Promotes Tumor Proliferation Research Articles

N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1.

Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality and poor prognosis. Important function invests circRNAs with tremendous potential in biomarkers and therapeutic targets. Nevertheless, it is still unknown how circRNAs contribute to the evolution of ICC. CircRNAs in paired ICC and adjacent tissues were screened by circRNAs sequencing. To explore the impact of circRNAs on ICC development, experiments involving gain and loss of function were conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, RNA pull-down, chromatin immunoprecipitation (ChIP), ubiquitination assays and so on were employed to identify the molecular regulatory role of circRNAs. Herein, we reported a new circRNA, which originates from exon 9 to exon 15 of the SLCO1B3 gene (named circSLCO1B3), orchestrated ICC progression by promoting tumor proliferation, metastasis and immune evasion. We found that the circSLCO1B3 gene was highly overexpressed in ICC tissues and related to lymphatic metastasis, tumor sizes, and tumor differentiation. Mechanically, circSLCO1B3 not only promoted ICC proliferation and metastasis via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity via suppressing ubiquitin-proteasome-dependent degradation of PD-L1 by E3 ubiquitin ligase SPOP. We further found that methyltransferase like 3 (METTL3) mediated the m6A methylation of circSLCO1B3 and stabilizes its expression. Our findings indicate that circSLCO1B3 is a potential prognostic marker and therapeutic target in ICC patients. Taken together, m6A-modified circSLCO1B3 was correlated with poor prognosis in ICC and promoted ICC progression not only by enhancing proliferation and metastasis via potentiating HOXC8 expression, but also by inducing immune evasion via antagonizing PD-L1 degradation. These results suggest that circSLCO1B3 is a potential prognostic marker and therapeutic target for ICC.

Challenges in Defining a Reference Set of Differentially Expressed lncRNAs in Ulcerative Colitis by Meta-Analysis.

The study aimed to identify common differentially expressed lncRNAs from manually curated ulcerative colitis (UC) gene expression omnibus (GEO) datasets. Nine UC transcriptomic datasets of clearly annotated human colonic biopsies were included in the study. The datasets were manually curated to select active UC samples and controls. R packages geneknitR, gprofiler, clusterProfiler were used for gene symbol annotation. The R EdgeR package was used to analyze differential expression. This resulted in a total of nineteen lncRNAs that were differentially expressed in at least three datasets of the nine GEO datasets. Several of the differentially expressed lncRNAs found in UC were associated with promoting colorectal cancer (CRC) through regulating gene expression, epithelial to mesenchymal transition (EMT), cell cycle progression, and by promoting tumor proliferation, invasion, and migration. The expression of several lncRNAs varied between disease states and tissue locations within the same disease state. The identified differentially expressed lncRNAs may function as general markers for active UC independent of biopsy location, age, gender, or treatment, thereby representing a comparative resource for future comparisons using available GEO UC datasets.

Linc00958 Promotes Lung Cancer Proliferation and Migration Through Regulating microRNA-490-3p

This study aimed to investigate the role of long intergenic non-protein coding RNA 00958 (Linc00958) in lung cancer (LCa) progression and its underlying mechanism. The study assessed Linc00958 expression in LCa tissues and adjacent tissues using qRT-PCR, and its impact on patient prognosis was analyzed through Kaplan-Meier survival analysis. Additionally, Linc00958 expression in LCa and normal lung cell lines was examined in vitro. Functional assays, including CCK-8, EdU, and transwell assays, were conducted to evaluate the effects of Linc00958 knockdown on LCa cells. To uncover the molecular mechanism, a dual-luciferase reporter assay was used to confirm the binding relationship between Linc00958 and microRNA-490-3p, a downstream gene. Co-transfection experiments were performed to elucidate microRNA-490-3p’s role in Linc00958’s impact on LCa cell functions. The results showed that Linc00958 was overexpressed in LCa tissues and cells, and high Linc00958 expression correlated with reduced patient survival. in vitro experiments revealed that Linc00958 promoted tumor proliferation and migration in LCa cells. Both computational predictions and dual-luciferase reporter assays demonstrated binding sites between microRNA-490-3p and Linc00958. Co-transfection experiments confirmed that Linc00958 facilitated LCa cell proliferation and migration through modulating microRNA-490-3p expression. In summary, Linc00958 promotes LCa cell proliferation and migration by regulating microRNA-490-3p.

