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Long non-coding RNA SOX2OT promotes the stemness phenotype of bladder cancer cells by modulating SOX2.

ABSTRACT: BACKGROUND:Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are potential biomarkers and key regulators of tumour development and progression. SOX2 overlapping transcript (SOX2OT) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancer and cancer stem cells. However, the clinical significance and molecular mechanism of SOX2OT in bladder cancer are still unknown. METHODS:The expression level of SOX2OT was determined by RT-qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell (BCC) lines. Bladder cancer stem cells (BCSCs) were isolated from BCCs using flow cytometry based on the stem cell markers CD44 and ALDH1. Loss-of-function experiments were performed to investigate the biological roles of SOX2OT in the stemness phenotype of BCSCs. Comprehensive transcriptional analysis, RNA FISH, dual-luciferase reporter assays and western blots were performed to explore the molecular mechanisms underlying the functions of SOX2OT. RESULTS:SOX2OT was highly expressed in bladder cancer, and increased SOX2OT expression was positively correlated with a high histological grade, advanced TNM stage and poor prognosis. Further experiments demonstrated that knockdown of SOX2OT inhibited the stemness phenotype of BCSCs. Moreover, inhibition of SOX2OT delayed xenograft tumour growth and decreased metastases in vivo. Mechanistically, we found that SOX2OT was mainly distributed in the cytoplasm and positively regulated SOX2 expression by sponging miR-200c. Furthermore, SOX2 overexpression reversed the SOX2OT silencing-induced inhibition of the BCSC stemness phenotype. CONCLUSION:This study is the first to demonstrate that SOX2OT plays an important regulatory role in BCSCs and that SOX2OT may serve as a potential diagnostic biomarker and therapeutic target in bladder cancer.

SUBMITTER: Zhan Y

PROVIDER: S-EPMC6998848 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Long non-coding RNA SOX2OT promotes the stemness phenotype of bladder cancer cells by modulating SOX2.

Zhan Yonghao Y Chen Zhicong Z He Shiming S Gong Yanqing Y He Anbang A Li Yifan Y Zhang Lianghao L Zhang Xuepei X Fang Dong D Li Xuesong X Zhou Liqun L

Molecular cancer 20200204 1

<h4>Background</h4>Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are potential biomarkers and key regulators of tumour development and progression. SOX2 overlapping transcript (SOX2OT) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancer and cancer stem cells. However, the clinical significance and molecular mechanism of SOX2OT in bladder cancer are still unknown.<h4>Methods</h4>The expression level of SOX2OT was determined by RT ...[more]

PMID: 32019566

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Project description:Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies.

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.

Dataset Information

Long non-coding RNA SOX2OT promotes the stemness phenotype of bladder cancer cells by modulating SOX2.

Publications

Long non-coding RNA SOX2OT promotes the stemness phenotype of bladder cancer cells by modulating SOX2.

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