Anti-tumor Role Research Articles

The Role of B Cells in Solid Tumors

A surge of recent studies have identified B cells as pivotal contributors to shaping the tumor microenvironment (TME) within solid tumors. B cells can both directly and indirectly antagonize tumor growth via antibody production, antigen presentation, and cytokine secretion, potentially through the formation of tertiary lymphoid structures. However, certain B cell states have demonstrated the ability to promote tumor growth via immunoregulatory mechanisms such as the production of immunosuppressive cytokines and the expression of immune checkpoints, both of which dampen T cell–dependent antitumor responses. Here, we discuss the dichotomy of B cell function in solid tumors, underscoring both the pro- and antitumor roles that B cells play in the TME. Furthermore, we summarize ongoing efforts to reprogram protumorigenic B cells and/or to promote the activity and abundance of effector B cells as potential immunotherapy approaches in solid tumors.

TMIC-09. DENDRITIC CELL DYSFUNCTION RESTRICTS TUMOR ANTIGEN SPREADING IN ADOPTIVE CELLULAR TRANSFER THERAPY-ESCAPED GLIOMAS: IMPLICATIONS FOR TUMOR IMMUNE EVASION

Abstract Dendritic cells (DCs) play a pivotal role in initiating anti-tumor immune responses. Our group has developed an adoptive cellular transfer therapy (ACT) that significantly increases the infiltration of DCs and T cells into tumors, markedly enhancing survival in murine brain tumor models. However, tumors develop mechanisms to restrict the immune surveillance and the efficacy of immunotherapy, leading to tumor escape. In this study, we identified a mechanism involving DC dysfunction in ACT-escaped brain tumors. The finding that DCs are enriched after ACT treatment prompts an investigation into whether DC function is impaired in ACT-escaped tumors. Our results showed that DCs from both primary and ACT-escaped tumors were dysfunctional in their ability to activate T cells when co-cultured with tumor-reactive T cells or OT1 T cells. RNA-seq data revealed that, compared to primary tumor DCs, ACT-escaped tumor DCs exhibited a more pronounced reduction in conventional DC markers and antigen-presenting genes, alongside increased tolerance markers. Gene set enrichment analysis indicated that epithelial-mesenchymal transition (EMT) and hypoxia pathways were significantly enriched in ACT-escaped tumor DCs, suggesting divergent DC dysfunction mechanisms in primary versus escaped tumors. The anti-tumor role of DCs is primarily exerted through the activation of tumor-reactive T cells. Therefore, we assessed the cytotoxicity and exhaustion status of T cells in tumors. Surprisingly, we found that T cells from ACT-escaped tumors exhibited significantly higher levels of cytotoxicity and lower levels of T cell exhaustion compared to primary tumors. This suggests a T cell exhaustion-independent mechanism in ACT-escaped tumors. We further demonstrated that T cells in ACT-escaped tumor are mainly sourced from the adoptive transferred T cells, which recognize primary tumor antigens but not escaped tumor antigens. These results suggest that a combined mechanism of tumor antigen shifting and impaired DC function leads to a failure of antigen spreading and tumor eradication.

Hsa_circ_0000423 promotes colorectal cancer EMT and immune escape by competitive adsorption of miR-369-3p mediating CCND1 expression

BackgroundThis investigation evaluated the mechanism of hsa_circ_0000423 in colorectal cancer (CRC).MethodsThe hsa_circ_0000423 gene was identified by bioinformatics analyses of GEO circRNA microarrays, and its expression in CRC was investigated. Based on this, in vitro experiments were conducted. Assays with dual luciferase reporter and RIP were conducted to detect interactions between hsa_circ_0000423, miR-369-3p and CCND1. Cell proliferation was measured by MTT and colony formation assay assays, apoptosis was detected by flow cytometry, migration and invasion were detected by Transwell, and expression of EMT-related proteins was detected by Western Blot. SW480 cells and T cells were co-cultured to assess immune escape.Resultshsa_circ_0000423 and CCND1 were elevated in CRC while miR-369-3p was downregulated Silencing hsa_circ_0000423 resulted in reduced CCND1 expression by upregulating miR-369-3p. Overexpressing CCND1 or down-regulating miR-369-3p both interrupted the anti-tumor role of silencing hsa_circ_0000423 on CRC cells.ConclusionHsa_circ_0000423 promotes CCND1 expression through competitive binding of miR-369-3p and promotes CRC cell development and immune escape.

