Long non‑coding RNAs XIST and MALAT1 hijack the PD‑L1 regulatory signaling pathway in breast cancer subtypes (original) (raw)
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Oncology Letters, 2019
The qualification of patients with non-small cell lung cancer (NSCLC) for anti-programmed cell death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) antibody therapy is based on an immunohistochemistry (IHC) assessment of PD-L1 expression. Immunological checkpoint inhibitors improve the overall survival of patients with expression of PD-L1; however certain PD-L1-negative patients may also benefit from immunotherapy. This indicates the requirement for novel predictive factors for the qualification of immunotherapy. It is also necessary to understand the mechanisms that effect the expression of PD-L1 in tumor cells. The expression of PD-L1 in 47 formalin-fixed, paraffin-embedded, NSCLC specimens was assessed using IHC and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of 8 microRNAs (miRNAs, miRs) complementary to PD-L1-mRNA was also evaluated using RT-qPCR. A positive correlation was revealed between the expression level of PD-L1-mRNA and 2 miRs, miR-141 (R= 0.533; P= 0.0029) and miR-1184 (R= 0.463; P= 0.049). There was also a positive correlation between the percentage of PD-L1-positive tumor cells and the expression levels of miR-141 (R= 0.441; P= 0.0024), miR-200b (R= 0.372; P= 0.011) and miR-429 (R= 0.430; P= 0.0028), and between the percentage of the tumor area with immune cell infiltration and the expression levels of miR-141 (R= 0.333; P= 0.03) and miR-200b (R= 0.312; P= 0.046). Additionally, the percentage of tumor cells expressing PD-L1 positively correlated with miR-141 expression (R= 0.407; P= 0.0055). Correlations between the expression of the investigated miRs (particularly miR-141) and PD-L1 indicated that miRs may regulate PD-L1 expression at a post-transcriptional level.
Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma
Cancer cell international, 2017
MiRNAs are vital in functioning as either oncogenes or tumor suppressors in the cell cycle. Target transcripts for immune checkpoint molecules such as PD-1/PD-L1 and (programmed cell death-1/its ligand and cytotoxic T-lymphocyte antigen 4) have proven to be beneficial against several solid tumors, including lung adenocarcinoma. Simultaneous quantification of the expression level of miR-33a and -, - and mRNAs with NanoString technology was performed in 88 lung adenocarcinoma specimens. A cohort of 323 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database was further analyzed, in order to test our hypothesis. Potential interference of -- and gene expression by miR-33a was predicted using the microRNA target prediction program High miR-33a expression was significantly associated with younger (p = 0.005), female (p = 0.04), patients with low grade (p < 0.0001), early stage (p = 0.03) tumors, and better survival. The hypothesis of the involvement of miR-33a in PD-1...
miRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy
Cancers
Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recently, the key roles of miRNA and lncRNAs as regulators of the immune-response in cancer have progressively emerged, since they may act (i) by shaping the intrinsic tumor cell and microenvironment (TME) properties; (ii) by regulating angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and drug resistance; and (iii) by acting as potential biomarkers for prognostic assessmen...
PD-L1, a key inhibitory immune receptor, has crucial functions in cancer immune evasion, but whether PD-L1 promotes the malignant properties of cervical cancer (CC) cells and the mechanism by which PD-L1 is regulated in CC remains unclear. We report that PD-L1 is overexpressed in CC, and shRNA-mediated PD-L1 depletion suppresses the proliferation, invasion, and tumorigenesis of CC cells. Loss of miR-140/142/340/383 contributes to PD-L1 upregulation. miR-18a enhances PD-L1 levels by targeting PTEN, WNK2 (ERK1/2 pathway inhibitor), and SOX6 (Wnt/β-catenin pathway inhibitor and p53 pathway activator) to activate the PI3K/AKT, MEK/ERK, and Wnt/β-catenin pathways and inhibit the p53 pathway, and miR-18a also directly suppresses the expression of the tumor suppressors BTG3 and RBSP3 (CTDSPL). miR-18a overexpression in CC cells is triggered by OCT4 overexpression. Our data implicate PD-L1 as a novel oncoprotein and indicate that miR-140/ 142/340/383 and miR-18a are key upstream regulators of PD-L1 and potential targets for CC treatment.
