Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

Yeh, Chung-Min; Chang, Liang-Yu; Lin, Shu-Hui; Chou, Jian–Liang; Hsieh, He-Yen; Zeng, Li-Han; Chuang, Sheng-Yu; Wang, Hsiao‐Wen; Dittner, Claudia; Lin, Cheng‐Yu; Lin, Jora M. J.; Huang, Yao‐Ting; Ng, Enders Kwok Wai; Cheng, Alfred S.L.; Wu, Shu-Fen; Lin, Jiayuh; Yeh, Kun‐Tu; Chan, Michael W.Y.

doi:10.1038/srep31690

Cited by 45 publications

(42 citation statements)

References 50 publications

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“…Among these genes, we noted NR4A3, which was up‐regulated after LINC00467 knockdown and inversely associated with LINC00467 in HCC tissues. NR4A3 is a member of nuclear receptors superfamily and frequently reported to act as a tumour suppressor in gastric, breast and lung cancer . Therefore, we further investigated whether LINC00467 regulates NR4A3 and whether the modulation of NR4A3 mediates the oncogenic roles of LINC00467 in HCC.…”

Section: Resultsmentioning

confidence: 99%

“…NR4A3 (orphan nuclear receptor 4A3) belongs to the nuclear receptor superfamily. NR4A3 has been shown to regulate cell proliferation, apoptosis and migration and have generally tumour‐suppressive roles in breast cancer, lung cancer, gastric cancer and leukaemia . Therefore, we hypothesized that the tumour suppressor NR4A3 may mediate the oncogenic roles of LINC00467 in HCC.…”

Section: Discussionmentioning

confidence: 99%

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Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Wang

Guo

Nampoukime

et al. 2020

J Cellular Molecular Medi

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Hepatocellular carcinoma (HCC) is a main cause of cancer‐related deaths globally. Long non‐coding RNAs (lncRNAs) play important roles in diverse cancers. Our previous microarray‐based lncRNA profiling showed that LINC00467 was highly expressed in HCC. Here, we further explored the expression, role and functional mechanism of lncRNA LINC00467 in HCC. Our findings revealed that LINC00467 was up‐regulated in HCC tissues and HCC cell lines. Increased expression of LINC00467 was positively associated with tumour size and vascular invasion. In vitro functional experiments revealed that LINC00467 accelerated HCC cell proliferation, cell cycle progression and migration and reduced HCC cell apoptosis. In vivo functional assays revealed that LINC00467 drove HCC xenograft growth and HCC cell proliferation and repressed HCC cell apoptosis in vivo. Moreover, LINC00467 inhibited NR4A3 post‐transcriptionally via interacting with NR4A3 mRNA to form double‐stranded RNA, which was further degraded by Dicer. The expression of NR4A3 was inversely associated with LINC00467 in HCC tissues. Functional rescue assays found that restore of NR4A3 expression blocked the oncogenic roles of LINC00467 in HCC. Taken together, our results demonstrated that lncRNA LINC00467 was a novel highly expressed and oncogenic lncRNA in HCC via inhibiting NR4A3. Targeting LINC00467 or enhancing NR4A3 may be potential therapeutic strategies against HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Wang

Guo

Nampoukime

et al. 2020

J Cellular Molecular Medi

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“…To determine whether STAT3 affects the expression of GATA6 directly, we examined the binding status of STAT3 in AGS cells showing constitutive activation of STAT3 [ 15 , 16 ]. The binding of STAT3 can be observed at the putative STAT3 binding site upstream of the GATA6 promoter ( Figure 3 A).…”

Section: Resultsmentioning

confidence: 99%

Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer

Wei

Chou

et al. 2016

IJMS

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Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation.

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“…In response to interleukin-6 signal, STAT3 could be activated and is involved in various types of pathological conditions. STAT3 plays important roles in various types of cancer 33–35. Yu et al found that activated STAT3 was correlated with prognosis of NSCLC 36.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-148a suppresses proliferation and invasion potential of non-small cell lung carcinomas via regulation of STAT3

He¹,

Xue²

2017

OTT

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Lung cancer has the highest morbidity and mortality in the world, and non-small cell lung carcinomas (NSCLC) account for 80% of cases of lung cancer. The mechanism of NSCLC is still largely unknown, and finding novel targets is of great importance for the treatment of NSCLC. The current study was designed to evaluate the role of miR-148a in NSCLC cell proliferation and invasion and to investigate the possible molecular mechanisms. We found that miR-148a expression was decreased in NSCLC tissues and cell lines. Upregulation of miR-148a significantly decreased A549 cell proliferation, and downregulation of miR-148a significantly increased A549 cell proliferation. Upregulation of miR-148a markedly increased apoptotic cell death and inhibited cell invasion potential. Upregulation of miR-148a significantly decreased signal transducer and activator of transcription 3 (STAT3) expression and 3′-untranslated region luciferase activity. Downregulation of miR-148a significantly increased STAT3 expression. Overexpression of STAT3 significantly inhibited the effect of miR-148a on cell viability and invasion potential. In conclusion, we found that miR-148a inhibited NSCLC cell proliferation and invasion potential through the inhibition of STAT3. Our findings highlight miR-148a/STAT3 axis as a novel therapeutic target for the inhibition of NSCLC growth.

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Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

Cited by 45 publications

References 50 publications

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Long non‐coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3

Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer

MicroRNA-148a suppresses proliferation and invasion potential of non-small cell lung carcinomas via regulation of STAT3

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