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Journal of Cancer 2024Bone cancer among adolescents and children exhibits varying survival outcomes based on disease state. While localized bone cancer cases have a survival rate exceeding... (Review)
Review
Bone cancer among adolescents and children exhibits varying survival outcomes based on disease state. While localized bone cancer cases have a survival rate exceeding 70%, metastatic, refractory, and recurrent forms are associated with significantly poorer prognoses. Initially believed to be mere vehicles for cellular waste disposal, exosomes are now recognized as extracellular vesicles facilitating intercellular communication. These vesicles influence cellular behaviors by transporting various biomolecules, such as proteins, DNA, RNA, and lipids, among cells. The role of exosomes in regulating the progression of bone cancer is increasingly evident, impacting critical processes like tumorigenesis, proliferation, metastasis, angiogenesis, immune evasion, and drug resistance. Current research underscores the substantial potential of exosomes in promoting the progression and development of bone cancer. This review delves into the complex process of exosome biogenesis, the variety of cell-derived exosome sources, and their applications in drug delivery and therapeutics. It also examines ongoing clinical trials focused on exosome cargo levels and discusses the challenges and future directions in exosome research. Unlike costly and invasive traditional diagnostic methods, exosomal biomarkers offer a non-invasive, cost-effective, and readily accessible routine screening through simple fluid collection that aims to inspire researchers to investigate the potential of exosomes for cancer theragnostic. Through comprehensive exploration of these areas, the review seeks to enhance understanding and foster innovative solutions to cancer biology in the near future.
PubMed: 38947401
DOI: 10.7150/jca.95709 -
Journal of Cancer 2024An increasing number of studies have demonstrated that differentially expressed circular RNAs (circRNAs) play critical roles in carcinogenesis. However, the biological...
An increasing number of studies have demonstrated that differentially expressed circular RNAs (circRNAs) play critical roles in carcinogenesis. However, the biological function and clinical significance of hsa_circ_0005927 during gastric carcinogenesis remain unclear. The aim of this study was to investigate the acting mechanism and clinical significance of hsa_circ_0005927 in the invasion and metastasis of gastric cancer (GC). Hsa_circ_0005927 was detected in GC tissues, plasma and gastric juice from patients with GC, and its correlations with clinicopathological parameters were investigated. Receiver operating characteristic curves, Kaplan-Meier survival curves and a prognostic nomogram model were generated to analyze the diagnostic and prognostic value. Real-time cell analyzer, plate colony formation, and Transwell migration and invasion assays were utilized to assess GC cell proliferation, migration and invasion, respectively. Nucleoplasmic separation was applied to determine the distribution of hsa_circ_0005927 in cells. TargetScan and miRanda software were used for target microRNA (miRNA) prediction. Transcriptome sequencing and bioinformatics analysis were performed to annotate the functions of hsa_circ_0005927 in gastric carcinogenesis and metastasis from an RNomic perspective. Key target genes and immune cell infiltrations were analysed. Hsa_circ_0005927 was found downregulated in high-grade intraepithelial neoplasia (HGIEN) tissues and GC tissues. Hsa_circ_0005927 levels in GC tissues were negatively correlated not only with lymphatic metastasis and distal metastasis but also with overall survival and disease-free survival. As a screening biomarker for GC, plasma hsa_circ_0005927 levels significantly increased in the early stages of GC, with a sensitivity and specificity of 52.38% and 76.19%, respectively. Hsa_circ_0005927 was mainly distributed in the cytoplasm, and structurally, it possesses multiple miRNA response elements (MREs) that interact with five miRNAs. A total of 421 downstream target genes of hsa_circ_0005927 were identified by transcriptome sequencing; and bioinformatics analysis suggested that these genes were involved mainly in the negative regulation of the T-cell apoptotic process, the interleukin-27-mediated signaling pathway, growth factor activity, guanylate cyclase activity, transcriptional misregulation in cancer, the cGMP-PKG signaling pathway, and the GnRH signaling pathway during gastric carcinogenesis and metastasis. GUCY1A2 and STK32A are key target genes significantly associated with immune infiltration. Our study revealed that hsa_circ_0005927 is a new player related to the invasion and metastasis of GC and is a potential indicator for early GC screening.