A computational analysis of the oncogenic and anti-tumor immunity role of P4HA3 in human cancers

Prolyl-4-hydroxylase subunit alpha3 (P4HA3) is a triple helical procollagen synthesis protein. The role of P4HA3 in cancer development is not well known and lacks comprehensive analyses among human cancers. This study aimed to investigate the relationship between P4HA3 expression and anti-tumor immunity and its prognostic value in pan-cancer. P4HA3 expression was analyzed from TIMER2.0, GTEx, GEPIA2.0 and TCGA databases. Genetic and DNA methylation alterations, survival analysis and proteins co-expression analysis of P4HA3 in cBio Cancer Genomics Portal, TCGA, GSCA and TIMER2.0. The correlation between P4HA3 expression and immune infiltration was analyzed by TIDE, XCELL, MCPCOUNTER, and EPIC. We performed EdU and transwell experiments to evaluate the influence of P4HA3 on the proliferation, migration and invasion abilities of different tumors. Patients derived xenograft (PDX) and subcutaneous transplantation models were utilized to explore the correlation between P4HA3 and immunotherapy response in triple-negative breast cancer (TNBC). Among 33 types of cancers, P4HA3 had generally different expression between different tumors, further analysis showed that the expression of P4HA3 was correlated with the cells infiltration of the tumor microenvironment (TME). The expression of P4HA3 was positively with the cell proliferation markers and epithelial-mesenchymal transition (EMT) markers. Moreover, P4HA3 deficiency inhibited the proliferation, migration and invasion abilities of tumor cells, and promoted anti-tumor immunotherapy of PD-1/PD-L1 inhibitor. This pan-cancer analysis of P4HA3 provides a comprehensive understanding of its oncogenic and prognosis role in different cancers, P4HA3 abnormal expression could be a useful biomarker for predicting the effectiveness of immunotherapy in cancer patients.

Integrative study to determine the anti-tumor role and mechanism of Chouchunpi San in colorectal cancer

IntroductionThe herbal formula Chouchunpi San (CCPS) is a traditional formula that has been widely used and proven effective in various clinical cancer treatments. However, the mechanism of its anticancer effect remains unclear. This study aims to determine the anti-tumor effect of CCPS on colorectal cancer (CRC) in vivo and in vitro and to explore the underlying molecular mechanisms. MethodsCell counting kit-8 assays, colony-forming assays, and flow cytometry for cell cycle and apoptosis assays were employed to determine the anti-tumor roles of CCPS. Liquid chromatography-mass spectrometry (LC-MS), network pharmacology, molecular docking, analysis of real-world clinical datasets of CRC, and western blotting were conducted to explore the molecular mechanism of CCPS on CRC. CRC xenografted mouse model, western blotting, and public CRC data analysis were conducted to evaluate the anti-tumor efficacy and mechanisms of CCPS on CRC. ResultsCCPS suppresses the growth of CRC cells and increases the number of apoptotic cells dose-dependently. CCPS targets and significantly downregulates RPA1 and enhances the phosphorylation of its downstream effectors, ATR and CHK1, which are critical for CRC progression. Additionally, CCPS shows a comparable anti-tumor effect in CRC xenografted mouse models compared to Capecitabine, a chemotherapy drug commonly used in clinics. DiscussionOur findings demonstrate the potential use of CCPS in cancer treatment by suppressing cancer cell growth and modulating the RPA1/ATR/CHK1 signaling pathway in CRC. Further investigations on the application of CCPS in cancer therapies could be extended to evaluate the potential in vivo toxicity and adverse events, as well as the synergistic effect of CCPS in combination with other chemotherapeutic agents.

