 5 (KLF5) is a zinc-finger-containing transcription factor implicated in several human malignancies, but its potential regulatory mechanisms implicated in esophageal squamous cell carcinoma (ESCC) remain elusive. Here, we show that KLF5 is upregulated in ESCC, where its level was significantly associated with tumor differentiation and lymph node metastasis status. Upregulated KLF5 expression promoted the proliferation, migration, and invasion of ESCC cells. Reduced KLF5 showed the opposite effects. Mechanistically, KLF5 exerts its tumor promotion effect by up-regulating fibroblast growth factor binding protein 1 (FGF-BP1) and snail family transcriptional repressor 2 (SNAIL2). KLF5 binds to the promoter regions of FGF-BP1 and transcriptionally activates its expression. Our study indicated that KLF5 could promote esophageal squamous cell cancer proliferation, migration, and invasion by upregulating FGF-BP1/SNAIL2 signaling. Our work suggests that KLF5 might be a proto-oncogene in ESCC and implicated in ESCC metastasis.

Heart Failure Promotes Cancer Progression in an Integrin β1-Dependent Manner.

Heart failure and cancer are currently the deadliest diseases in the Western world, posing the most pressing clinical challenges that remain unmet today. Both conditions share similar risk factors, including age, genetics, lifestyle, chronic inflammation, stress, and more. Furthermore, medications that are being used to counteract cancer frequently result in cardiotoxicity and the spontaneous emergence of heart failure. Thus, heart failure and cancer display an intimate connection and share similarities. Recent studies show that cardiac remodeling and heart failure promote cancer progression and metastasis. Using three different mouse models for heart failure revealed that the communication between the remodeled heart and the tumor is facilitated through multiple secreted factors. Among these factors, Periostin was consistently found to be elevated in all models and was shown to be required in vitro. Yet, whether Periostin is necessary for tumor promotion in vivo is unknown. Towards this end, we examined tumor promotion in mice lacking Periostin following transverse aortic constriction (TAC). Despite the loss of Periostin, tumor growth was promoted in the TAC-operated mice. This likely occurred due to increased levels of various cytokines and growth factors in Periostin KO mice. Many of these factors are potential ligands of Integrin receptors. Therefore, we next studied the role of Integrin receptors in the tumor-promotion phenotype following heart failure. We generated cancer cells with an Integrin β1 loss of function mutation and examined tumor growth in the presence and absence of heart failure. Integrin β1 KO cancer cells fail to display cardiac-remodeling-dependent tumor-promotion. Interestingly, a previous study showed that renal cell carcinoma cells (Renca) fail to be promoted following a myocardial infarction. Consistently, we show that Renca cells do not respond to secreted factors derived from the failing heart both in vitro and in vivo. Interestingly, Renca cells display low basal mRNA levels of Integrin β1 which may explain the inability of heart failure to promote their growth. The findings may have significant clinical relevance to cardio-oncology patients who suffer from cancers with high levels of Integrin β1. Chemotherapy leading to cardiotoxicity in these patients may generate a vicious cycle with poor prognosis.

Epigenetic targeting of autophagy for cancer: DNA and RNA methylation.

Autophagy, a crucial cellular mechanism responsible for degradation and recycling of intracellular components, is modulated by an intricate network of molecular signals. Its paradoxical involvement in oncogenesis, acting as both a tumor suppressor and promoter, has been underscored in recent studies. Central to this regulatory network are the epigenetic modifications of DNA and RNA methylation, notably the presence of N6-methyldeoxyadenosine (6mA) in genomic DNA and N6-methyladenosine (m6A) in eukaryotic mRNA. The 6mA modification in genomic DNA adds an extra dimension of epigenetic regulation, potentially impacting the transcriptional dynamics of genes linked to autophagy and, especially, cancer. Conversely, m6A modification, governed by methyltransferases and demethylases, influences mRNA stability, processing, and translation, affecting genes central to autophagic pathways. As we delve deeper into the complexities of autophagy regulation, the importance of these methylation modifications grows more evident. The interplay of 6mA, m6A, and autophagy points to a layered regulatory mechanism, illuminating cellular reactions to a range of conditions. This review delves into the nexus between DNA 6mA and RNA m6A methylation and their influence on autophagy in cancer contexts. By closely examining these epigenetic markers, we underscore their promise as therapeutic avenues, suggesting novel approaches for cancer intervention through autophagy modulation.

PPARβ/δ-ANGPTL4 axis mediates the promotion of mono-2-ethylhexyl phthalic acid on MYCN-amplified neuroblastoma development

Di-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various daily plastic products through wear and leaching into the surrounding environment and decompose into the more toxic metabolite mono-2-ethylhexyl phthalic acid (MEHP) after entering the human body. However, the impacts and mechanisms of MEHP on neuroblastoma are unclear. We exposed MYCN-amplified neuroblastoma SK-N-BE(2)C cells to an environmentally related concentration of MEHP and found that MEHP increased the proliferation and migration ability of tumor cells. The peroxisome proliferator-activated receptor (PPAR) β/δ pathway was identified as a pivotal signaling pathway in neuroblastoma, mediating the effects of MEHP through transcriptional sequencing analysis. Because MEHP can bind to the PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPARβ/δ and ANGPTL4 in the metabolic process, a non-targeted metabolomics analysis revealed that MEHP altered multiple metabolic pathways, particularly lipid metabolites involving fatty acyls, glycerophospholipids, and sterol lipids, which may also be potential factors promoting tumor progression. We have demonstrated for the first time that MEHP can target binding to PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma.

