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Identification of Potential Long Non-Coding RNA Candidates that Contribute to Triple-Negative Breast Cancer in Humans through Computational Approach.

ABSTRACT: Breast cancer (BC) is the most frequent malignancy identified in adult females, resulting in enormous financial losses worldwide. Owing to the heterogeneity as well as various molecular subtypes, the molecular pathways underlying carcinogenesis in various forms of BC are distinct. Therefore, the advancement of alternative therapy is required to combat the ailment. Recent analyses propose that long non-coding RNAs (lncRNAs) perform an essential function in controlling immune response, and therefore, may provide essential information about the disorder. However, their function in patients with triple-negative BC (TNBC) has not been explored in detail. Here, we analyzed the changes in the genomic expression of messenger RNA (mRNA) and lncRNA in standard control in response to cancer metastasis using publicly available single-cell RNA-Seq data. We identified a total of 197 potentially novel lncRNAs in TNBC patients of which 86 were differentially upregulated and 111 were differentially downregulated. In addition, among the 909 candidate lncRNA transcripts, 19 were significantly differentially expressed (DE) of which three were upregulated and 16 were downregulated. On the other hand, 1901 mRNA transcripts were significantly DE of which 1110 were upregulated and 791 were downregulated by TNBCs subtypes. The Gene Ontology (GO) analyses showed that some of the host genes were enriched in various biological, molecular, and cellular functions. The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that some of the genes were involved in only one pathway of prostate cancer. The lncRNA-miRNA-gene network analysis showed that the lncRNAs TCONS_00076394 and TCONS_00051377 interacted with breast cancer-related micro RNAs (miRNAs) and the host genes of these lncRNAs were also functionally related to breast cancer. Thus, this study provides novel lncRNAs as potential biomarkers for the therapeutic intervention of this cancer subtype.

SUBMITTER: Rahman MM

PROVIDER: S-EPMC8619140 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer with the absence of targeted therapy, resulting in poor prognosis in patients. Chemotherapy remains the mainstay of treatment for TNBC; however, development of drug resistance is the main obstacle for successful treatments. In recent years, long non-coding RNA (lncRNA) has been implicated in multiple biological functions in various diseases, particularly cancers. Accumulating evidence suggested that lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression is dysregulated in many human cancers and thus is a useful prognostic marker for cancer patients. Nevertheless, the mechanism of how NEAT1 confers drug resistance in TNBC is still largely unknown. We performed lncRNA profiling by the LncRNA Profiler qPCR Array Kit in normal control (NC) and breast cancers (BC) blood samples and further validated in a larger cohort of samples by qRT-PCR. Gene expression level and localization were investigated by qRT-PCR, western blotting, and immunofluorescence staining. Flow cytometric analysis was carried out to detect cancer stem cells. Functional studies were performed both in vitro and in vivo xenograft model. Among 90 lncRNAs, NEAT1 was highly expressed in the blood samples of breast cancer patients than in NC. In particular, the expression of NEAT1 was higher in TNBC tissues than other subgroups. Functional studies revealed that NEAT1 conferred oncogenic role by regulating apoptosis and cell cycle progression in TNBC cells. We identified that knockdown of NEAT1 sensitized cells to chemotherapy, indicating the involvement in chemoresistance. Importantly, shNEAT1 reduced stem cell populations such as CD44+/CD24-, ALDH+, and SOX2+, implicating that NEAT1 was closely related to cancer stemness in TNBC. Our data highlighted the roles of NEAT1 chemoresistance and cancer stemness, suggesting that it could be used as a new clinical therapeutic target for treating TNBC patients especially those with drug resistance.

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Identification of Potential Long Non-Coding RNA Candidates that Contribute to Triple-Negative Breast Cancer in Humans through Computational Approach.

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