DEVELOPMENTAL MEDICO-LIFE-SCIENCES, 2024
Background: Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is a nuclear-enriched long non-coding RNA, implicated in the tumorigenesis of various cancers, including breast carcinoma (BC). It is associated with cancer proliferation, invasion, migration, and metastasis, and plays a role in immune system modulation. Aims and Objectives: This in silico study investigates MALAT1's diagnostic, prognostic, and therapeutic potential in BC. It examines MALAT1's differential expression in Breast Cancer (BC) versus normal tissues, its impact on patient survival, and its interaction with miR-561 affecting TOP2A mRNA degradation. Methodology: Using publicly available datasets from GEO and TCGA, we conducted differential expression, survival, and prognostic analyses, along with network and pathway studies and drug repurposing analyzes and Tools like Graph Pad Prism and GEPIA data set was used for demographics. Results: Our analyzes indicate overexpression of MALAT1 in BC tissues, its correlation with poorer survival rates, and involvement in key oncogenic pathways. Additionally, drug repurposing analyzes have identified potential MALAT1-targeted therapeutic strategies. Conclusion: MALAT1 serves as a significant biomarker for BC diagnosis and prognosis and is identified as a potential therapeutic target. This study lays the groundwork for future research into MALAT1-targeted therapies in BC
Background Triple negative breast cancer (TNBC) is an immunogenically hot tumor. The immune checkpoint blockades (ICBs) have been recently emerged as promising therapeutic candidates for several malignancies including TNBC. Yet, the development of innate and/or adaptive resistance by TNBC patients towards ICBs such as programmed death-ligand 1 (PD-L1) inhibitors (e.g. Atezolizumab) shed the light on importance of identifying the underlying mechanisms regulating PD-L1 in TNBC. Recently, it was reported that non-coding RNAs (ncRNAs) perform a fundamental role in regulating PD-L1 expression in TNBC. Hence, this study aims to explore a novel ncRNA axis tuning PD-L1 in TNBC patients and investigate its possible involvement in fighting Atezolizumab resistance. Methods In-silico screening was executed to identify ncRNAs that could eventually target PD-L1. Screening of PD-L1 and the nominated ncRNAs (miR-17-5p, let-7a and CCAT1 lncRNA) was performed in BC tissues and cell lines. Ectopic exp...
Investigating the Expression of Oncogenic and Tumor Suppressive MicroRNA in DLBCL
Journal of the Association of Genetic Technologists, 2013
Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of lymphoma, accounting for 40 percent of newly diagnosed cases each year. DLBCL is an aggressive abnormal growth of tissue characterized by the accumulation of abnormal B-lymphocytes in the lymphatics of affected individuals. The goal of this study was to analyze microRNA (miRNA) as an alternative method of diagnosis and treatment for patients affected with the observed cancer. MiRNAs are small, non-coding, endogenous RNA that control gene expression at the post-transcriptional level. Emerging evidence suggests that miRNA-mediated gene regulation has a functional role in cancer and could prove to be crucial targets for therapeutic intervention. Here, we provide a quantitative study on the expression of a diverse class of oncogenic and tumor suppressive miRNA that have shown to regulate oncoproteins involved in differentiation, proliferation, and/or apoptosis.
Non-coding RNAs, including Inc-RNA and miRNA, had been reported to regulate gene expression and were associated with cancer progression. MicroRNA-561-3p (miR-561-3p), as a tumor suppressor, has been reported to play a role in preventing cancer cell progression, and MALAT1 (Lnc-RNA) has also been demonstrated to promote malignancy in various cancer, such as breast cancer (BC). In this study, we aimed to determine the correlation between miR-561-3p and MALAT1 and their roles in breast cancer progression. The expression of MALAT1, mir-561- 3p, and topoisomerase alpha 2 (TOP2A) as a target of miR-561-3p was determined in BC clinical samples and cell lines via qRT-PCR. The binding site between MALAT1, miR-561-3p, and TOP2A was investigated by performing the dual luciferase reporter assay. MALAT1 was knocked down by siRNA, and cell proliferation, apoptotic assays, and cell cycle arrest were evaluated. MALAT1 and TOP2A were significantly upregulated, while mir-561-3p expression was downreg...