Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential

Kwon, Jason J.; Willy, Jeffrey A.; Quirin, Kayla; Wek, Ronald C.; Korc, Murray; Yin, Xiao Ming; Kota, Janaiah

doi:10.18632/oncotarget.11928

Cited by 65 publications

(64 citation statements)

References 89 publications

(103 reference statements)

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“…MicroRNAs are small noncoding RNAs severing as important post‐transcriptional regulators of gene expression, and their abnormal expression has been shown to contribute to tumorigenesis . MiR‐29a has been recognized as a critical tumor suppressor and downregulated in several different types of solid tumor tissues, including PC . Our findings indicated that DRP1 is a novel target of miR‐29a in PC cells, and introduction of synthetic miR‐29a significantly attenuated both the growth and metastasis promoted by DRP1 overexpression in PC cells, suggesting that downregulated miR‐29a may contribute to the upregulation of DRP1 and thus tumor growth and metastasis in PC cells.…”

Section: Discussionmentioning

confidence: 65%

“…MicroRNAs are small noncoding RNAs that serve as important post‐transcriptional regulators of gene expression. MiR‐29a has been proved as a frequently downregulated tumor suppressor in various types of cancers, including PC . Because of several previous studies that have revealed DRP1 as a novel target of miR‐29a, we thus hypothesized that downregulated miR‐29a could be involved in the overexpression of DRP1 in PC cells.…”

Section: Resultsmentioning

confidence: 99%

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DRP1 upregulation promotes pancreatic cancer growth and metastasis through increased aerobic glycolysis

Liang

Yang²,

Bai

et al. 2020

J of Gastro and Hepatol

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Background: Mitochondrial shape is dynamically changed by fusion and fission processes in cells, and dysfunction of this process has become one of the emerging hallmarks of cancer. However, the expression patterns and biological effects of mitochondrial fission and fusion proteins in pancreatic cancer (PC) are still unclear. Methods: The expressions of mitochondrial fission and fusion proteins were first evaluated by quantitative reverse transcription polymerase chain reaction and western blot analysis in both PC cell lines and tissue samples. In addition, the biologic functions of the differentially expressed proteins in PC cell growth and metastasis both in vitro and in vivo and their potential underlying mechanisms were systematically explored. Results: We first found that DRP1 was substantially upregulated in PC cell lines and tissue samples mainly due to the downregulation of miR-29a, which contributed to the poor survival of PC patients. DRP1 promoted the growth and metastasis of PC cells both in vitro and in vivo by inducing G1-S cell cycle transition and matrix metalloproteinase 2 secretion. Mechanistic investigations revealed that increased DRP1 upregulation-mediated mitochondrial fission and subsequently enhanced aerobic glycolysis were involved in the promotion of growth and metastasis by DRP1 in PC cells. Conclusions: Our findings demonstrate that mitochondrial fusion protein DRP1 plays a critical oncogenic role in PC cells by enhancing aerobic glycolysis, which could serve as a novel therapeutic target for PC treatment. bs_bs_banner DRP1 promotes PC growth and metastasis J Liang et al. DRP1 promotes PC growth and metastasis J Liang et al.

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

DRP1 upregulation promotes pancreatic cancer growth and metastasis through increased aerobic glycolysis

Liang

Yang²,

Bai

et al. 2020

J of Gastro and Hepatol

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“…Among them, miR-21, miR-31-3p, miR-203, miR-16 were up-regulated which were found to be engaged in regulating apoptosis (miR-21) [31], migration and invasion (miR-31 and miR-203) [32,33], and diagnosis(miR-16) [34] of pancreatic cancer. On the other hand, miR-210-3p, miR-29a, miR-125b, miR-133a were down-regulated, they have been reported to be associated with pancreatic cancer such as regulating cells interaction (miR-210) [35], as an autophagy inhibitor (miR-29a) [36], as a tumor suppressor(miR-125b and miR-133a) [36]. However, none of the miRNAs above is well characterized in PCSCs.…”

Section: Panc-1 Spheroid Cells Have Higher Tumorigenic Potential In Vivomentioning

confidence: 99%

Transcriptome Profiling of Panc-1 Spheroid Cells with Pancreatic Cancer Stem Cells Properties Cultured by a Novel 3D Semi-Solid System