PubMed: 38947400
DOI: 10.7150/jca.96749 -
Journal of Cancer 2024Tamoxifen is commonly used in the treatment of hormonal-positive breast cancer. However, 30%-40% of tumors treated with tamoxifen develop resistance; therefore, an...
Tamoxifen is commonly used in the treatment of hormonal-positive breast cancer. However, 30%-40% of tumors treated with tamoxifen develop resistance; therefore, an important step to overcome this resistance is to understand the underlying molecular and metabolic mechanisms. In the present work, we used metabolic profiling to determine potential biomarkers of tamoxifen resistance, and gene expression levels of enzymes important to these metabolites and then correlated the expression to the survival of patients receiving tamoxifen. Tamoxifen-resistant cell lines previously developed and characterized in our laboratory were metabolically profiled with nuclear magnetic resonance spectroscopy (NMR) using cryogenic probe, and the findings were correlated with the expression of genes that encode the key enzymes of the significant metabolites. Moreover, the effect of significantly altered genes on the overall survival of patients was assessed using the Kaplan-Meier plotter web tool. We observed a significant increase in the levels of glutamine, taurine, glutathione, and xanthine, and a significant decrease in the branched-chain amino acids, valine, and isoleucine, as well as glutamate and cysteine in the tamoxifen-resistant cells compared to tamoxifen sensitive cells. Moreover, xanthine dehydrogenase and glutathione synthase gene expression were downregulated, whereas glucose-6-phosphate dehydrogenase was upregulated compared to control. Additionally, increased expression of xanthine dehydrogenase was associated with a better outcome for breast cancer patients. Overall, this study sheds light on metabolic pathways that are dysregulated in tamoxifen-resistant cell lines and the potential role of each of these pathways in the development of resistance.
PubMed: 38947399
DOI: 10.7150/jca.96659 -
Journal of Cancer 2024TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have...
TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have investigated the involvement of TMEM132A in specific cancers, further systematic studies are required to elucidate its specific mechanisms of action in different cancer types. We investigated the pan-cancer role of TMEM132A using several databases. We analyzed TMEM132A expression and its correlation with clinical survival, immune checkpoints, tumor stemness score, prognostic value, immunomodulators, genomic profiles, immunological characteristics, immunotherapy and functional enrichment. First, it was observed that TMEM132A expression levels were higher in the majority of tumors compared to non-tumor tissues. In addition, high TMEM132A expression may have a higher prognostic value in some cancers. Furthermore, TMEM132A was significantly associated with immune checkpoints, immunomodulators, prognosis, immunomodulatory genes, tumor stemness score, cell function status and immune infiltration in most tumors. Further analysis of TMEM132A-related gene enrichment, mutation sites and types, RNA modification and genomic heterogeneity showed that the major mutations of TMEM132A were missense mutations and that TMEM132A plays a very important role in UCEC, LUAD and LIHC. Finally, these results suggest that high TMEM132A expression may be associated with a better response to specific immunotherapies. : This comprehensive study uncovers an important function for TMEM132A in different types of cancer. It also has the potential to identify TMEM132A as a potential biomarker for predicting treatment response. This may help us to better understand how TMEM132A plays a role in cancer and provide valuable insights for developing personalised treatments.
PubMed: 38947398
DOI: 10.7150/jca.96396 -
Journal of Cancer 2024Metabolic reprogramming plays a crucial role in the development of colorectal cancer (CRC), influencing tumor heterogeneity, the tumor microenvironment, and metastasis....