8595 Brain Penetration Impedes SERD Efficacy in Breast Cancer Pre-clinical Models

Abstract Disclosure: S.E. Wardell: None. B. Chakraborty: None. S. Artham: None. M.A. Newlin: None. M. Kirkland: None. C. Chang: None. D.P. McDonnell: None. Most breast cancers express the estrogen receptor (ER, ESR1), and agents that target ER remain the cornerstone of interventions used to treat this disease at all stages. Aromatase inhibitors (AI), which block estrogen synthesis, and the selective ER downregulator (SERD) fulvestrant were developed with the goal of achieving absolute inhibition of ER signaling in tumors. However, it has been assumed that the clinical efficacy (and utility) of fulvestrant is somewhat limited by its poor pharmaceutical properties and the requirement that it be administered by intramuscular injection. This, together with the observation that the activating ESR1 mutations selected for during AI treatment are not effectively inhibited by fulvestrant, encouraged the development of new classes of SERDs that achieve sufficient exposure to saturate and degrade ER in tumors. The recent approval of the second-generation SERD elacestrant for the treatment of breast cancers harboring ESR1 mutations was a major advance in approaches to target ER in advanced breast cancer. Several additional oral SERDs have been developed and evaluated as potential treatments for advanced metastatic breast cancer. Despite showing substantial efficacy in pre-clinical assays that assess ER downregulation and gene transcription, and notably equivalent antitumor activities in cell line derived and PDX tumors in immunocompromised mice, the clinical development of the majority of these SERDs has been discontinued for lack of efficacy. In reviewing the available clinical data across many SERD programs, we noted that some drugs demonstrated a paradoxical, non-linear response curve with higher doses exhibiting less efficacy than lower doses. Probing this pharmacology in animal models we determined that the ability of SERDs to cross the blood brain barrier and attenuate ER signaling in the hypothalamus was a key differentiator of SERDs. In validated syngeneic models of breast cancer, we observed doses of fulvestrant having confirmed brain exposure stimulated tumor growth independent of tumor ER-status. We evaluated the ability of several next generation SERDs for their brain penetrance and demonstrated that SERD presence in the brain was associated with a stimulatory effect on tumor growth. Interestingly, administration of a low dose of 17b-estradiol (E2) together with a brain excluded SERD further repressed tumor growth, highlighting a potentially beneficial anti-tumor role for estrogen signaling in the brain. Furthermore, combination of a brain excluded SERM with E2 also resulted in increased tumor growth repression; thus, ER downregulation is dispensable for the cooperative activity observed for estrogens administered together with a peripheral ER antagonist. These data suggest that differences in tissue pharmacology, as opposed to differences in ability to degrade ER, is likely to be a major differentiator of ER modulators. Presentation: 6/3/2024

Prognostic value and anti-tumor immunity role of TMED9 in pan-cancer: a bioinformatics study.