Abstract 5153: Pyramidobacter-DMMR synergy in colorectal cancer: Unveiling prognostic impact, mechanistic insights, and tumor microenvironment dynamics

Abstract Background: Colorectal cancer (CRC) exhibits a heightened presence of intratumoral bacteria, and deficient DNA mismatch repair (dMMR) contributes to nucleotide mismatch accumulation, fostering mutagenesis. However, the combined impact of intratumoral bacteria and dMMR on the tumor immune microenvironment (TIME) in CRC, and its consequential influence on patient prognosis, remains elusive. Methods: We utilized samples from the Cancer Microbiome Atlas project (TCMA), collecting tumor and matched paracancer tissues from colorectal cancer patients. Phyloseq in R was employed to scrutinize microbial abundance differences. The effects of microbial enrichment on prognosis were assessed through survival analysis, and GSEA enrichment analysis provided mechanistic insights. Results: A total of 173 samples, including 28 dMMR tumors, 112 proficient MMR (pMMR) tumors, and 22 paired para-cancer tissues, were collected. Following stringent filtration, we analyzed 230 bacterial genera. Notably, 26 genera, including Fusobacterium and Streptococcus, showed significant enrichment in dMMR tumors compared to para-cancer tissues. Furthermore, 18 genera were enriched in dMMR tumors compared to pMMR tumors. Of these, 8 genera like Desulfovibrio and Pyramidobacter consistently exhibited enrichment in dMMR CRC compared to either para-cancer tissues or pMMR tumors. Survival analysis highlighted Pyramidobacter as the only genus significantly associated with prognosis in dMMR CRC. Increased Pyramidobacter abundance correlated with decreased overall survival (OS) (P value: 0.049). Stratifying dMMR CRC patients based on Pyramidobacter abundance further emphasized the significantly worse survival in the Pyramidobacter-High group (HR 0.93, 95%CI 1.03-9.60, log-rank p = 0.015). Exploring the impact of Pyramidobacter infection on tumor progression, we assessed TIME and oncogenic pathways between Pyramidobacter-Low and Pyramidobacter-High groups. While overall immune infiltration was higher in the Pyramidobacter-High group, it primarily stemmed from increased B cell and naive CD8+ T cell infiltration. Importantly, pathways enriched in the Pyramidobacter-High group included inflammatory response, epithelial-mesenchymal transition (EMT), and KRAS signaling, while those enriched in the Pyramidobacter-Low group encompassed IFNα response, IFNγ response, and DNA damage repair. These findings suggest Pyramidobacter's role in inducing inflammation, promoting tumor proliferation and metastasis, and suppressing interferon response. Conclusion: Pyramidobacter emerges as a key player in the development of dMMR CRC, exerting a pivotal influence on patient prognosis through the induction of inflammatory responses and EMT. Citation Format: Shisen LI, Yunlong LI, Hongjiang Ma, Shihao Qin, Feilong Zhao, Jipeng Li. Pyramidobacter-DMMR synergy in colorectal cancer: Unveiling prognostic impact, mechanistic insights, and tumor microenvironment dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5153.

