The C/EBPβ-LINC01133 axis promotes cell proliferation in pancreatic ductal adenocarcinoma through upregulation of CCNG1

Huang, Chen‐Song; Chu, Jianping; Zhu, Xiao-Xu; Li, Jianhui; Yin, Xiao‐Yu; Cai, Jinhua; Zhao, Wei; Yin, Xiaoyu

doi:10.1016/j.canlet.2018.02.020

Cited by 48 publications

(51 citation statements)

References 22 publications

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“…Immunohistochemical (IHC) staining was performed as previously described [14]. Two experienced pathologists independently scored the samples for the percentage of CDK-7-positive cells (IHC score) and staining intensity.…”

Section: Icc Specimens and Ihc Stainingmentioning

confidence: 99%

“…The cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), and maintained at 37 °C in a humidified incubator with 5% CO2. Transient transfection of siRNA or plasmids was performed according to the manufacturers' protocols, as described previously [14]. The sequences of primers and siRNAs used in this study are listed in Table S2.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

“…The procedure for qRT-PCR has been described previously [14]. Briefly, the total RNA was extracted using TRIzol reagent (Life Technologies, USA) according to the manufacturer's instructions.…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma

Chen¹,

Huang²,

Xu³

et al. 2020

Int. J. Biol. Sci.

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Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy with high mortality and lack of effective therapeutic targets. Here, we found that expression of cyclin-dependent kinase 7 (CDK7) was significantly associated with higher tumor grade and worse prognosis in 96 ICC specimens. Depletion of CDK7 significantly inhibited cell growth, induced a G2/M cell cycle arrest, and reduced the migratory and invasive potential in ICC cells. Subsequent experiments demonstrated that ICC cells were highly sensitive to the CDK7 inhibitor THZ1. A low concentration of THZ1 markedly inhibited cell growth, cell cycle, migration, and invasion in ICC cell lines. RNA-sequencing (RNA-seq) analysis revealed that THZ1 treatment decreased the levels of massive oncogene transcripts, particularly those associated with cell cycle and cell migration. Quantitative reverse transcriptase PCR (qRT-PCR) analysis confirmed that transcription of oncogenes involved in cell cycle regulation (AURKA, AURKB, CDC25B, CDK1, CCNA2, and MKI67) and the c-Met pathway (c-Met, AKT1, PTK2, CRK, PDPK1, and ARF6) was selectively repressed by THZ1. In addition, THZ1 exhibited significant anti-tumor activity in a patient-derived xenograft (PDX) model of ICC, without causing detectable side effects.

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Section: Icc Specimens and Ihc Stainingmentioning

confidence: 99%

Section: Cell Culture and Transfectionmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma

Chen¹,

Huang²,

Xu³

et al. 2020

Int. J. Biol. Sci.

Self Cite

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“…Prior work in other cancer contexts has mostly described positive associations of LINC01133 levels with patient survival. Indeed, high levels of LINC01133 were shown to predict poor outcome in lung cancer , pancreatic ductal adenocarcinoma , cervical cancer , and osteosarcoma . To the best of our knowledge, however, ours is the first study that demonstrates LINC01133 involvement in breast cancer, and which provides molecular evidence of its nonprotein coding nature.…”

Section: Discussionmentioning

confidence: 74%

Microenvironmental Regulation of Long Noncoding RNA LINC01133 Promotes Cancer Stem Cell-Like Phenotypic Traits in Triple-Negative Breast Cancers

