MicroRNA-324 in Human Cancer: miR-324-5p and miR-324-3p Have Distinct Biological Functions in Human Cancer

Kuo, Wei-Ting; Yu, Shou Yu; Li, Sung Chou; Lam, Hing‐Chung; Chang, Hong; Chen, Wei Shone; Yeh, Chung-Yu; Hung, Syue Fen; Liu, Tsai Chi; Wu, Tsung-Tien; Yu, Chia Cheng; Tsai, Kuo‐Wang

doi:10.21873/anticanres.11089

Cited by 60 publications

(58 citation statements)

References 17 publications

(20 reference statements)

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“…In fact, this difference was not surprising because TCGA analysis was not always consistent with the experimental data. And the similar inconsistency between TCGA analysis and the experimental results had been reported before, which indicates that large numbers of samples or more patient cohorts are possibly helpful to further verify the prognostic role of Dyrk3 in HCC patients in future studies.…”

Section: Discussionsupporting

confidence: 60%

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

Zhu

Liu

et al. 2019

Hepatology

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Cancer cells metabolize different energy sources to generate biomass rapidly. The purine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. However, very little was known about the regulatory mechanisms of purine metabolism in hepatocellular carcinoma (HCC). We explored the role of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly down-regulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through down-regulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3. We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which has been shown to be a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. However, the phosphorylation-resistant NCOA3-S1330A mutant has the opposite effect. Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. Importantly, levels of Dyrk3 and phospho-NCOA3-S1330 inversely correlate with the expression of ATF4 in human HCC specimens. Conclusion: Our findings not only illustrate a function of Dyrk3 in reprograming HCC metabolism by negatively regulating NCOA3/ATF4 transcription factor complex but also identify NCOA3 as a phosphorylation substrate of Dyrk3, suggesting the Dyrk3/NCOA3/ATF4 axis as a potential candidate for HCC therapy. (Hepatology 2019;70:1785-1803).D ual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) is one of five members of the mammalian kinase family which includes Dyrk1A, Dyrk1B, Dyrk2, Dyrk3, and Dyrk4. (1) Although this family shares a highly conserved amino acid sequence in the catalytic domain with a Tyr-X-Tyr motif in the activation loop, the individual members are totally different in their N-terminal and C-terminal regions. Numerous studies have confirmed the critical role of Dyrk family kinases in

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Section: Discussionsupporting

confidence: 60%

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

Zhu

Liu

et al. 2019

Hepatology

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“…Since miR-3163, miR-324-5p and miR-532-3p were the top three upregulated miRs shown by qPCR validation assay and the relationship of miR-3163/miR-324-5p to cancer were reported [8, 19, 20], we chose to study the role of miR-532-3p in the anti-cancer role of 20(S)-Rg3. We reported that 20(S)-Rg3 inhibited the Warburg effect in the ovarian cancer cells [10].…”

Section: Resultsmentioning

confidence: 99%

“…We have reported that 20(S)-Rg3, one of the bioactive extracts from ginsenosides, reversed the vicious phenotype of ovarian cancer cells partly via inhibiting the Warburg effect [8, 9]. The preliminary study has found that 20(S)-Rg3 inhibits the Warburg effect via STAT3/HK2 pathways [10].…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside 20(S)-Rg3 Inhibits the Warburg Effect Via Modulating DNMT3A/ MiR-532-3p/HK2 Pathway in Ovarian Cancer Cells