Abstract 7228: In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine prostate cancer

Abstract Neuroendocrine prostate cancer (NEPC) is an aggressive histologic subtype associated with poor prognosis that commonly arises in later stages as a mechanism of treatment resistance. Activation of oncogenic drivers, in combination with epigenetic changes (such as EZH2 overexpression and DNA methylation) further promotes tumor proliferation and expression of downstream neuroendocrine lineage pathways (in part controlled by transcription factors, including SOX2, ASCL1, and BRN2). Importantly, EZH2 inhibitors (EZH2i) can restore AR expression in CRPC (Ku et al., 2017). Imipridones, including Dordaviprone (ONC201), show promise in treating neuroendocrine tumors by interacting with DRD2 and CLpP (Anderson et al., 2022). These results warrant investigation into the potential for synergism in imipridone/EZH2i combination therapies. In the PCa cell lines LNCap, PC3, 22Rv1, and DU145 the combination of ONC201 and EZH2i GSK126 was assessed. Cell viability data after treatment with ONC201 and GSK126 reveals several dose ranges with potential synergistic activity after 72h. Preliminary western blots after 72 hours of GSK126 treatment indicate modulation of proteins relevant to the mechanism of action of imipridones, specifically DR5 and CLpP, in LNCap, PC3, and 22Rv1. Notably, the decrease in DR5 expression warrants investigation into the effects of EZH2i on TRAIL sensitivity and whether imipridones may rescue DR5 expression to maintain TRAIL sensitivity. Subsequent experiments will investigate dosing and time point-based effects on viability and protein expression, in addition to assessing the synergy of other imipridones and EZH2i’s. Further, while the cell lines PC3, 22Rv1, and DU145 are castration-resistant, the neuroendocrine prostate cell line NCI-H660 will be used as a positive control as it expresses higher neuroendocrine features, including DRD2. Additionally, the modulation in DR5 expression warrants inquiry into the effects of combination therapy on tumor-immune cell interactions. Further, we will manipulate the expression of neuroendocrine transcription factors to assess changes in therapy sensitivity. Citation Format: Connor Purcell, Praveen Srinivasan, Maximilian Pinho-Schwermann, William MacDonald, Elizabeth C. Ding, Vida Tajiknia, Wafik El-Deiry. In-vitro efficacy of Dordaviprone/GSK126 combination therapy on castration resistant and neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7228.

The use of methylene blue to control the tumor oxygenation level

BackgroundHypoxia is a characteristic feature of many tumors. It promotes tumor proliferation, metastasis, and invasion and can reduce the effectiveness of many types of cancer treatment. ObjectiveThe aim of this study was to investigate the pharmacokinetics of methylene blue (MB) and its impact on the tumor oxygenation level at mouse Lewis lung carcinoma (LLC) model using spectroscopic methods. ApproachThe pharmacokinetics of MB were studied qualitatively and quantitatively using video fluorescence imaging and fluorescence spectroscopy. The degree of hemoglobin oxygenation in vivo was examined by calculating hemoglobin optical absorption from the measured diffuse reflectance spectra. The distribution of MB fluorescence and the lifetime of NADH were analyzed using laser scanning microscopy and fluorescence lifetime imaging microscopy (FLIM) to assess cellular metabolism. ResultsAfter intravenous administration of MB at 10–20 mg/kg, it quickly transitioned in the tumor to a colorless leucomethylene blue, with maximum accumulation in the tumor occurring after 5–10 min. A concentration of 10 mg/kg resulted in a relative increase of the tumor oxygenation level for small tumors (volume 50–75 mm3) and normal tissue 120 min after the introduction of MB. A shift in tumor metabolism towards oxidative phosphorylation (according to the lifetime of the NADH coenzyme) was measured using FLIM method after intravenous administration of 10 mg/kg of MB. Intravenous administration of MB at 20 mg/kg results in a long-term decrease in oxygenation, which persisted for at least 120 min after the administration and did not return to its initial level. ConclusionsAdministration of MB at 10 mg/kg shown to increase tumor oxygenation level, potentially leading to more effective antitumor therapy. However, at higher doses (20 mg/kg), MB may cause long-term decrease in oxygenation.