Schmöllerl

Cuiffo

et al. 2019

Stem Cells

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The fibrotic tumor microenvironment is a critical player in the pathogenesis of triple-negative breast cancers (TNBCs), with the presence of fibroblastic infiltrates particularly correlating with tumors that are clinically advanced. On this front, we previously demonstrated that TNBCs are highly enriched in fibroblastic stromal progenitor cells called mesenchymal stem/stromal cells (MSCs) and that such cells play critical roles in promoting TNBC initiation and progression. How TNBC cells respond to MSC stimulation, however, is not fully understood, and stands to reveal contextual signals used by TNBC cells during tumor development and provide biomarkers and therapeutic targets of pertinence to TNBC management. Here, we report that MSCs strongly induced the long noncoding RNA (lncRNA) LINC01133 in neighboring TNBC cells. Indeed, although lncRNAs have been tightly associated with cancer development, their contributions to breast cancer in general, and to TNBC pathogenesis in particular, have not been fully elucidated, and we set out to determine if LINC01133 regulated malignant traits in TNBC cells. We establish that LINC01133 is sufficient, on its own, in promoting phenotypic and growth characteristics of cancer stem cell-like cells, and that it is a direct mediator of the MSC-triggered miR-199a-FOXP2 pathway in TNBC models. Furthermore, we show that LINC01133 is a critical regulator of the pluripotency-determining gene Kruppel-Like Factor 4 (KLF4), and that it represents a biomarker and prognosticator of disease outcome in the clinic. Collectively, our findings introduce LINC01133 as a novel functional driver of malignancy and a potential theranostic in TNBC. STEM CELLS 2019;37:1281-1392 SIGNIFICANCE STATEMENTMesenchymal stem/stromal cells trigger a long noncoding RNA LINC01133 pathway in neighboring triple-negative breast cancer cells, which stimulates the propagation of cancer stem cell-like phenotypic traits via upregulation of the pluripotency determining factor KLF4.

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“…6 Furthermore, another study revealed that LINC01133 was overexpressed in pancreatic ductal adenocarcinoma. 15 In this study, we evaluated the effect of LINC01133 on pancreatic cancer. Our findings confirmed that LINC01133 could inhibit the Wnt signaling pathway by downregulating DKK1 expression, thereby promoting growth and metastasis of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA LINC01133 silencing exerts antioncogenic effect in pancreatic cancer through the methylation of DKK1 promoter and the activation of Wnt signaling pathway

Weng

Zhang

et al. 2018

Cancer Biology & Therapy

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Recent studies have acknowledged the critical roles played by long non-coding RNAs (lncRNAs) in the development and progression of pancreatic cancer. Therefore, the present study aimed to elucidate the mechanism underlying on how LINC01133 regulates the Wnt signaling pathway in pancreatic cancer. A microarray-based gene expression analysis was performed to identify the differentially expressed lncRNAs in pancreatic cancer. In addition, ectopic expression assays, knockdown experiments and gene reporter assays were conducted to clarify the role of LINC01133 in pancreatic cancer and to understand the interaction between LINC01133 and the methylation of DKK1 promoter. The expression of LINC01133, DKK1, and other genes related to the Wnt signaling pathway was also measured. EDU staining, scratch test and Transwell assay were employed to measure the proliferation, migration and invasion of pancreatic cancer cells, respectively. GSE32676 and GSE16515 revealed that LINC01133 was upregulated in pancreatic cancer, which was also associated with increased DKK1 methylation and higher expression of genes related to the Wnt signaling pathway, although the expression of DKK1 decreased in pancreatic cancer. In addition, LINC01133 bound to the promoter region of DKK1, resulting in the trimethylation of H3K27 and decreased DKK1 expression, while the expression of Wnt-5a, MMP-7, and β-catenin increased upon LINC01133 binding. Finally, over-expressed LINC01133 enhanced the growth, proliferation, migration, metastasis, and invasion of pancreatic cancer cells. The present study clarified the distinct effect of LINC01133 on pancreatic cancer. In summary, by inducing the methylation of DKK1 promoter, LINC01133 silencing suppresses the development of pancreatic cancer cells through the Wnt signaling pathway. ARTICLE HISTORY

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The C/EBPβ-LINC01133 axis promotes cell proliferation in pancreatic ductal adenocarcinoma through upregulation of CCNG1

Cited by 48 publications

References 22 publications

Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma

Therapeutic Targeting of CDK7 Suppresses Tumor Progression in Intrahepatic Cholangiocarcinoma

Microenvironmental Regulation of Long Noncoding RNA LINC01133 Promotes Cancer Stem Cell-Like Phenotypic Traits in Triple-Negative Breast Cancers

Long non-coding RNA LINC01133 silencing exerts antioncogenic effect in pancreatic cancer through the methylation of DKK1 promoter and the activation of Wnt signaling pathway

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