Sp1-mediated transcriptional regulation of MALAT1 plays a critical role in tumor

Li, Shufeng; Wang, Qiwei; Qiang, Qian; Shan, Haitao; Shi, Minke; Chen, Baojun; Zhao, Sheng; Liu, Yuan

doi:10.1007/s00432-015-1951-0

Cited by 52 publications

(62 citation statements)

References 39 publications

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“…Up-regulation of MALAT1 facilitates cell proliferation, migration, and invasion in lung cancer, glioblastoma, esophageal squamous cell carcinoma, renal cell carcinoma, colorectal cancer, osteosarcoma, multiple myeloma, gastric cancer, gallbladder cancer. [10][11][12][13][14][15][16][17][18][19][20] In addition, MALAT1 is associated with the malignant status and poor prognosis in glioma and clear cell renal cell carcinoma. 21,22 Finally, the high level of MALAT1 can act as a marker to predict disease progression in colorectal cancer, multiple myeloma, pancreatic cancer, and non-small cell lung cancer.…”

Section: Introductionmentioning

confidence: 99%

MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

Cai

et al. 2015

Cell Cycle

113

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Abbreviations: a-SMA, smooth muscle a-actin; Ad-shCtrl, adenoviral vectors expressing the scrambled shRNA; Ad-shMALAT1, adenoviral vectors expressing shRNA against MALAT1. EdU, 5-Ethyny-2 0 -deoxyuridine; Ago2, Argonaute-2; BDL, bile duct ligation; CCl 4 , carbon tetrachloride; ceRNAs, competing endogenous RNAs; Col1a1, collagen type I, a 1; DMEM, Dulbecco's modified Eagle's medium; HSCs, hepatic stellate cells; IgG, immunoglobulin G; IHC, immunohistochemical; lncRNAs, long noncoding RNAs; MALAT1, Metastasis-associated lung adenocarcinoma transcript 1; miR-101, microRNA-101; miR-NC, miR-101b negative control; miRNAs, microRNAs; ncRNAs, non-coding RNAs; qRT-PCR, quantitative real-time PCR; Rac1, RAS-related C3 botulinum substrate 1; siCtrl, scrambled siRNA; siRNAs, small interfering RNAs.Emerging evidence shows that Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a pivotal role in cell proliferation, migration, and invasion in tumors. However, the biological role and underlying mechanism of MALAT1 in liver fibrosis remains undefined. In this study, up-regulation of MALAT1 was observed in fibrotic liver tissues and in activated hepatic stellate cells (HSCs). In addition, depletion of MALAT1 inhibited the activation of HSCs in vitro and attenuated collagen deposits in vivo. Our results demonstrated that MALAT1 expression is negatively correlated with microRNA-101b (miR-101b) expression. Furthermore, there was a negative feedback loop between the levels of MALAT1 and miR-101b. Luciferase reporter assay indicated that MALAT1 and RAS-related C3 botulinum substrate 1 (Rac1) are targets of miR-101b. We uncovered that MALAT1 regulates Rac1 expression through miR-101b as a competing endogenous RNA (ceRNA), thereby influencing the proliferation, cell cycle and activation of primary HSCs. Collectively, The ceRNA regulatory network may prompt a better understanding of liver fibrogenesis and contribute to a novel therapeutic strategy for liver fibrosis.

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Section: Introductionmentioning

confidence: 99%

MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

Cai

et al. 2015

Cell Cycle

113

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“…Thus, we sought to understand the inference of miR338-5p/miR-421/MALAT1 axis in cell cycle regulation. Putative binding sites of E2F1, an important regulator of G1/S phase transition, were found within critical region (+50bp to -700bp) of the 13 MALAT1 promoter (26). To explore the functional interplay between E2F1 and MALAT1, we silenced E2F1 in VCaP cells, which resulted in significant decrease in MALAT1 expression (Fig.…”