Identification of macrophage-related genes correlated with prognosis and immunotherapy efficacy in non-small cell lung cancer

BackgroundMalignant tumours, particularly non-small cell lung cancer (NSCLC), pose a significant threat to human health due to their prevalence and lethality. Treatment methods for NSCLC vary greatly among individuals, making it crucial to identify predictive markers. Moreover, during tumour initiation and progression, tumour cells can release signaling molecules to induce polarization of macrophages towards a more tumour friendly M2 phenotype, which can promote tumour growth, metastasis, and drug resistance. MethodsWe employed a comprehensive approach, combining bulk RNA-seq and single-cell sequencing analysis. ResultsIn our study, we used bulk RNA-seq and single-cell sequencing methods to analyze differential cells in NSCLC and adjacent tissues, searching for relevant marker genes that can predict prognosis and drug efficacy. We scrutinized biological phenomena such as macrophage-related gene methylation, copy number variation, and alternative splicing. Additionally, we utilized a co-culture technique of immune and tumour cells to explore the role of these genes in macrophage polarization. Our findings revealed distinct differences in macrophages between cancerous and adjacent tissues. We identified ANP32A, CCL20, ERAP2, MYD88, TMEM126B, TUBB6, and ZNF655 as macrophage-related genes that correlate with NSCLC patient prognosis and immunotherapy efficacy. Notably, ERAP2, TUBB6, CCL20, and TMEM126B can induce macrophage M0 to M2 polarization, promoting tumour proliferation. ConclusionThese findings significantly contribute to our understanding of the NSCLC tumour immune microenvironment. They pave the way for further research into the potential of these genes as targets for regulating tumour occurrence and development.

Super enhancer related gene ANP32B promotes the proliferation of acute myeloid leukemia by enhancing MYC through histone acetylation

BackgroundAcute myeloid leukemia (AML) is a malignancy of the hematopoietic system, and childhood AML accounts for about 20% of pediatric leukemia. ANP32B, an important nuclear protein associated with proliferation, has been found to regulate hematopoiesis and CML leukemogenesis by inhibiting p53 activity. However, recent study suggests that ANP32B exerts a suppressive effect on B-cell acute lymphoblastic leukemia (ALL) in mice by activating PU.1. Nevertheless, the precise underlying mechanism of ANP32B in AML remains elusive.ResultsSuper enhancer related gene ANP32B was significantly upregulated in AML patients. The expression of ANP32B exhibited a negative correlation with overall survival. Knocking down ANP32B suppressed the proliferation of AML cell lines MV4-11 and Kasumi-1, along with downregulation of C-MYC expression. Additionally, it led to a significant decrease in H3K27ac levels in AML cell lines. In vivo experiments further demonstrated that ANP32B knockdown effectively inhibited tumor growth.ConclusionsANP32B plays a significant role in promoting tumor proliferation in AML. The downregulation of ANP32B induces cell cycle arrest and promotes apoptosis in AML cell lines. Mechanistic analysis suggests that ANP32B may epigenetically regulate the expression of MYC through histone H3K27 acetylation. ANP32B could serve as a prognostic biomarker and potential therapeutic target for AML patients.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with limited treatment options. Deubiquitinases (DUBs) have been confirmed to play a crucial role in the development of malignant tumors. JOSD2 is a DUB involved in controlling protein deubiquitination and influencing critical cellular processes in cancer. To investigate the impact of JOSD2 on the progression of ESCC. Bioinformatic analyses were employed to explore the expression, prognosis, and enriched pathways associated with JOSD2 in ESCC. Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines (KYSE30 and KYSE150). Functional assays, including cell proliferation, colony formation, drug sensitivity, migration, and invasion, were performed, revealing the impact of JOSD2 on ESCC cell lines. JOSD2's role in xenograft tumor growth and drug sensitivity in vivo was also assessed. The proteins that interacted with JOSD2 were identified using mass spectrometry. Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues, which was associated with poor prognosis. Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells. JOSD2 knockdown inhibited ESCC cell activity, including proliferation and colony-forming ability. Moreover, JOSD2 knockdown decreased the drug resistance and migration of ESCC cells, while JOSD2 overexpression enhanced these phenotypes. In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC. Mechanistically, JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways. Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2, which identified the four primary proteins that bind to JOSD2, namely USP47, IGKV2D-29, HSP90AB1, and PRMT5. JOSD2 plays a crucial role in enhancing the proliferation, migration, and drug resistance of ESCC, suggesting that JOSD2 is a potential therapeutic target in ESCC.

