Abstract Background High-intensity chemotherapy regimens are often used in adult T-cell lymphoblastic lymphoma (T-LBL) patients. Nevertheless, the response rate remains unsatisfactory due to emergence of chemoresistance. Growing evidence has shown that long non-coding RNAs (lncRNAs) are involved in tumor progression and chemoresistance. Herein, we investigated the potential role of lncRNAs in T-LBLs. Methods RNAseq was used to screen and identify candidate lncRNAs associated with T-LBL progression and chemoresistance. Luciferase reporter assay was used to examine the binding of miR-371b-5p to the 3’UTR of Smad2 and LEF1 , and the binding of TCF-4/LEF1 to the promoter of LINC00183. Chromatin immunoprecipitation assay was undertaken to analyze the connection between LEF1 and the LINC00183 promoter region. RNA immunoprecipitation assays were used to explore the mechanism whereby LINC00183 regulated miR-371b-5p. MTT and flow cytometry assays were used to measure apoptosis of T-LBL cells. Results LINC00183 was upregulated in T-LBL progression and chemoresistant tissues in both the Sun Yat-sen University Cancer Center dataset and the First Affiliated Hospital of Anhui Medical University dataset. High expression of LINC00183 was correlated with poorer overall survival and progression-free survival of T-LBL patients compared to those with low expression of LINC00183. Furthermore, miR-371b-5p was negatively regulated by LINC00183. In vivo and in vitro assays showed that LINC00183-mediated T-LBL chemoresistance depended on miR-371b-5p expression. The direct binding of miR-371b-5p to Smad2 and LEF1 was verified by luciferase assays. It was shown that TCF4/LEF1 could bind to the LINC00183 promoter site and increase its transcript level. Downregulation of miR-371b-5p led to increased expression of Smad2/LEF1, and in turn increased LINC00183 expression. Additionally, phospho-Smad2 promotes nuclear translocation of β-catenin, LINC00183 downregulation decreased chemoresistance induced by β-catenin and TGF-β1 in T-LBL cells. Conclusion We unraveled a β-catenin-LINC00183-miR-371b-5p-Smad2/LEF1 feedback loop that promotes T-LBL progression and chemoresistance, indicating that LINC00183 may serve as a potential therapeutic target in T-LBLs. 

The β-catenin-LINC00183-miR-371b-5p-Smad2/LEF1 axis promotes adult T-cell lymphoblastic lymphoma progression and chemoresistance

The aberrant expression of adipocyte enhancer binding protein 1 (AEBP1) has been observed in many cancers and it seems to be involved in the tumorigenesis, progression, and metastasis in numerous tumor types. However, the contribution of AEBP1 in breast cancer (BCa) remains inexplicable.Information related to the diagnostic significance and expression of AEBP1 in BCa was obtained from the public dataset Kaplan-Meier Plotter (http://kmplot.com/analysis/) and the dataset UALCAN (https://ualcan.path.uab.edu/index.html). The MTT (methyl thiazolyl tetrazolium) assay, colony formation assay, Transwell® assay, and FACS (fluorescence-activated cell sorting) assay were used to detect the proliferation, invasive and apoptotic ability of cells before and after treatment. In addition, we constructed an AEBP1 overexpression vector and silenced AEBP1, combined with Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), western blot, immunohistochemistry and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) assay to investigate the prognostic significance, biological functions and potential mechanisms of AEBP1 in BCa.Higher expression of AEBP1 mRNA (message RNA) was observed in BCa patients with later-stage, who obtained poorer overall survival. Meanwhile, compared with adjacent noncancerous tissues, AEBP1 protein expression was dramatically upregulated in the BCa ones. Furthermore, overexpressed AEBP1 enhanced cell proliferation, migration, invasion, and blocked cell apoptosis in BCa cells. Moreover, the research certificated that AEBP1 upregulated the expression of MMP (matrix metalloproteinase)-2, 9, vimentin, N-cadherin (neural-cadherin), phosphorylation of ERK (extracellular signal-regulated kinase), Smad2/3 (Abbreviated from Sma for nematode and Mad for Drosophila) and AKT (V-akt murine thymoma viral oncogene homolog), while down-regulated the expression of E-cadherin (epithelial cadherin) and PTEN (phosphatase and tensin homolog deleted on chromosome 10). To inhibit cell apoptosis, enforced expression of AEBP1 effectively blocked the cleavage of caspase 9 and p53 (protein 53) and promoted the expression of anti-apoptotic protein Bcl-2 (B-cell lymphoma-2). Finally, AEBP1 accelerated subcutaneously transplanted tumor growth in nude mice by increasing the expression of the cell proliferation biomarker ki67, the phosphorylation of AKT, and blocked apoptosis in vivo.In summary, these data suggested the important role of AEBP1 in the BCa progression, which could be used as a potential biomarker for prognostic hallmark and a novel therapeutic strategy. 