Transmembrane p24 trafficking protein 9 (TMED9) belongs to the TMED family, and its overexpression frequently induces cancer. Studies have demonstrated the association between the overexpression of TMED9 and cancer development and proliferative migration in cancers such as ovarian cancer, hepatocellular carcinoma, and breast cancer. However, there has been no study investigating the clinical value, biological function, and anti-tumor immune effects of TMED9 from a pan-cancer perspective. The aim of this study is to evaluate the prognostic value and anti-tumor immunity role of TMED9 across pan-cancers. We utilized R language along with The Cancer Genome Atlas (TCGA), UCSC Xena (University of California, Santa Cruz Xena Browser), Human Protein Atlas (HPA), and other datasets to investigate TMED9 expression in various tumors. The association between high TMED9 expression and clinical prognosis and patient survival was examined using the Kaplan-Meier method, log-rank test, as well as univariate and multivariate Cox regression analyses. Tumor Immune Estimation Resource 2.0 (TIMER2.0) and various algorithms were employed to explore the relationship between TMED9 and the tumor microenvironment (TME). Additionally, the biological function of TMED9 in cancer was investigated through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) analyses. TMED9 was over-expressed in the majority of cancers. Patients exhibiting elevated TMED9 expression typically experienced diminished survival rates and unfavorable clinical outcomes. TMED9 played a role as a mediator in the aggressive phenotype of numerous tumors, actively engaging in various biological and signaling pathways linked to cancer development. TMED9 demonstrated the capacity to modulate the anti-tumor immune response in pan-cancer patients, exerting its influence on the infiltration levels of immune cells and cancer-associated fibroblasts (CAFs). TMED9 serves as a novel "cancer indicator" and "clinical prognostic marker", capable of reshaping the TME, impacting the immunotherapeutic response, and guiding precise treatments for cancers to a certain extent.

Pterostilbene Induces Pyroptosis in Breast Cancer Cells through Pyruvate Kinase 2/Caspase-8/Gasdermin C Signaling Pathway.

The incidence and mortality of breast cancer increase year by year, and it is urgent to find high-efficiency and low-toxicity anti-cancer drugs. Pterostilbene (PTE) is a natural product with antitumor activity, but the specific antitumor mechanism is not very clear. Aerobic glycolysis is the main energy supply for cancer cells. Pyroptosis is an inflammatory, programmed cell death. The aim of this study was to investigate the effect of PTE on glycolysis and pyroptosis in EMT6 and 4T1 cells and the specific mechanism, and to elucidate the role of pyruvate kinase 2 (PKM2), a key enzyme in glycolysis, in the antitumor role of PTE. Our study suggested that PTE induced pyroptosis by inhibiting tumor glycolysis. PKM2 played an important role in both the inhibition of glycolysis and the induction of pyroptosis by PTE.

Corynoxine exerts the anti-tumor effect on esophageal squamous cell carcinoma principally via the EZH2-DUSP5-ERK1/2-mediated cell growth inhibition

BackgroundEsophageal cancer is one of the most prevalent malignant tumors and the sixth largest cause of tumor-associated death worldwide. Squamous cell carcinoma (ESCC) accounts for 85 % of all esophageal cancer cases. ESCC treatment remains to be significantly difficult. Corynoxine (Cory) is a tetracyclic hydroxyindole alkaloid isolated from Uncaria macrophylla. It is unclear whether Cory has an anti-tumor effect on ESCC. PurposeTo determine the anti-tumor activity of Cory and the associated mechanisms in ESCC. Study designCory's effects on proliferation, apoptosis, migration, and invasion, as well as the underlying molecular causes were assessed using two ESCC cell lines, KYSE150 and TE-1. A xenograft mouse model was then applied to evaluate the anti-tumor activity of Cory in vivo. MethodsWestern blot, assays including CCK-8, colony formation, EdU staining, TUNEL staining, cell scratch and Transwell, and a xenograft mouse model were used in this study. ResultsCory suppressed cell growth, provoked cell apoptosis, and hindered cell migration and invasion of ESCC cells. DUSP5 knockdown reduced the Cory-induced cell death and restored cell migration and invasion through ERK1/2 activation. Further analyses showed that Cory promoted DUSP5 expression via inhibiting EZH2 expression, leading to inactivation of ERK1/2 signaling and the subsequent cell growth inhibition of ESCC. In vivo experiments disclosed that Cory suppressed tumor growth of ESCC through upregulating DUSP5 expression. ConclusionsCory plays an anti-tumor role in ESCC by regulating EZH2-DUSP5-ERK1/2 signaling pathway. Cory may be promising to be a novel therapy for treating ESCC.