LncRNA HCG18 promotes prostate cancer progression by regulating the miR-512-3p/HK-2 axis

ObjectiveLong non-coding RNAs (lncRNAs) play an important role in tumor progression. Numerous studies show that lncRNAs are strongly associated with prostate cancer (PCa) progression. The aim of this study was to investigate the pathway through which lncRNA HCG18 regulates PCa progression by bioinformatics analysis and experiments. MethodsWe compared HCG18 expression in PCa versus normal tissue and cells by data and cell lines, followed by comparing the changes in tumor cell proliferation, migration, and invasive ability after knockdown of HCG18. Then we searched for its downstream pathway by database and validated the pathway in vivo and in vitro. ResultsHCG18 was highly expressed in PCa and has the ability to promote tumor proliferation, migration, and invasion; knockdown of HCG18 led to a decrease in the ability of cells to do so, which can be reversed by knockdown of miR-512-3p or overexpression of hexokinase 2. ConclusionOur in vivo and in vitro experiments suggest that HCG18 can play a role in promoting PCa progression by blocking the inhibition of hexokinase 2 by miR-512-3p via sponge adsorption.

PRDX2 regulates stemness contributing to cisplatin resistance and metastasis in bladder cancer.

Cisplatin (CDDP)-based chemotherapy has emerged as the primary treatment for muscle-invasive bladder cancer and metastatic bladder cancer. Nevertheless, a significant proportion of patients experience rapidly developed chemoresistance, leading to treatment ineffectiveness. Existing evidence suggests that chemoresistance is governed by various factors, including tumor stem cells, epithelial mesenchymal transition, and reactive oxygen species (ROS). However, limited research has been conducted on the role of PRDX2, a crucial ROS scavenger, in the modulation of chemoresistance in bladder cancer. Cisplatin-resistant cell lines were established using the concentration gradient overlay method, and differentially expressed genes in resistant cells were screened through RNA sequencing. The expression of PRDX2 in cells and tissues was assessed using RT-qPCR, Western Blot, and immunohistochemistry. The expression of PRDX2 in bladder cancer and adjacent tissues was evaluated using a bladder cancer tissue microarray. Furthermore, the impact of PRDX2 knockdown on tumor formation and metastasis was investigated in vivo by applying subcutaneous tumor xenografts tail vein metastasis assays. We demonstrated that PRDX2 is significantly upregulated in bladder tumors and cisplatin-resistant bladder tumor cell lines. Overexpression of PRDX2 can promote tumor proliferation, migration, and invasion both in vitro and in vivo. We have found that knockdown of PRDX2 expression can effectively reverse cell resistance to cisplatin. Mechanistically, our findings suggest that PRDX2 is involved in regulating tumor stemness and epithelial-mesenchymal transition (EMT). Knockdown of PRDX2 affects the PI3K-AKT and mTOR signaling pathways, thereby influencing tumor stemness and EMT, ultimately impacting the chemotherapy resistance of the tumor. This study provides a new insight into the regulation of chemotherapy resistance in bladder cancer by PRDX2. Targeting PRDX2 can serve as a potent therapeutic target for chemotherapy resistance.

Anti-tumor therapy of glycyrrhetinic acid targeted liposome co-delivery of doxorubicin and berberine for hepatocellular carcinoma.

