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LncRNA TTN-AS1 Regulates miR-524-5p and RRM2 to Promote Breast Cancer Progression.

ABSTRACT: BackgroundRecent studies suggest many long non-coding RNAs (lncRNAs) are crucial oncogenes or tumor suppressors. This study intended to investigate the biological function and mechanism of lncRNA TTN antisense RNA 1 (TTN-AS1) in the progression of breast cancer (BC).Materials and MethodsBC tissue samples were collected. The expression of TTN-AS1 in BC tissues and adjacent tissues was detected by qRT-PCR, and the relationship between pathological indicators and TTN-AS1 expression was analyzed by chi-square test. BC cell lines T47D and BT549 were utilized as cell models. CCK-8 assay and BrdU assay were used to detect the effect of TTN-AS1 on BC cell proliferation. Transwell assay was used to detect the effects of TTN-AS1 on cell migration and invasion. In addition, dual-luciferase reporter gene assay was used to confirm the targeting relationship between miR-524-5p and TTN-AS1. Western blot was used to detect the function of TTN-AS1 on regulating ribonucleotide reductase subunit 2 (RRM2) and survivin. Additionally, subcutaneous xenotransplanted tumor model and tail vein injection model were constructed in vivo.ResultsThe expression of TTN-AS1 in BC tissues was significantly higher than that in normal tissues, and its high expression was correlated with adverse pathological indicators. Overexpression of TTN-AS1 significantly promoted the proliferation, migration and invasion of BC cells. TTN-AS1 knockdown suppressed the malignant phenotypes of BC cells. TTN-AS1 overexpression significantly impeded the expression of miR-524-5p, but increased the expression of RRM2.ConclusionTTN-AS1 exerts oncogenic function in BC by repressing miR-524-5p and increasing the expression of RRM2.

SUBMITTER: Feng H

PROVIDER: S-EPMC7261692 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Project description:Neuropilin-1 regulated by miR-320a participates in the progression of cholangiocarcinoma by serving as a co-receptor that activates multiple signaling pathways. The present study sought to investigate upstream lncRNAs that control the expression of miR-320a/neuropilin-1 axis and dissect some of the underlying mechanisms. Here we report lncRNA TTN-AS1 (titin-antisense RNA1) acts as a sponging ceRNA to downregulate miR-320a and is highly expressed in human cholangiocarcinoma tissues and cells. The expression of the above three molecules is correlated with the clinicopathologic parameters of cholangiocarcinoma patients. In this study, multiple bioinformatics tools and databases were employed to seek potential lncRNAs that have binding sites with miR-320a and TTN-AS1 was identified because it exhibited the largest folds of alteration between cholangiocarcinoma and normal bile duct epithelial cells. The regulatory role of TTN-AS1 on miR-320a was further evaluated by luciferase reporter and RNA pulldown assays, coupled with in situ hybridization and RNA immunoprecipitation analyses, which showed that TTN-AS1 bound to miR-320a through an argonaute2-dependent RNA interference pathway in the cytoplasm of cholangiocarcinoma cells. Knockdown and overexpression assays showed that the regulatory effect between TTN-AS1 and miR-320 was in a one-way manner. TTN-AS1 promoted the proliferation and migration of cholangiocarcinoma cells via the miR-320a/ neuropilin-1 axis. The function of TTN-AS1 on tumor growth and its interaction with miR-320a were confirmed in animal models. Further mechanistic studies revealed that TTA-AS1, through downregulating miR-320a, promoted cell cycle progression, epithelial-mesenchymal transition, and tumor angiogenesis by upregulating neuropilin-1, which co-interacted with the hepatocyte growth factor/c-Met and transforming growth factor (TGF)-β/TGF-β receptor I pathways. In conclusion, the present results demonstrate that lncRNA TTA-AS1 is a sponging ceRNA for miR-320a, which in turn downregulates neuropilin-1 in cholangiocarcinoma cells, indicating these three molecules represent potential biomarkers and therapeutic targets in the management of cholangiocarcinoma.

Project description:BackgroundBreast cancer (BC) is a prevalent malignancy with complex etiology and varied clinical behavior. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer progression, including BC. Among these, lncRNA TDRKH-AS1 has been implicated in several cancers, but its role in BC remains unclear.MethodsWe conducted a comprehensive investigation to elucidate the role of TDRKH-AS1 in BC. Clinical samples were collected from BC patients, and BC cell lines were cultured. Bioinformatics analysis using the starBase database was carried out to assess TDRKH-AS1 expression levels in BC tissue samples. Functional experiments, including knockdown, colony formation, CCK-8, Transwell, and wound-healing assays, were conducted to determine the role of TDRKH-AS1 in BC cell proliferation and invasion. Luciferase reporter and RIP assays were used to examine the interactions between TDRKH-AS1 and miR-134-5p. In addition, the downstream target gene of miR-134-5p, cAMP response element-binding protein 1 (CREB1), was identified and studied using various methods, including RT-qPCR, immunoprecipitation, and rescue experiments. In vivo experiments using mouse tumor xenograft models were conducted to examine the role of TDRKH-AS1 in BC tumorigenesis.ResultsTDRKH-AS1 was found to be significantly upregulated in BC tissues and cell lines. High TDRKH-AS1 expression correlated with advanced BC stages and worse patient outcomes. Knockdown of TDRKH-AS1 led to decreased BC cell proliferation and invasion. Mechanistically, TDRKH-AS1 acted as a sponge for miR-134-5p, thereby reducing the inhibitory effects of miR-134-5p on CREB1 expression. Overexpression of CREB1 partially rescued the effects of TDRKH-AS1 knockdown in BC cells. In vivo studies further confirmed the tumor-promoting role of TDRKH-AS1 in BC.ConclusionsOur study unveiled a novel regulatory axis involving TDRKH-AS1, miR-134-5p, and CREB1 in BC progression. TDRKH-AS1 functioned as an oncogenic lncRNA by promoting BC cell proliferation and invasion through modulation of the miR-134-5p/CREB1 axis. These findings highlighted TDRKH-AS1 as a potential diagnostic biomarker and therapeutic target for BC treatment.

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LncRNA TTN-AS1 Regulates miR-524-5p and RRM2 to Promote Breast Cancer Progression.

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