Swertianin Promotes Anti-Tumor activity by facilitating Macrophage M1 polarization via STING signaling

To investigate the mechanism by which swertiamarin (swertianin, SWE) regulates the polarization of tumor microenvironment-associated macrophages to M1 phenotype, thereby exerting anti-tumor effects.SWE promoted the formation of M1 cells and increased the proportion of CD86 + cells in both RAW264.7 and primary monocyte-derived macrophages, while activating the STING-NF-κB pathway. When STING or P65 was knocked out, the effects of SWE were antagonized, inhibiting the formation of CD86 + M1 cells. At the animal level, SWE inhibited tumor growth, activated STING-NF-κB, and promoted the formation of CD86 + cells. STING-KO inhibited the effects of SWE.SWE can activate the STING-NF-κB signal to promote macrophage M1 polarization, playing an anti-tumor role.

Abstract B040: B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) carries a low survival rate. Several factors contribute to its dismal prognosis, including resistance to available therapies and high invasiveness. Lymph nodes act as an early systemic source of circulating malignant cells, allowing their dissemination to other organs early in disease progression. Lymphatic colonization is linked to worse prognosis, and a better understanding of mechanisms regulating lymph node metastasis is clinically needed. To study each step in the metastatic cascade to the lymph nodes, we have developed a mouse co-clinical model of resectable pancreatic cancer. This model mimics the frequency of human PDAC metastatic recurrence, on a similar time scale relative to the lifespans of mice and humans and allows us to investigate very early events in the metastatic cascade. In contrast to the established anti-tumor role of T cells, the role of B cells in cancer immunology is more complex. B cells are a predominant immune population in lymph nodes, but their role in relation to lymph node colonization has never been fully addressed. Using our model of PDAC spontaneous metastasis and a mouse model of B cell depletion, we showed that lymph node metastasis does not form in the absence of B cells. We demonstrated that B cells, but not secreted antibodies, are required for successful lymph node colonization. We also gained evidence that B cells are orchestrating a complex interplay between disseminated cancer cells and other immune cells in the draining lymph node. Particularly, T cells seem to be involved in preventing cancer cell from growing into macro-metastasis only in the absence of B cells. We are now investigating the mechanisms employed by B cells to facilitate this cellular network to facilitate lymph node colonization in PDAC. The ultimate outcome of our work will be the design of effective immune strategies to prevent and treat lymph node dissemination of such a deadly disease. Citation Format: Alice Bertocchi, Megan T Hoffman, Li Qiang, Massiel Morell, Lauren L Hsu, Michael L Dougan, Judith Agudo, Stephanie K Dougan. B cells facilitate lymph node colonization in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B040.

Single-cell transcriptional atlas of tumor-associated macrophages in breast cancer

BackgroundThe internal heterogeneity of breast cancer, notably the tumor microenvironment (TME) consisting of malignant and non-malignant cells, has been extensively explored in recent years. The cells in this complex cellular ecosystem activate or suppress tumor immunity through phenotypic changes, secretion of metabolites and cell-cell communication networks. Macrophages, as the most abundant immune cells within the TME, are recruited by malignant cells and undergo phenotypic remodeling. Tumor-associated macrophages (TAMs) exhibit a variety of subtypes and functions, playing significant roles in impacting tumor immunity. However, their precise subtype delineation and specific function remain inadequately defined.MethodsThe publicly available single-cell transcriptomes of 49,141 cells from eight breast cancer patients with different molecular subtypes and stages were incorporated into our study. Unsupervised clustering and manual cell annotation were employed to accurately classify TAM subtypes. We then conducted functional analysis and constructed a developmental trajectory for TAM subtypes. Subsequently, the roles of TAM subtypes in cell-cell communication networks within the TME were explored using endothelial cells (ECs) and T cells as key nodes. Finally, analyses were repeated in another independent publish scRNA datasets to validate our findings for TAM characterization.ResultsTAMs are accurately classified into 7 subtypes, displaying anti-tumor or pro-tumor roles. For the first time, we identified a new TAM subtype capable of proliferation and expansion in breast cancer-TUBA1B+ TAMs playing a crucial role in TAMs diversity and tumor progression. The developmental trajectory illustrates how TAMs are remodeled within the TME and undergo phenotypic and functional changes, with TUBA1B+ TAMs at the initial point. Notably, the predominant TAM subtypes varied across different molecular subtypes and stages of breast cancer. Additionally, our research on cell-cell communication networks shows that TAMs exert effects by directly modulating intrinsic immunity, indirectly regulating adaptive immunity through T cells, as well as influencing tumor angiogenesis and lymphangiogenesis through ECs.ConclusionsOur study establishes a precise single-cell atlas of breast cancer TAMs, shedding light on their multifaceted roles in tumor biology and providing resources for targeting TAMs in breast cancer immunotherapy.