Metabolic reprogramming plays a crucial role in the development of colorectal cancer (CRC), influencing tumor heterogeneity, the tumor microenvironment, and metastasis. While the interaction between metabolism and CRC is critical for developing personalized treatments, gaps remain in understanding how tumor cell metabolism affects prognosis. Our study introduces novel insights by integrating single-cell and bulk transcriptome analyses to explore the metabolic landscape within CRC cells and its mechanisms influencing disease progression. This approach allows us to uncover metabolic heterogeneity and identify specific metabolic genes impacting metastasis, which have not been thoroughly examined in previous studies. We sourced microarray and single-cell RNA sequencing datasets from the Gene Expression Omnibus (GEO) and bulk sequencing data for CRC from The Cancer Genome Atlas (TCGA). We employed Gene Set Variation Analysis (GSVA) to assess metabolic pathway activity, consensus clustering to identify CRC-specific transcriptome subtypes in bulkseq, and rigorous quality controls, including the exclusion of cells with high mitochondrial gene expression in scRNA seq. Advanced analyses such as AUCcell, infercnvCNV, Non-negative Matrix Factorization (NMF), and CytoTRACE were utilized to dissect the cellular landscape and evaluate pathway activities and tumor cell stemness. The hdWGCNA algorithm helped identify prognosis-related hub genes, integrating these findings using a random forest machine learning model. Kaplan-Meier survival curves identified 21 significant metabolic pathways linked to prognosis, with consensus clustering defining three CRC subtypes (C3, C2, C1) based on metabolic activity, which correlated with distinct clinical outcomes. The metabolic activity of the 13 cell subpopulations, particularly the epithelial cell subpopulation with active metabolic levels, was evaluated using AUCcell in scRNA seq. To further analyze tumor cells using infercnv, NMF disaggregated these cells into 10 cellular subpopulations. Among these, the C2 subpopulation exhibited higher stemness and tended to have a poorer prognosis compared to C6 and C0. Conversely, the C8, C3, and C1 subpopulations demonstrated a higher level of the five metabolic pathways, and the C3 and C8 subpopulations tended to have a more favorable prognosis. hdWGCNA identified 20 modules, from which we selected modules primarily expressed in high metabolic tumor subgroups and highly correlated with clinical information, including blue and cyan. By applying variable downscaling of RF to a total of 50 hub genes, seven gene signatures were obtained. Furthermore, molecules that were validated to be protective in GEO were screened alongside related molecules, resulting in the identification of prognostically relevant molecules such as UQCRFS1 and GRSF1. Additionally, the expression of GRSF1 was examined in colon cancer cell lines using qPCR and phenotypically verified by experiments. Our findings emphasize that high activity in specific metabolic pathways, including pyruvate metabolism and the tricarboxylic acid cycle, correlates with improved colon cancer outcomes, presenting new avenues for metabolic-based therapies. The identification of hub genes like GRSF1 and UQCRFS1 and their link to favorable metabolic profiles offers novel insights into tumor neovascularization and metastasis, with significant clinical implications for targeting metabolic pathways in CRC therapy.
PubMed: 38947396
DOI: 10.7150/jca.94630 -
Journal of Cancer 2024Acute myeloid leukemia (AML) is the leukemia with the worst prognosis, and current knowledge of AML pathogenesis and available therapies for AML remain limited. 40% of...
Acute myeloid leukemia (AML) is the leukemia with the worst prognosis, and current knowledge of AML pathogenesis and available therapies for AML remain limited. 40% of AML patients exhibit elevated nuclear factor kappa B (NF-κB) activity, which provides a compelling rationale for targeting the NF-κB pathway in AML. Guanine nucleotide-binding protein-like 3-like protein (GNL3L) is a recently identified pro-oncogene that promotes NF-κB activation in a variety of malignancies. For the first time, we comprehensively examined GNL3L expression in AML, reporting GNL3L as a poor prognostic factor in three independent AML cohorts. GNL3L enhanced RELA activity, activated NF-κB, promoted AML cell proliferation, resisted apoptosis, and encouraged cytarabine resistance in AML. In conclusion, these data suggest a role for GNL3L in the malignant process of AML and as a promising therapeutic target.
