Dataset Information

LncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer.

ABSTRACT: Previous studies have reported that long noncoding RNAs (lncRNAs) have acted as new players during tumorigenesis. Metallothionein also plays an important role in tumor progression. It is mainly considered to be involved in the process of cell proliferation, oxidative stress, and multidrug resistance. However, the potential involvement of metallothionein-related lncRNAs in colon cancer remains poorly understood. In our study, we found that MT1M affected the expression of lncRNA STEAP3-AS1. STEAP3-AS1 is located in physical contiguity with STEAP3 and notably increased in colon cancer tissues and cell lines. STEAP3-AS1 expression was negatively associated with the expression of STEAP3. High levels of STEPA3-AS1 were associated with poor overall survival in colon cancer patients. In in vitro assays, STEAP3-AS1 knockdown could inhibit colon cancer cell proliferation and migration and arrest colon cancer cells at the G0-G1 phase. In tumorigenicity assays, STEAP3-AS1 knockdown could strongly inhibit tumor growth. Mechanistic investigations demonstrated that STEAP3-AS1 downregulation could increase the expression of cyclin-dependent kinase inhibitor 1C (CDKN1C) by STEAP3 upregulation. Overall, we identify the underlying role of MT1M-related lncRNA STEAP3-AS1 in colon cancer progression, which provides a novel strategy for colon cancer therapy.

SUBMITTER: Na H

PROVIDER: S-EPMC7360886 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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lncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer.

Na Heya H Li Xiaomeng X Zhang Xinsheng X Xu Yue Y Sun Yuzhu Y Cui Jingyi J Chen Zihao Z Shi Xiaomeng X Ren Shuangyi S Zuo Yunfei Y

Molecular therapy. Nucleic acids 20200618

Previous studies have reported that long noncoding RNAs (lncRNAs) have acted as new players during tumorigenesis. Metallothionein also plays an important role in tumor progression. It is mainly considered to be involved in the process of cell proliferation, oxidative stress, and multidrug resistance. However, the potential involvement of metallothionein-related lncRNAs in colon cancer remains poorly understood. In our study, we found that MT1M affected the expression of lncRNA STEAP3-AS1. STEAP3 ...[more]

PMID: 32679543

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Project description:Background Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined. Methods The TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNA STEAP3-AS1 in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation of STEAP3-AS1 mediated by HIF-1α. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role of STEAP3-AS1/STEAP3/Wnt/β-catenin axis in CRC proliferation and metastasis. Results Here, we identified a hypoxia-induced antisense lncRNA STEAP3-AS1 that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNA STEAP3-AS1, which was induced by HIF-1α-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, STEAP3-AS1 interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N6-methyladenosine (m6A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m6A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe2+). Increased Fe2+ levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and inhibited its kinase activity, thus releasing β-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression. Conclusions Taken together, our study highlights the mechanisms of lncRNA STEAP3-AS1 in facilitating CRC progression involving the STEAP3-AS1/STEAP3/Wnt/β-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment. Graphical abstract Hypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNA STEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability of STEAP3 and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe2+), which induces the Ser 9 phosphorylation and inactivation of GSK3β, releasing β-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01638-1.

Project description:IntroductionColon adenocarcinoma (COAD) is the third most common tumor of the digestive tract. Recent studies reported that lncRNA's abnormal expression might play a vital role in the occurrence and development of COAD.MethodsIn the present study, we investigated the expression of ILF3-AS1 in COAD cell lines, human normal colon epithelial cell line, patient tumor tissues and adjacent normal tissues by real-time quantitative PCR (RT-qPCR). Small interfering RNAs (siRNAs) were transfected into COAD cells to inhibit the expression of ILF3-AS1. The effects of ILF3-AS1 on cell proliferation, migration, invasion and apoptosis were measured by CCK-8 assay, transwell migration and invasion assay, and flow cytometry apoptosis assay, respectively. The direct binding of ILF3-AS1 and miR-619-5p/CAMK1D was validated by the luciferase reporter assay. The expression of CAMK1D and epithelial-mesenchymal transformation (EMT)-related proteins was detected by Western Blot analysis. Besides, in vivo experiments were conducted to demonstrate the oncogenic role of ILF3-AS1 in COAD.ResultsThe results showed that the expression of ILF3-AS1 was significantly higher in COAD tissue than in normal adjacent samples, and this conclusion was confirmed in the available public datasets. After ILF3-AS1 knockdown, the proliferation of COAD cell lines SW480 and HT29 was significantly inhibited. At the same time, the apoptosis was increased, and the invasion and migration abilities were decreased. After further exploring the mechanisms, we found that ILF3-AS1 serves as a competitive endogenous RNA of mir-619-5p. It can bind to mir-619-5p and reduce its expression, thus regulating the target gene CAMK1D. In addition, we found that high expression of ILF3-AS1 was significantly associated with tumor grade, tumor size, and distant metastasis in COAD samples. In vivo experiments confirmed that ILF3-AS1 promotes tumor growth in COAD models.ConclusionThe present study demonstrated that ILF3-AS1 plays an oncogenic role in COAD through regulating the miR-619-5p/CAMK1D axis, and inhibition of ILF3-AS1 may pave the way for COAD treatment.

Dataset Information

LncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer.

Publications

lncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer.

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