Reynoutria multiflora (Thunb.) Moldenke and its ingredient suppress lethal prostate cancer growth by inducing CDC25B-CDK1 mediated cell cycle arrest

BackgroundReynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb, PM) is a medicinal plant that was an element of traditional Chinese medicine (TCM) for centuries as a treatment for a wide range of conditions. Recent studies reported that PM suppressed prostate cancer growth in an AR-dependent manner. However, its role and mechanism in the treatment of advanced prostate cancer remain to be explored. This study aims to explore the anti-tumor role and potential mechanism of PM on prostate cancer. MethodsCell viability, colony formation, fluorescence-activated cell sorting (FACS), and wound-healing assays were conducted to evaluate the tumor suppression effect of PM on lethal prostate cancer models in vitro. A xenograft mice model was established to detect the impact of PM on tumor growth and evaluate its biosafety in vivo. Integrative network pharmacology, RNA-seq, and bioinformatics were applied to determine the mechanisms of PM in prostate cancer. Molecular docking, cellular thermal shift assay (CETSA), CRISPR-Cas13, RT-qPCR, and WB were collaboratively employed to identify the potential anti-tumor ingredient derived from PM and its corresponding targets. ResultsPM significantly suppressed the growth of prostate cancer and sensitized prostate cancer to AR antagonists. Mechanistically, PM induced G2/M-phase cell-cycle arrest by modulating the phosphorylation of CDK1. Additionally, polygalacic acid derived from PM and its structural analog suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDK1 phosphorylation. ConclusionPM and its ingredient polygalacic acid suppress lethal prostate cancer growth by regulating the CDC25B-CDK1 axis to induce cell cycle arrest.

The pro-tumoral and anti-tumoral roles of EphA4 on T regulatory cells and tumor associated macrophages during HNSCC tumor progression.

EphA4 in regulatory T cells has a pro-tumoral effect while EphA4 in macrophages plays an anti-tumoral role underscoring the necessity of developing biologically rational therapeutics.

Comprehensive analysis, diagnosis, prognosis, and cordycepin (CD) regulations for GSDME expressions in pan-cancers.