Zhou

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: The Warburg effect is one of the main energy metabolism features supporting cancer cell growth. 20(S)-Rg3 exerts anti-tumor effect on ovarian cancer partly by inhibiting the Warburg effect. microRNAs are important regulators of the Warburg effect. However, the microRNA regulatory network mediating the anti-Warburg effect of 20(S)-Rg3 was largely unknown. Methods: microRNA deep sequencing was performed to identify the 20(S)-Rg3-influenced microRNAs in SKOV3 ovarian cancer cells. miR-532-3p was overexpressed by mimic532-3p transfection in SKOV3 and A2780 cells or inhibited by inhibitor532-3p transfection in 20(S)-Rg3-treated cells to examine the changes in HK2 and PKM2 expression, glucose consumption, lactate production and cell growth. Dual-luciferase reporter assay was conducted to verify the direct binding of miR-532-3p to HK2. The methylation status in the promoter region of pre-miR-532-3p gene was examined by methylation-specific PCR. Expression changes of key molecules controlling DNA methylation including DNMT1, DNMT3A, DNMT3B, and TET1-3 were examined in 20(S)-Rg3-treated cells. DNMT3A was overexpressed in 20(S)-Rg3-treated cells to examine its influence on miR-532-3p level, HK2 and PKM2 expression, glucose consumption and lactate production. Results: Deep sequencing results showed that 11 microRNAs were increased and 9 microRNAs were decreased by 20(S)-Rg3 in SKOV3 cells, which were verified by qPCR. More than 2-fold increase of miR-532-3p was found in 20(S)-Rg3-treated SKOV3 cells. Forced expression of miR-532-3p reduced HK2 and PKM2 expression, glucose consumption and lactate production in SKOV3 and A2780 ovarian cancer cells. Inhibition of miR-532-3p antagonized the suppressive effect of 20(S)-Rg3 on HK2 and PKM2 expression, glucose consumption and lactate production in ovarian cancer cells. Dual-luciferase reporter assay showed that miR-532-3p directly suppressed HK2 rather than PKM2. miR-532-3p level was controlled by the methylation in the promoter region of its host gene. 20(S)-Rg3 inhibited DNMT3A expression while exerted insignificant effect on DNMT1, DNMT3B and TET1-3. 20(S)-Rg3 reversed DNMT3A-mediated methylation in the promoter of the host gene of miR-532-3p, and thus elevated miR-532-3p level followed by suppression of HK2 and PKM2 expression, glucose consumption and lactate production. Conclusions: 20(S)-Rg3 modulated microRNAs to exert the anti-tumor effect in ovarian cancer. 20(S)-Rg3 lessened the DNMT3A-mediated methylation and promoted the suppression of miR-532-3p on HK2 to antagonize the Warburg effect of ovarian cancer cells.

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“…5 However, both the 5p and 3p mature variants have been reported to be differentially expressed in various cancers, and their expressions have been associated with both tumor suppressor and oncogenic functions. 5,13,14 This observation is supported by evidence that different mature miRNAs, cleaved from the 5# or 3# arms of the same stem-loop pre-miRNA, can be independently functional and have different targets. 10 In addition, the 5p/3p pairs can be differentially expressed from tissue to tissue, indicating that their expression might have tissue-dependent regulatory roles.…”

Section: Introductionmentioning

confidence: 80%

Emerging role of microRNA 628-5p as a novel biomarker for cancer and other diseases

2019

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MicroRNAs are a family of small, single-stranded RNAs that have key roles in regulating multiple signaling pathways within a cell. Studies have implicated aberrant expression of microRNAs in the development and progression of several pathologies including cancer. MicroRNAs are relatively stable and readily available in body fluids and tissues, making them desirable biomarkers for prognostic and diagnostic purposes in an array of diseases. MicroRNA 628 (5p/3p variants) is located in the 15q21.3 cancer-related region, and evidence suggests its association with various pathologies. The -5p mature variant, microRNA 628-5p, has been reported to be differentially expressed in various cancers, and its expression has been mostly associated with tumor suppression but there are few reports identifying its role in cancer progression. Several studies have also suggested its utility in diagnosis and prognosis of various cancers. Dysregulation of microRNA 628-5p has also been implicated in embryonal implantation defects, autism, immune modulation, myogenesis, cardiovascular disease, viral infection, and skeletal muscle repair. Here, we have provided a comprehensive review on available literature explaining the role of microRNA 628-5p as a potential cancer biomarker as well as briefly describe its function in other diseases and normal physiological conditions. Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

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MicroRNA-324 in Human Cancer: miR-324-5p and miR-324-3p Have Distinct Biological Functions in Human Cancer

Cited by 60 publications

References 17 publications

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

Dual‐Specificity Tyrosine Phosphorylation–Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression

Ginsenoside 20(S)-Rg3 Inhibits the Warburg Effect Via Modulating DNMT3A/ MiR-532-3p/HK2 Pathway in Ovarian Cancer Cells

Emerging role of microRNA 628-5p as a novel biomarker for cancer and other diseases

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