PubMed: 38947394
DOI: 10.7150/jca.95339 -
Journal of Cancer 2024Kidney clear cell carcinoma (KIRC) commonly presents with metastases upon diagnosis, highlighting the critical need to identify more precise biomarkers for early...
Kidney clear cell carcinoma (KIRC) commonly presents with metastases upon diagnosis, highlighting the critical need to identify more precise biomarkers for early detection, intervention, and personalized treatment. Although The REEP family has been investigated in cancer development, the specific relationship between REEP4 and cancer remains unclear. In our study, we employed bioinformatics analysis and conducted fundamental experiments to evaluate the potential of REEP4 as a biomarker for predicting the prognosis and therapeutic efficacy of KIRC. Comparing KIRC tumor tissues to normal tissues, we observed a significant upregulation in REEP4 expression, with higher levels of REEP4 correlating positively with tumor malignancy. Further COX regression analysis, as well as single and multifactorial analyses, confirmed that high REEP4 expression indicated lower survival rates in KIRC. Gene function analysis also identified associations between REEP4 and critical pathways such as the cell cycle, along with its involvement in protein binding. Furthermore, our investigation of the immune response suggests that a favorable immunotherapeutic response is linked to a reduction in REEP4 expression. Subsequently, we conducted in experiments to confirm the overexpression of REEP4 in KIRC tumor tissues and renal cancer cells. In summary, our study revealed a close association between REEP4 expression and KIRC, emphasizing its correlation with prognosis and the immune response. These findings suggest that REEP4 is a potential biomarker for KIRC.
PubMed: 38947393
DOI: 10.7150/jca.96135 -
Journal of Cancer 2024Breast cancer (BC) is the most common tumor in women worldwide. TRIM28 (RNF96) plays pleiotropic biological functions, such as silencing target genes, facilitating DNA...
Breast cancer (BC) is the most common tumor in women worldwide. TRIM28 (RNF96) plays pleiotropic biological functions, such as silencing target genes, facilitating DNA repair, stimulating cellular proliferation and differentiation, and contributing to cancer progression. TRIM28 plays an increasingly crucial role in cancer, but its impact on BC, including breast invasive carcinoma, remains poorly understood. In the current study, analyses of online databases, quantitative real-time quantitative PCR, immunohistochemistry, and western blotting were performed on patients with breast invasive carcinoma (BRCA). Cordycepin (CD) was used to monitor BC progression and TRIM28 expression . As a result, we observed that TRIM28 is highly expressed in breast invasive carcinoma tissues compared with the corresponding normal tissues and is correlated with metastatic / invasive progression. High expression of TRIM28 might serve as a prognostic marker for long-term survival in triple-negative BC, advanced BC, or breast invasive carcinoma. Although TRIM28 methylation in tumor tissues of breast invasive carcinoma is not significantly changed compared to the matched normal tissues, the expressions and methylation of TRIM28 are significantly reversely correlated. TRIM28 expression was inhibited by CD in the mouse model, indicating its role in preventing BC progression. Thus, TRIM28 might be a potentially valuable molecular target for forecasting the progression / prognosis of patients with breast invasive carcinoma. CD, which represses BC growth/metastasis, may be involved partially through suppressing TRIM28 expression.
PubMed: 38947392
DOI: 10.7150/jca.95876 -
Journal of Cancer 2024Gastric cancer (GC) is one of the most common malignancies worldwide, with high incidence and mortality rate. Tripartite motif-containing 28 (TRIM28) is an important...