The Gasdermin E gene (GSDME) plays roles in deafness and cancers. However, the roles and mechanisms in cancers are complex, and the same gene exhibits different mechanisms and actions in different types of cancers. Online databases, such as GEPIA2, cBioPortal, and DNMIVD, were used to comprehensively analyze GSDME profiles, DNA methylations, mutations, diagnosis, and prognosis in patients with tumor tissues and matched healthy tissues. Western blotting and RT-PCR were used to monitor the regulation of GSDME by Cordycepin (CD) in cancer cell lines. We revealed that GSDME expression is significantly upregulated in eight cancers (ACC, DLBC, GBM, HNSC, LGG, PAAD, SKCM, and THYM) and significantly downregulated in seven cancers (COAD, KICH, LAML, OV, READ, UCES, and UCS). The overall survival was longer only in ACC, but shorter in four cancers, including COAD, KIRC, LIHC, and STAD, when GSDME was highly expressed in cancers compared with the corresponding normal tissues. Moreover, the high expression of GSDME was negatively correlated with the poor prognosis of ACC, while the low expression of GSDME was negatively correlated with the poor prognosis of COAD, suggesting that GSDME might serve as a good prognostic factor in these two cancer types. Accordingly, results indicated that the DNA methylations of those 7 CpG sites constitute a potentially effective signature to distinguish different tumors from adjacent healthy tissues. Gene mutations for GSDME were frequently observed in a variety of tumors, with UCES having the highest frequency. Moreover, CD treatment inhibited GSDME expression in different cancer cell lines, while overexpression of GSDME promoted cell migration and invasion. Thus, we have systematically and successfully clarified the GSDME expression profiles, diagnostic values, and prognostic values in pan-cancers. Targeting GSDME with CD implies therapeutic significance and a mechanism for antitumor roles in some types of cancers via increasing the sensitivity of chemotherapy. Altogether, our study may provide a strategy and biomarker for clinical diagnosis, prognostics, and treatment of cancers by targeting GSDME.

Nc-RNA-mediated low expression of AZIN1 correlated with unfavorable prognosis in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC, ccRCC) is the most common type of renal cancer with high recurrence and mortality. It has long been recognized that Antizyme inhibitor 1 (AZIN1) serves as a pro-oncogenic molecule in multiple cancers. However, the clinicopathological features of AZIN1 in KIRC remain unexplored. The Cancer Genome Atlas (TCGA, TIMER, and GEPIA) were employed for pan-cancer expression and survival analysis of AZIN1, indicating the unique anti-tumor role of AZIN1 in KIRC. The expression and clinical characteristics of AZIN1 in KIRC were further proven via Human Protein Atlas and TCGA. single-sample GSEA was employed to investigate the immune infiltration of AZIN1. Then the downstream pathways were illustrated via the LinkedOmics, Metascape, and Cytoscape databases. The possible upper regulating noncoding RNAs (ncRNAs) were analyzed from five programs-TargetScan, StarBase, miRanda, PITA, and miRmap. AZIN1 is downregulated in KIRC patients. Lower levels of AZIN1 were linked with unfavorable outcomes in KIRC patients. The AZIN1 expression was positively related to immune cell infiltration in KIRC. We also elucidated a possible upstream regulatory ncRNA of AZIN1 in KIRC namely STK4-AS1/AC068338.2-miR-106b-5p-AZIN1 axis as well as the downstream signaling pathways. This study illustrated the unique anti-tumor role of AZIN1 in KIRC and provided potential value for guiding immunotherapy and targeted therapy.

Advances in the anti-tumor mechanisms of saikosaponin D.

Saikosaponin D, a saponin compound, is extracted from Bupleurum and is a principal active component of the plant. It boasts a variety of pharmacologic effects including anti-inflammatory, antioxidant, immunomodulatory, metabolic, and anti-tumor properties, drawing significant attention in anti-tumor research in recent years. Research indicates that saikosaponin D inhibits the proliferation of numerous tumor cells, curbing the progression of cancers such as liver, pancreatic, lung, glioma, ovarian, thyroid, stomach, and breast cancer. Its anti-tumor mechanisms largely involve inhibiting tumor cell proliferation, promoting tumor cell apoptosis, thwarting tumor-cell invasion, and modulating tumor cell autophagy. Moreover, saikosaponin D enhances the sensitivity to anti-tumor drugs and augments body immunity. Given its multi-faceted anti-tumor roles, saikosaponin D offers promising potential in anti-tumor therapy. This paper reviews recent studies on its anti-tumor effects, aiming to furnish new theoretical insights for clinical cancer treatments.