Section: Mir-338-5p and Mir-421 Regulate Oncogenic Long Non-coding Rnmentioning

confidence: 99%

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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PurposeSerine Peptidase Inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer (PCa) subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in PCa remains largely unknown.Experimental DesignMicroRNA-prediction tools were employed to examine the SPINK1-3’UTR for miRNAs binding. Luciferase reporter assays were performed to confirm the SPINK1-3’UTR binding of shortlisted miR-338-5p/miR-421. Further, miR-338-5p/-421 overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and mice xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. Immunohistochemistry and RNA in-situ hybridization was carried-out on PCa patients’ tissue microarray for SPINK1 and EZH2 expression respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421 regulatory regions. Bisulfite sequencing and methylated DNA-immunoprecipitation was performed on PCa cell lines and patients’ specimens.ResultsWe established a critical role of miRNA-338-5p/-421 in post-transcriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive PCa cells abrogate oncogenic properties including cell-cycle progression, stemness and drug resistance, and show reduced tumor burden and distant metastases in mice model. Importantly, we show SPINK1-positive PCa patients exhibit increased EZH2 expression, suggesting its role in miRNA-338-5p/-421 epigenetic silencing. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive PCa cells and patients’ specimens confirms epigenetic silencing.ConclusionOur findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive PCa, while restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.TRANSLATIONAL IMPACTWe establish a regulatory model involving the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2, thereby, revealing hitherto unknown mechanism of SPINK1 up-regulation in SPINK1-positive subtype. Our findings provide a strong rationale for the development of potential therapeutic strategies for SPINK1-positive malignancies. We demonstrate that restoring miRNA-338-5p/miRNA-421 expression using epigenetic drugs including DNMTs inhibitors in combination with HDACs or HKMTs inhibitors or miRNA synthetic mimics in SPINK1-positive prostate cancer abrogate SPINK1-mediated oncogenicity. The major findings of this study will not only advance the prostate cancer field, but will also be valuable for treatment and disease management of other SPINK1-positive malignancies.

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“…In cancer growth and metastasis, Sp1 influences a variety of cancer cell types through the regulation of oncogenes, tumor suppressor genes, cell cycle regulators, growth related signal transduction pathways, angiogenic factors and apoptosis (5,6). Sp1 is expressed at high levels in many cancers (7) and is closely associated with EMT (8,9).…”

Section: Introductionmentioning

confidence: 99%

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

Shan

Hu³

et al. 2016

International Journal of Oncology

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Abstract. Sp1 plays critical roles in epithelial-mesenchymal transition (EMT) of certain cancer. However, few studies have indicated whether Sp1 is involved in the EMT of gastric cancer, and whether abnormal expression of Sp1 in gastric cancer EMT is regulated in a post-transcriptional manner, and the involvement of miRNAs in this regulation. In this study, we selected 20 cases of gastric cancers, their liver metastases and para-carcinoma tissues to examine the levels of Sp1 protein and mRNA by immunohistochemistry and fluorescent PCR, which showed that Sp1 was increased in gastric cancers and their metastases compared with adjacent tissues, but there was no difference in Sp1 mRNA between these three groups, suggesting changes in Sp1 may be attributed to inactivation of post-transcriptional regulation. We verified by a luciferase reporter system that miRNA-223 binds to 3'-UTR of Sp1 gene and inhibits its translation, in agreement with negative correlation between miRNA-223 and Sp1 protein levels in gastric cancer cells. By employing TGF-β1 to induce MGC-803, BGC-823 and SGC-7901, we successfully built cellular EMT model. Then, we overexpressed miRNA-223 in the model by using a lentiviral system, which diminished EMT indicators and suppressed proliferation and invasion ability, and induced apoptosis. Finally, we verified the specificity of the regulation pathway miRNA-223/Sp1/EMT. These findings suggest that low expression of miRNA-223 in gastric cancer cells is an important cause for EMT. miRNA-223 specifically regulates the EMT process of gastric cancer cells through its target gene Sp1. Overexpression of miRNA-223 in these cells inhibits EMT via the miRNA-223/Sp1/EMT pathway.

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Sp1-mediated transcriptional regulation of MALAT1 plays a critical role in tumor

Abstract: Taken together, our data suggest that upregulation of MALAT1 was mediated by the transcription factor Sp1 in A549 lung cancer cells, and Sp1 could be therapeutic target for cancer.

Cited by 52 publications

References 39 publications

MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

miRNA-223 inhibits epithelial-mesenchymal transition in gastric carcinoma cells via Sp1

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