Gastric cancer (GC) is one of the most common malignancies worldwide, with high incidence and mortality rate. Tripartite motif-containing 28 (TRIM28) is an important molecule that affects the occurrence and development of tumors, but its function in GC has not been elucidated clearly. The purpose of this study is to explore the molecular mechanism by which TRIM28 affect the GC. TRIM28 expression was tested in RNA-seq data from TCGA database, tumor tissue samples from patients and GC cell lines. Genes were silenced or overexpressed by siRNA, lentivirus-mediated shRNA, or plasmids. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to explore the proliferation of GC cells after TRIM28 knockdown. RNA-seq and TCGA database were used to identify target genes. Luciferase report assay was employed to detect the possible mechanism between TRIM28 and Indoleamine 2,3-dioxygenase (IDO1). Tryptophan concentration in cell supernatant was measured using a fluorometric assay kit. MGC-803 and 746T cells were injected into mice to establish xenograft animal models. The expression of TRIM28 was positively correlated with tumor size and poorer prognosis. Upregulation of TRIM28 was observed in GC tissues and cells. , we proved that knockdown of TRIM28 significantly inhibited the proliferation of GC cells. Then TRIM28 was found to be positively correlated with the expression of IDO1 in GC cells. In accordance with this, tryptophan levels in cell supernatants were increased in TRIM28 knockdown GC cells and overexpression of IDO1 could reverse this phenotype. Serum response factor (SRF), a reported regulator of IDO1, was also regulated by TRIM28 in GC cells. And decreased expression of IDO1 induced by TRIM28 knockdown could be partly reversed through overexpression of serum response factor (SRF) in GC cells. Functional research demonstrated that the expression of IDO1 was increased in GC and IDO1 knockdown could also inhibited the proliferation of GC cells. Furthermore, overexpression of IDO1 could partly reverse proliferation inhibited by TRIM28 knockdown in GC cells. , knockdown of TRIM28 significantly inhibited the tumor growth and overexpression of IDO1 and SRF both could reverse proliferation inhibited by TRIM28 knockdown. TRIM28 is crucial in the development of GC, and may regulate IDO1 through SRF. TRIM28 promote GC cell proliferation through SRF/IDO1 axis.
PubMed: 38947391
DOI: 10.7150/jca.95094 -
Journal of Cancer 2024Elderly patients with locally advanced esophageal adenocarcinoma (EAC) have a poor prognosis. The purpose of this study was to identify prognostic factors and construct...
Elderly patients with locally advanced esophageal adenocarcinoma (EAC) have a poor prognosis. The purpose of this study was to identify prognostic factors and construct a risk stratification for assessing the prognosis of elderly (≥ 70 years old) EAC patients who receiving neoadjuvant chemoradiotherapy (NCRT) and esophagectomy. A total of 688 patients with non-metastatic locally advanced EAC who underwent NCRT and esophagectomy were selected from the Surveillance Epidemiology and End Results (SEER) database. Multivariable Cox analysis was used to identify prognostic factors of overall survival (OS). Restricted Cubic Splines (RCS) was used to examine the linear relationship between the number of lymph node dissection (LND) and OS. RCS showed a linear relationship between LND and OS (P = 0.690). As the number of LND increased, the risk of death decreased. Multivariable analysis demonstrated that LND > 23, grade III/IV, and regional node positive were independent prognostic factors. Subgroup analysis indicated that enlarged lymph node dissection (LND > 23) did not improve OS in patients with grade I/II or T1-2 stage, whereas enlarged lymph node dissection significantly improved OS in patients with grade III/IV or T3-4 stage. Furthermore, we constructed a novel risk score based on LND, grade, and regional node status, which stratified patients into low-, medium-, and high-risk groups. Patients in the high-risk group (risk score = 3) had a worse prognosis. Enlarged lymph node dissection (LND > 23) improved OS in patients with grade III/IV or T3-4 stage. Moreover, a novel risk score was constructed, which facilitated risk stratification and postoperative surveillance in elderly EAC patients.
PubMed: 38947388
DOI: 10.7150/jca.96574