NPC1 promotes autophagy with tumor promotion and acts as a prognostic model for hepatocellular carcinoma

Backgroundmore and more studies have indicated that autophagy plays a crucial role in hepatocellular carcinoma (HCC) in recent years. Hence, our study aimed to establish a prognostic signature for HCC based on autophagy-related genes (ARGs) in order to predict the prognosis of HCC. MethodsAll original gene-expression data and clinical information were downloaded from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). ARGs were obtained from the Human Autophagy Database (HADb). Univariate Cox regression analysis, Least absolute shrinkage and selection operator (LASSO) and Principal Component Analysis (PCA) analysis were performed to identify and validate the validity and reliability of our eight-gene signature, Gene Set Enrichment Analysis (GSEA) was used to perform enrichment analysis by comparing high-risk and low-risk groups in KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) gene sets. Finally, we verified the gene (NPC1) by functional experiments in vitro and in vivo. Results8 ARGs were identified for establishing an eight-gene signature. Then, we validated our eight-gene signature in training, internal, external, and entire testing cohorts. Besides, we also explored the relationships between the eight-gene signature and immune infiltration or immune checkpoints. We also identified NPC1 was closely related to Activated CD4 T cell and Type I IFN Response, and higher expressed level of HCC patients was more sensitive to CTLA4 and TNFRSF9 immune checkpoint inhibitors. NPC1 is highly expressed in HCC cells and tumor tissues, which promotes the proliferation, migration, and invasion of tumor cells by activating autophagy.. Conclusion8 ARGs were used to establish a gene signature to predict the prognosis of HCC. we inferred that NPC1 can promote late autophagy, it could be a future novel therapeutic target of HCC.

Krüppel-like Factor-9 and Krüppel-like Factor-13: Highly Related, Multi-Functional, Transcriptional Repressors and Activators of Oncogenesis

Specificity Proteins/Krüppel-like Factors (SP/KLF family) are a conserved family of transcriptional regulators. These proteins share three highly conserved, contiguous zinc fingers in their carboxy-terminus, requisite for binding to cis elements in DNA. Each SP/KLF protein has unique primary sequence within its amino-terminal and carboxy-terminal regions, and it is these regions which interact with co-activators, co-repressors, and chromatin-modifying proteins to support the transcriptional activation and repression of target genes. Krüppel-like Factor 9 (KLF9) and Krüppel-like Factor 13 (KLF13) are two of the smallest members of the SP/KLF family, are paralogous, emerged early in metazoan evolution, and are highly conserved. Paradoxically, while most similar in primary sequence, KLF9 and KLF13 display many distinct roles in target cells. In this article, we summarize the work that has identified the roles of KLF9 (and to a lesser degree KLF13) in tumor suppression or promotion via unique effects on differentiation, pro- and anti-inflammatory pathways, oxidative stress, and tumor immune cell infiltration. We also highlight the great diversity of miRNAs, lncRNAs, and circular RNAs which provide mechanisms for the ubiquitous tumor-specific suppression of KLF9 mRNA and protein. Elucidation of KLF9 and KLF13 in cancer biology is likely to provide new inroads to the understanding of oncogenesis and its prevention and treatments.

Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology.

Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host-cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.

LINC02532 by Mediating miR-541-3p/HMGA1 Axis Exerts a Tumor Promoter in Breast cancer.

The newly discovered LINC02532 is abnormally expressed in a variety of cancers and promotes cancer progression. The research proposed to discover the biological and molecular mechanisms of LINC02532 in breast cancer (BCa). In the resected BCa tissue samples and adjacent normal tissues, LINC02532, miR-541-3p, and High Mobility Group A1 (HMGA1) levels were determined. Cell function experiments were carried out on the premise of cell transfection with relevant plasmids. Based on that, the influence of LINC02532, miR-541-3p, and HMGA1 on MCF-7 cell activities (proliferation, migration, invasion, cell cycle, and apoptosis) was determined, as well as on EMT. Additionally, animal experiments were allowed to support cell experimental conclusions on LINC02532. Finally, the mechanistic network of LINC02532, miR-541-3p, and HMGA1 was identified. It was BCa tissues highly expressing LINC02532 and HMGA1, while lowly expressing miR-541-3p. Functionally, LINC02532 depletion repressed the activities and EMT process of MCF-7 cells. Silencing LINC02532 delayed tumor growth in mice. In terms of mechanism, LINC02532 mainly existed in the cytoplasm and could mediate HMGA1 expression by absorbing miR-541-3p. The findings offer new insights into the molecular mechanisms of LINC02532 in BCa and, more importantly, new strategies for the clinical treatment of BCa.