During the development of hepatocellular carcinoma (HCC), hepatic stellate cells undergo activation and transform into cancer-associated fibroblasts (CAFs) due to the influence of tumor cells. The interaction between CAFs and tumor cells can compromise the effectiveness of chemotherapy drugs and promote tumor proliferation, invasion, and metastasis. This study explores the potential of glycyrrhetinic acid (GA)-modified liposomes (lip-GA) as a strategy for co-delivery of berberine (Ber) and doxorubicin (Dox) to treat HCC. The characterizations of liposomes, including particle size, zeta potential, polydispersity index, stability and in vitro drug release, were investigated. The study evaluated the anti-proliferation and anti-migration effects of Dox&Ber@lip-GA on the Huh-7 + LX-2 cell model were through MTT and wound-healing assays. Additionally, the in vivo drug distribution and anti-tumor efficacy were investigated using the H22 + NIH-3T3-bearing mouse model. The results indicated that Dox&Ber@lip-GA exhibited a nanoscale particle size, accumulated specifically in the tumor region, and was efficiently taken up by tumor cells. Compared to other groups, Dox&Ber@lip-GA demonstrated higher cytotoxicity and lower migration rates. Additionally, it significantly reduced the deposition of extracellular matrix (ECM) and inhibited tumor angiogenesis, thereby suppressing tumor growth. In conclusion, Dox&Ber@lip-GA exhibited superior anti-tumor effects both in vitro and in vivo, highlighting its potential as an effective therapeutic strategy for combating HCC.

Retraction: Decreased long intergenic noncoding RNA P7 predicts unfavorable prognosis and promotes tumor proliferation via the modulation of the STAT1-MAPK pathway in hepatocellular carcinoma.

Retraction: Decreased long intergenic noncoding RNA P7 predicts unfavorable prognosis and promotes tumor proliferation via the modulation of the STAT1-MAPK pathway in hepatocellular carcinoma.

Lamin B1: a novel biomarker in adult and pediatric adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a malignancy with a poor prognosis and high mortality rate. A high tumor mutational burden (TMB) has been found to be associated with poor prognosis in ACC. Thus, exploring ACC biomarkers based on TMB holds significant importance for patient risk stratification. In our research, we utilized weighted gene coexpression network analysis and an assay for transposase-accessible chromatin with high-throughput sequencing to identify genes associated with TMB. Through the comprehensive analysis of various public datasets, Lamin B1 (LMNB1) was identified as a biomarker associated with a high TMB and low chromatin accessibility. Immunohistochemical staining demonstrated high expression of LMNB1 in ACC compared to noncancerous tissues. Functional enrichment analyses revealed that the function of LMNB1 is associated with cell proliferation and division. Furthermore, cell assays suggested that LMNB1 promotes tumor proliferation and invasion. In addition, mutation analysis suggested that the high expression of LMNB1 is associated with TP53 mutations. Additionally, LMNB1 was highly expressed in the vast majority of solid tumors across cancers. In our immune analysis, we discovered that the high expression of LMNB1 might suppress the infiltration of CD8+ T cells in the ACC microenvironment. In summary, LMNB1 is a predictive factor for the poor prognosis of adult and pediatric ACC. Its high expression in ACC is positively associated with high TMB and lower chromatin accessibility, and it promotes ACC cell proliferation and invasion. Therefore, LMNB1 holds promise as a novel biomarker and potential therapeutic target for ACC.

ARID1A deficiency promotes progression and potentiates therapeutic antitumour immunity in hepatitis B virus-related hepatocellular carcinoma.

Exploring predictive biomarkers and therapeutic strategies of ICBs has become an urgent need in clinical practice. Increasing evidence has shown that ARID1A deficiency might play a critical role in sculpting tumor environments in various tumors and might be used as pan-cancer biomarkers for immunotherapy outcomes. The current study aims to explored the immune-modulating role of ARID1A deficiency in Hepatitis B virus (HBV) related hepatocellular carcinoma (HBV-HCC) and its potential immunotherapeutic implications. In the current study, we performed a comprehensive analysis using bioinformatics approaches and pre-clinical experiments to evaluate the ARID1A regulatory role on the biological behavior, and immune landscape of Hepatitis B virus (HBV) related hepatocellular carcinoma (HBV-HCC). A total of 425 HBV-related hepatocellular carcinoma patients from TCGA-LIHC, AMC and CHCC-HBV cohort were enrolled in bioinformatics analysis.Immunohistochemical staining of HBV-HCC specimens and ARID1A deficiency cellular models were used to validate the results of the analysis. Our results have shown that ARID1A deficiency promoted tumor proliferation and metastasis. More importantly, ARID1A deficiency in HBV-HCC was associated with the higher TMB, elevated immune activity, and up-regulated expression of immune checkpoint proteins, especially TIM-3 in HBV-HCC. Further, the expression of Galectin-9, which is the ligand of TIM-3, was elevated in the ARID1A knockout HBV positive cell line. To conclude, we have shown that the ARID1A deficiency was correlated with more active immune signatures and higher expression of immune checkpoints in HBV-HCC. Additionally, the present study provides insights to explore the possibility of the predictive role of ARID1A in HBV-HCC patients responsive to immunotherapy.