The clinical significance and anti-tumor role of PRKG1 in bladder cancer.

cGMP-dependent protein kinase 1 (PRKG1) has shown to be associated with some tumorigenesis, while the role of PRKG1 in bladder cancer is unclear. To investigate the biological and clinical significance of PRKG1 in bladder cancer, we detected the expression of PRKG1 and explored the function of PRKG1 in bladder cancer cells. The PRKG1 transcripts data was downloaded from The Cancer Genome Atlas (TCGA) database, and immunohistochemistry staining was conducted on formalin-fixed paraffin-embedded (FFPE) sample tissues. Relationship between clinical characteristics of patients and expression of PRKG1 was analyzed in FFPE samples, TCGA database, and GSE19423 dataset. PRKG1 was over-expressed, and cell proliferation, migration, invasion, apoptosis, and spheroidizing ability were then detected. Chemosensitivity to cisplatin was detected with cell viability, and half-maximal drug inhibitory concentration (IC50) was calculated. In addition, the relation between PRKG1 expression and the infiltration level of tumor immune cells in tumor microenvironment were analyzed. The results showed expression of PRKG1 was lower in bladder cancer, compared with normal tissues both at protein and transcript levels. Lower PRKG1 expression was related to higher tumor grade, T stage, and muscle invasion, also predicted worse overall survival and recurrence free survival in patients treated with Bacillus Calmette-Guerin (BCG) intravesical immunotherapy. Analysis of tumor immune cells infiltration showed lower PRKG1 was associated with non-inflamed tumor microenvironment. The present study firstly identified the anti-tumor role and tumor immune regulatory role of PRKG1, also found loss of PRKG1 could be used as a prognosis factor. The present study provided a potential biomarker and therapy target to bladder cancer.

USP53 Affects the Proliferation and Apoptosis of Breast Cancer Cells by Regulating the Ubiquitination Level of ZMYND11

Breast cancer is the most common female malignancy worldwide. Ubiquitin-specific peptidase 53 (USP53) has been shown to exert cancer-suppressing functions in several solid tumors, but its role and the underlying mechanism in breast cancer has not been clearly elucidated. Therefore, we have carried out a series of detailed studies on this matter at the levels of bioinformatics, clinical tissue, cell function and animal model. We found that USP53 expression was downregulated in breast cancer specimens and was negatively correlated with the clinical stages. Gain- and loss-of-function experiments demonstrated USP53 inhibited proliferation, clonogenesis, cell cycle and xenograft growth, as well as induced apoptosis and mitochondrial damage of breast cancer cells. Co-immunoprecipitation data suggested that USP53 interacted with zinc finger MYND-type containing 11 (ZMYND11), and catalyzed its deubiquitination and stabilization. The 33–50 amino acid Cys-box domain was key for USP53 enzyme activity, but not essential for its binding with ZMYND11. The rescue experiments revealed that the anti-tumor role of USP53 in breast cancer cells was at least partially mediated by ZMYND11. Both USP53 and ZMYND11 were prognostic protective factors for breast cancer. USP53-ZMYND11 axis may be a good potential biomarker or therapeutic target for breast cancer, which can provide novel insights into the diagnosis, treatment and prognosis.

The Role and Therapeutic Potential of Pyroptosis in Colorectal Cancer: A Review.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms and developing effective therapeutic strategies have become key in CRC treatment. Pyroptosis is an emerging type of regulated cell death (RCD) that has a significant role in cells proliferation and growth. For the last few years, numerous studies have indicated a close correlation between pyroptosis and the occurrence, progression, and treatment of many malignancies, including CRC. The development of effective therapeutic strategies to inhibit tumor growth and proliferation has become a key area in CRC treatment. Thus, this review mainly summarized the different pyroptosis pathways and mechanisms, the anti-tumor (tumor suppressor) and protective roles of pyroptosis in CRC, and the clinical and prognostic value of pyroptosis in CRC, which may contribute to exploring new therapeutic strategies for CRC.