Yang¹,

Zhang²,

Tang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Pancreatic cancer remains one of the deadliest human malignancies, the lethality of which may be attributed to the presence of pancreatic cancer stem cells (PCSCs), a small subpopulation of cells existing within pancreatic tumor with high carcinogenesis. Therefore, it is crucial to establish an efficient enrichment and culture system of PCSCs and identify the key genes involved in the regulation of PCSCs. The three-dimensional (3D) liquid suspension mammosphere culture system has been established for enrichment and culture of PCSCs in vitro as the cell spheres are likely to originate from individual cell clone, but it has been challenged because the cell spheroids could be a result of cell aggregation. Methods: We optimized the existing culture system by adding methylcellulose to create a 3D semi-solid system which prevented the non-specific aggregation. Then we identified the CSC properties of Panc-1 spheroid cells cultured by this system by detecting the genes associated with stemness and by evaluation of the tumorigenicity in vitro and in vivo through invasion, migration and xenograft experiments methods. Subsequently, we performed high-throughput sequencing (HTS) of the Panc-1 spheroid cells. Results: We confirmed the PCSCs properties and high malignancy of the Panc-1 spheroid cells enriched by our novel 3D semi-solid system both in vitro and in vivo. Hundreds of mRNA, microRNA (miRNA) and dozens of long non-coding RNA (LncRNA) were identified to be differentially regulated in PCSCs-like Panc-1 spheroid cells compared with their parental cells by HTS. Conclusions: Our results demonstrate an efficient enrichment and culture system for Panc-1 spheroid cells with the PCSCs properties. The differentially expressed genes and their targets identified by the HTS of the Panc-1 spheroid cells can serve as new potential biomarkers for pancreatic cancer diagnosis and targeted therapy.

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“…17 Interestingly, Ap1/Ets-1 binding region plays a central function in transforming growth factor betamediated the regulation of miR-29. 18 Given that restoring miR-29a expression has been demonstrated to repress the development and aggravation of malignant tumors, 6,15 miR-29a, as a potent therapeutic agent target, is considered to be applied in hepatocellular therapies. 19 SEVO commonly emerged as an anesthetic for subjects.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of sevoflurane in HCC cell line is mediated by miR‐29a‐induced suppression of Dnmt3a

Guang-ming

Tian

Cheng

et al. 2019

J of Cellular Biochemistry

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Sevoflurane (SEVO) is widely applied as an anesthetic. More recently, its antitumor capacity has been reported. However, potent mechanisms are still incompletely ascertained. In our current study, we attempted to elucidate a potent mechanism associated with microRNA (miR)‐29a/DNA methyltransferase 3 alpha (Dnmt3a) in hepatocellular carcinoma (HCC) cells. After transfection and stimulation with SEVO, biological activities of Huh7 and HepG2 cells were evaluated using the cell counting kit‐8, Annexin V‐fluorescein isothiocyanate apoptosis detection kit, 24‐well cell migration assay kit, and tumor invasion 24‐well plates. miR‐29a and protein expression were quantified with quantitative reverse transcription polymerase chain reaction and Western blot assay, respectively. A Dual‐Luciferase Reporter Assay System was used to verify whether miR‐29a targets Dnmt3a. We found that SEVO alleviated cell viability, aggrandized apoptosis, and impeded migration and invasion of the Huh7 and HepG2 cells. Besides, SEVO enhanced phosphatase and tensin homolog (PTEN) expression, and phosphorylated expression of phosphatidylinositol 3 kinase (PI3K), and protein kinase B (AKT) was eliminated by SEVO. Of note, SEVO restored miR‐29a which was downregulated in HCC tissues and cells. miR‐29a inhibitor abolished the positive effects of SEVO on the biological processes. Dual‐Luciferase Reporter assay showed miR‐29a repressed Dnmt3a expression via targeting its 3′‐untranslated region. Further, exogenous expression of Dnmt3a partially repressed PTEN and enhanced phosphorylated expression of PI3K and AKT which were originally elevated or diminished by SEVO. In conclusion, SEVO restored the expression of miR‐29a, which posttranscriptionally downregulated Dnmt3a, and then exhibited an antitumor property in HCC cells.

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Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential

Cited by 65 publications

References 89 publications

DRP1 upregulation promotes pancreatic cancer growth and metastasis through increased aerobic glycolysis

DRP1 upregulation promotes pancreatic cancer growth and metastasis through increased aerobic glycolysis

Transcriptome Profiling of Panc-1 Spheroid Cells with Pancreatic Cancer Stem Cells Properties Cultured by a Novel 3D Semi-Solid System

Antitumor activity of sevoflurane in HCC cell line is mediated by miR‐29a‐induced suppression of Dnmt3a

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