PDK3 drives colorectal carcinogenesis and immune evasion and is a therapeutic target for boosting immunotherapy.

Pyruvate Dehydrogenase Kinase 3 (PDK3) has emerged as a significant player in various cancer types, yet its specific impact on cancers including colon cancer remains ambiguous. Through pan-cancer analysis using TCGA data, we found that the expression of PDK3 and the composition of the immune microenvironment for different tumors were highly heterogeneous across tumors. PDK3 is highly expressed in colorectal cancer and may promote tumor proliferation by activating PI3K-AKT signaling. In addition, we found that PDK3 was able to inhibit tumor antigen presentation signals to suppress immune killing. High PDK3 expression predicts less CD8+ T cell infiltration and effector function. Moreover, inhibition of PDK3 expression bolstered CD8+ T cell-mediated cytotoxicity CD8+ T cell infiltration and activation in vivo. Notably, PDK3 was found to facilitate STAT1 activation and elevate programmed death-ligand 1 (PD-L1) expression in colon cancer cells. Importantly, PDK3 inhibition combination with PD-1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. In summary, these findings underscore PDK3's role in fueling colon cancer growth by orchestrating PI3K-AKT signaling and PD-L1 expression and dampening CD8+ T cell function.

Fibroblast activation protein (FAP) as a prognostic biomarker in multiple tumors and its therapeutic potential in head and neck squamous cell carcinoma.

Fibroblast activation protein (FAP), a cell surface serine protease, plays roles in tumor invasion and immune regulation. However, there is currently no pan-cancer analysis of FAP. Objective: We aimed to assess the pan-cancer expression profile of FAP, its molecular function, and its potential role in head and neck squamous cell carcinoma (HNSC). We analyzed gene expression, survival status, immune infiltration, and molecular functional pathways of FAP in The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) tumors. Furthermore, to elucidate the role of FAP in HNSC, we performed proliferation, migration, and invasion assays post-FAP overexpression or knock-down. FAP expression was elevated in nine tumor types and was associated with poor survival in eight of them. In the context of immune infiltration, FAP expression negatively correlated with CD8+ T-cell infiltration in five tumor types and positively with regulatory T-cell infiltration in four tumor types. Our enrichment analysis highlighted FAP's involvement in the PI3K-Akt signaling pathway. In HNSC cells, FAP overexpression activated the PI3K-Akt pathway, promoting tumor proliferation, migration, and invasion. Conversely, FAP knockdown showed inhibitory effects. Our study unveils the association of FAP with poor tumor prognosis across multiple cancers and highlights its potential as a therapeutic target in HNSC.

Manipulating macrophage polarization with nanoparticles to control metastatic behavior in heterotypic breast cancer micro-tissues via exosome signaling.