https://www.discovmed.com/EN/PDF/10.24976/Discov.Med.202335174.6

AEBP1 Contributes to Breast Cancer Progression by Facilitating Cell Proliferation, Migration, Invasion, and Blocking Apoptosis

Triple-negative breast cancer (TNBC) is considered about 12-24 % of all breast cancer cases. Patients experience poor overall survival, high recurrence rate, and distant metastasis compared to other breast cancer subtypes. Numerous studies have highlighted the crucial roles of non-coding RNAs (ncRNAs) in carcinogenesis and proliferation, migration, and metastasis of tumor cells in TNBC. Recent research has demonstrated that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play a role in the regulation of the immune system by affecting the tumor microenvironment, the epithelial-mesenchymal transition, the regulation of dendritic cells and myeloid-derived stem cells, and T and B cell activation and differentiation. Immune-related miRNAs and lncRNAs, which have been established as predictive markers for various cancers, are strongly linked to immune cell infiltration and could be a viable therapeutic target for TNBC. In the current review, we discuss the recent updates of ncRNAs, including miRNAs and lncRNAs in TNBC, including their biogenesis, target genes, and biological function of their targets, which are mostly involved in the immune response. 

Non-coding RNAs, another side of immune regulation during triple-negative breast cancer.

Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.

https://www.mdpi.com/2073-4409/11/19/2973/pdf?version=1664176724

Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs

MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression, and their deregulation contributes to many aspects of cancer development and progression. Thus, miRNAs provide insight into oncogenic mechanisms and represent promising targets for new therapeutic approaches. A type of cancer that is still in urgent need of improved treatment options is triple negative breast cancer (TNBC). Therefore, we aimed to characterize a novel miRNA with a potential role in TNBC. Based on a previous study, we selected miR-4646-5p, a miRNA with a still unknown function in breast cancer. We discovered that higher expression of miR-4646-5p in TNBC patients is associated with better survival. In vitro assays showed that miR-4646-5p overexpression reduces growth, proliferation, and migration of TNBC cell lines, whereas inhibition had the opposite effect. Furthermore, we found that miR-4646-5p inhibits the tube formation ability of endothelial cells, which may indicate anti-angiogenic properties. By whole transcriptome analysis, we not only observed that miR-4646-5p downregulates many oncogenic factors, like tumor-promoting cytokines and migration- and invasion-related genes, but were also able to identify a direct target, the GRAM domain-containing protein 1B (GRAMD1B). GRAMD1B is involved in cellular cholesterol transport and its knockdown phenocopied the growth-reducing effects of miR-4646-5p. We thus conclude that GRAMD1B may partly contribute to the diverse tumor-suppressive effects of miR-4646-5p in TNBC.

MiR-4646-5p Acts as a Tumor-Suppressive Factor in Triple Negative Breast Cancer and Targets the Cholesterol Transport Protein GRAMD1B.