Biological evaluation of indolactams for in vitro bryostatin 1-like activity

Small molecule activators of protein kinase C (PKC) have traditionally been classified as either tumor promoters or suppressors. Although bryostatin 1 has well established anti-cancer activity, most natural products that target the PKC regulator domain exhibit tumor promotion properties. In this study, we examine a focused library of indolactam analogues in cell-based assays to establish the structural features of the scaffold that enhance bryostatin 1-like activity. These systematic biological assessments identified specific indole substitution patterns that impart diminished tumor promotion behavior in vitro for indolactam analogues, while still maintaining nanomolar potency for PKC.

Targeting the Cgas-Sting Pathway Inhibits the Progression and Enhances the Chemotherapy Efficacy of Peripheral T-Cell Lymphoma

Objective Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous group of mature T-cell malignancies. Owing to its complex clinicopathological characteristics and diagnostic difficulties, the underlying molecular mechanism leading to the high invasiveness and rapid progression remains significantly unidentified. The efficacy of current first-line treatment is dismal, novel agents and therapeutic strategies are urgently needed to improve the prognosis of PTCL patients, especially for relapsed/refractory (RR) ones. Recent studies have indicated a close association between the cGAS-STING pathway and tumor promotion, which may provide new therapeutic targets. Herein, we investigated the role of the cGAS-STING pathway and its underlying mechanism in PTCL progression. Methods Firstly, we conducted single-cell RNA sequencing (scRNA-seq) to examine cellular identity and investigate the expression heterogeneity of cGAS-STING pathway. The cGAS-STING pathway score (CSPS) was calculated based on the expression of seven marker genes of this pathway. Immunofluorescence was performed to detect cGAS and STING expression in PTCL tissue microarray containing 35 PTCL samples and 8 normal lymph node biopsies. To assess the tumor-killing activity of cGAS-STING pathway inhibitors, here we tested five drugs including cGAS inhibitors G150 and G140, STING inhibitor H151, TANK binding kinase-1 (TBK1) inhibitor TBK1/Ikkε-IN-5 and signal transducer and activator of transcription 3 (STAT3) inhibitor Stattic. Protein mass spectrometry was used to evaluate the protein changes in PTCL cell lines after G150 treatment. Next, we established a xenograft model to test the anti-tumor effect of G150 and TG003 (an inhibitor of CLK1) single-agent or combination therapy in vivo. Furthermore, we applied single-cell dynamic RNA sequencing to investigate the mechanism on the synergistic effect of TG003 and G150 in inhibition of cell proliferation. CCK8 and flow cytometric analysis were performed to detected the cellular viability and the apoptotic rate with the drug combination compared with single-drug treatment. Results scRNA-seq and showed the cGAS-STING pathway was overexpressed in PTCL with high heterogeneity and could be used as a prognostic marke (Fig. A-D). cGAS expression was positively correlated with DNA repair. cGAS inhibition effectively suppressed tumor growth via cGAS-STING-RELB-STAT3 signaling pathway and impairing DNA damage repair in PTCL. G150 treatment led to a concentration-dependent DNA damage (Fig. E-G). Moreover, single-cell dynamic RNA sequencing revealed that TG003 functions through inducing the reduction of proliferation-related nascent RNAs on the basis of G150 treatment (Fig. H,I). CLK1 played a critical role in the survival of residual tumor cells after treatment with cGAS inhibitors, and CLK1 suppression could enhance the sensitivity to cGAS inhibitors (Fig. J). In first-line therapy, chemotherapy-induced DNA damage activated the cGAS-STING pathway, which may ultimately lead to relapse or progression. cGAS inhibitors could synergize with chemotherapeutic agents in tumor killing (Fig. K-N). Fig. O summarized the oncogenic role of cGAS-STING pathway and the interaction between Tfh cells and B cells in AITL. Conclusion Herein, we demonstrated for the first time that the activated cGAS-STING pathway plays an oncogenic role in PTCL progression, in part by enhancing DNA repair and proliferation, which may also trigger chemotherapy resistance and ultimate relapse. CLK1 may serve as an indicator for the sensitivity to cGAS inhibitors. This may partly unveil the deficiency of first-line therapy and lay foundation for clinical application of cGAS-STING pathway-associated inhibitors.

Oxidative DNA damage: Induction by fructose, in vitro, and its enhancement by hydrogen peroxide

Sucrose and high-fructose corn syrup comprise nearly equal amounts of glucose and fructose. With the use of high-fructose corn syrup in the food industry, consumption of fructose, which may be a tumor promoter, has increased dramatically. We examined fructose-induced oxidative DNA damage in the presence of Cu(II), with or without the addition of H2O2. With isolated DNA, fructose induced Cu(II)-mediated DNA damage, including formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), to a greater extent than did glucose, and H2O2 enhanced the damage. In cultured human cells, 8-oxodG formation increased significantly following treatment with fructose and the H2O2-generating enzyme glucose oxidase. Fructose may play an important role in oxidative DNA damage, suggesting a possible mechanism for involvement of fructose in carcinogenesis.