This study aimed to investigate the effects of nanoparticles on macrophage polarization and their subsequent influence on post-tumorigenic behavior. Initially, seven different nanoparticles were applied to macrophages, and Zn-Ni-FeO (100 nm) and palladium nanoparticles (PdNPs, ∼25 nm) were found to induce M1-polarization in macrophages. A co-culture experiment was then conducted to examine the effects of macrophages on MCF-7 breast cancer micro-tissues. The M2-macrophages promoted tumor proliferation, while M1- and PdNPs-induced macrophages showed anti-tumor effects by suppressing cell proliferation. To reveal the mechanisms of effect, exosomes isolated from M1 (M1-Exo), M0 (M0-Exo), M2 (M2-Exo), and PdNPs-induced (PdNPs-Exo) macrophages were applied to the heterotypic tumor micro-tissues including MCF-7, human umbilical vein endothelial cells (HUVECs), and primary human dermal fibroblasts (phDFs). M2-Exo was seen to promote the migration of cancer cells and induce epithelial-mesenchymal transition (EMT), while M1-Exo suppressed these behaviors. PdNPs-Exo was effective in suppressing the aggressive nature of breast cancer cells similar to M1-Exo, moreover, the efficacy of 5-fluorouracil (5-FU) was increased in combination with PdNPs-Exo in both MCF-7 and heterotypic micro-tissues. In conclusion, PdNPs-Exo has potential anti-tumor effects, can be used as a combination therapy to enhance the efficacy of anti-cancer drugs, as well as innovative implants for breast cancer treatment.

GABA induced by sleep deprivation promotes the proliferation and migration of colon tumors through miR-223-3p endogenous pathway and exosome pathway

BackgroundResearch has indicated that long-term sleep deprivation can lead to immune dysfunction and participate in the occurance and progression of tumors. However, the relationship between sleep deprivation and colon cancer remains unclear. This study explored the specific mechanism through which sleep deprivation promotes the proliferation and migration of colon cancer, with a focus on the neurotransmitter GABA.MethodsChronic sleep deprivation mice model were used to investigate the effect of sleep disorder on tumors. We detected neurotransmitter levels in the peripheral blood of mice using ELISA. CCK-8 assay, colony formation assay, wound healing assay, and transwell assay were performed to investigate the effect of GABA on colon cancer cells, while immunofluorescence showed the distribution of macrophages in lung metastatic tissues. We isolated exosomes from a GABA-induced culture medium to explore the effects of GABA-induced colon cancer cells on macrophages. Gain- and loss-of-function experiments, luciferase report analysis, immunohistochemistry, and cytokine detection were performed to reveal the crosstalk between colon cancer cells and macrophages.ResultsSleep deprivation promote peripheral blood GABA level and colon cancer cell proliferation and migration. Immunofluorescence analysis revealed that GABA-induced colon cancer metastasis is associated with enhanced recruitment of macrophages in the lungs. The co-culture results showed that GABA intensified M2 polarization of macrophage induced by colon cancer cells. This effect is due to the activation of the macrophage MAPK pathway by tumor-derived exosomal miR-223-3p. Furthermore, M2-like macrophages promote tumor proliferation and migration by secreting IL-17. We also identified an endogenous miR-223-3p downregulation of the E3 ligase CBLB, which enhances the stability of cMYC protein and augments colon cancer cells proliferation and migration ability. Notably, cMYC acts as a transcription factor and can also regulate the expression of miR-223-3p.ConclusionOur results suggest that sleep deprivation can promote the expression of miR-223-3p in colon cancer cells through GABA, leading to downregulation of the E3 ligase CBLB and inhibition of cMYC ubiquitination. Simultaneously, extracellular miR-223-3p promotes M2-like macrophage polarization, which leads to the secretion of IL-17, further enhancing the proliferation and migration of colon cancer cells.

VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature.

V-domain Ig suppressor of T cell activation (VISTA), encoded by the human VSIR gene, is a B7 family checkpoint homologous to the programmed death-Ligand 1 sequence. In gynecologic malignancies, VISTA is abnormally expressed and regulates the tumor immune microenvironment, causing a high upregulation of VISTA expression in T-cells and myeloid cells in the tumor microenvironment and promoting tumor proliferation, progression, and immune tolerance. Here, we review the research progress of VISTA in ovarian, cervical, and endometrial cancers through its structure and immunomodulatory mechanism. The comprehensive study of VISTA is expected to improve the current problem of poor immunotherapeutic effects and provide new ideas for immune therapy in patients with gynecologic tumors.