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer; however, specific prognostic biomarkers have not yet been developed. In this study, we identified dysregulated microRNAs (miRNAs) in TNBC by profiling miRNA and mRNA expression. In patients with TNBC, miR-371b-5p expression was reduced, and miR-371b-5p overexpression significantly mitigated TNBC cell growth, migration, and invasion. In addition, we found that expression of cold shock domain-containing protein E1 (CSDE1), a direct target gene of miR-371b-5p, was upregulated in TNBC cells, and inhibition of CSDE1 expression alleviated TNBC cell growth by regulating RAC1 transcription. Mechanistically, CSDE1, phosphorylated C-terminal domain (p-CTD) of RNA polymerase II (RNAPII), and CDK7 form a complex, and downregulation of CSDE1 leads to weak interaction between RNAPII p-CTD and CDK7, resulting in a decrease in RNAPII p-CTD expression to reduce RAC1 transcript levels in CSDE1-deficient TNBC cells. Our data demonstrate that miR-371b-5p is a tumor-suppressive miRNA that regulates the CSDE1/Rac1 axis and could be a potential prognostic biomarker for TNBC. 

/pdf/reduced-mir-371b-5p-expression-drives-tumor-progression-via-8d98t1y2.pdf

Reduced miR-371b-5p expression drives tumor progression via CSDE1/RAC1 regulation in triple-negative breast cancer

: Dysregulated DNA methylation in cancer is critical in the transcription machinery associated with cancer progression. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, but no treatment targeting TNBC biomarkers has yet been developed. To identify specific DNA methylation patterns in TNBC, methyl-binding domain protein 2 (MBD) sequencing data were compared in TNBC and the three other major breast cancer subtypes. Integrated analysis of DNA methylation and gene expression identified a gene set showing a correlation between DNA methylation and gene expression. ATPase Na+/K+-transporting subunit alpha 1 (ATP1A1) was found to be specifically hypomethylated in the coding sequence (CDS) region and to show increased expression in TNBC. The Cancer Genome Atlas (TCGA) database also showed that hypomethylation and high expression of ATP1A1 were strongly associated with poor survival in patients with TNBC. Furthermore, ATP1A1 knockdown significantly reduced the viability and tumor-sphere formation of TNBC cells. These results suggest that the hypomethylation and overexpression of ATP1A1 could be a prognostic marker in TNBC and that the manipulation of ATP1A1 expression could be a therapeutic target in this disease.

Hypomethylation of ATP1A1 Is Associated with Poor Prognosis and Cancer Progression in Triple-Negative Breast Cancer


 Triple negative breast cancer (TNBC) is the most aggressive type of all breast cancer subtypes. Although various studies have been performed to identify prognostic and therapeutic targets for TNBC, the TNBC specific biomarkers have not yet been elucidated. Herein, we identified dysregulated miRNAs in TNBC via analysis of miRNA microarray in breast cancer tissues and found the oncogenic RNA (miR-374a-5p) and tumor suppressive miRNAs (miR-320c, miR-371b-5p). These miRNAs were closely related to overall survival of TNBC patients and status and involved in TNBC progression or drug responsiveness. Collectively, these results suggest that dysregulated miRNAs might serve as potential prognostic marker or therapeutic target for TNBC.
 Citation Format: Minyoung Lee, Yesol Kim, Dasom Son, Sera Lim, Jong Hoon Park. Identification of dysregulated miRNAs involved in TNBC progression [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 5681.

Abstract 5681: Identification of dysregulated miRNAs involved in TNBC progression

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Reduced miR-371b-5p expression drives tumor progression via CSDE1/RAC1 regulation in triple-negative breast cancer

Hypomethylation of ATP1A1 Is Associated with Poor Prognosis and Cancer Progression in Triple-Negative Breast Cancer

Abstract 5681: Identification of dysregulated miRNAs involved in TNBC progression