Combination of miR‑143 and miR‑506 reduces lung and pancreatic cancer cell growth through the downregulation of cyclin‑dependent kinases

Hossian, A K M Nawshad; Mackenzie, Gerardo G.; Mattheolabakis, George

doi:10.3892/or.2021.7953

Cited by 9 publications

(11 citation statements)

References 61 publications

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“…The deregulation of cell-cycle-dependent proteins may thus contribute to therapeutic effects of miR506-3p in PDAC therapy as well. This is also supported by a recent study demonstrating miR-506 mediated downregulation of CDK1 and CDK4 [ 18 ]. Moreover, the induction of reactive oxygen species and autophagy, as well as of alterations in mitochondrial potential and structure, are additional steps towards cellular stress response and cell death.…”

Section: Discussionsupporting

confidence: 78%

“…In parallel, PIM-3, a member of the proto-oncogene PIM family, was found upregulated in pancreatic cancer tissue and negatively correlated with miR-506 levels [ 13 ]. Reduced miR-506 expression was associated with pancreatic progression, while upregulated exerted inhibitory effects [ 14 , 15 , 16 , 17 , 18 ]. In this context, STAT3 [ 17 ] and sphingosine kinase 1 (SPHK1 [ 14 ]) were identified as direct targets, and miR-506 levels were described to be affected by the oncogenic lncRNA NEAT1 [ 15 ] or by rosmarinic acid [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic miR-506-3p Replacement in Pancreatic Carcinoma Leads to Multiple Effects including Autophagy, Apoptosis, Senescence, and Mitochondrial Alterations In Vitro and In Vivo

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality. Considering its very poor prognosis, novel treatment options are urgently needed. MicroRNAs (miRNAs) are involved in the regulation of various physiological and pathological processes. In tumors, aberrant downregulation of given miRNAs may result in pathological overexpression of oncogenes, rendering miRNA replacement as a promising therapeutic strategy. In different tumor entities, miRNA-506-3p (miR506-3p) has been ambivalently described as tumor suppressing or oncogenic. In PDAC, miR-506 is mainly considered as a tumor-suppressing miRNA. In this study, we extensively analyze the cellular and molecular effects of miRNA-506-3p replacement in different PDAC cell lines. Beyond profound antiproliferation and induction of cell death and autophagy, we describe new cellular miR506-3p effects, i.e., induction of senescence and reactive oxygen species (ROS), as well as alterations in mitochondrial potential and structure, and identify multiple underlying molecular effects. In a preclinical therapy study, PDAC xenograft-bearing mice were treated with nanoparticle-formulated miRNA-506 mimics. Profound tumor inhibition upon systemic miRNA-506 administration was associated with multiple cellular and molecular effects. This demonstrates miRNA replacement as a potential therapeutic option for PDAC patients. Due to its broad mechanisms of action on multiple relevant target genes, miR506-3p is identified as a particularly powerful tumor-inhibitory miRNA.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Therapeutic miR-506-3p Replacement in Pancreatic Carcinoma Leads to Multiple Effects including Autophagy, Apoptosis, Senescence, and Mitochondrial Alterations In Vitro and In Vivo

et al. 2022

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“…It is generally accepted that CDKs regulate cell cycle progression at several irreversible transition points with formation of different cyclin/CDK/CKI (cyclin kinase inhibitor) complexes involved at different cell cycle stages [32,33]. p27 and p21 belong to the CKI family and bind to such cyclin/CDK complexes as cyclin D1/CDK6, cyclin E1/CDK2, and cyclin A2/CDK2, C-Myc and P53 also exhibit indispensable effects on the proliferation, transformation, cellular death and cell cycle progression of mammalian cells [34], and their dysregulation or mutation may convert them into pure oncogenes to promote development and progression of cancer [35,36].…”

Section: Discussionmentioning

confidence: 99%

SNHG16 lncRNAs are overexpressed and may be oncogenic in human gastric cancer by regulating cell cycle progression

Zhao

Liu

Zhang

et al. 2022

neo

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The small nucleolar RNA host gene 16 (SNHG16) has recently been shown to be a putative oncogene in gastric cancer (GC) and other cancer types, but how its four lncRNA variants are expressed in any physiological and pathological situation remains unknown. To investigate the expression and function of the four lncRNA varia nts of SNHG16, mainly the variant 1, in GC, we performed quantitative PCR to determine the RNA levels of the four variants in 60 GC tissue samples and several cell lines. We also studied how knocking down of SNHG16 with siRNA affected proliferation, apoptosis, cell cycle progression, as well as migration and invasion of GC cells. Our results showed that variants 1 and 4 were overexpressed in GC tissues compared with adjacent uninvolved tissues. Knockdown of the four variants, mainly the variant 1, enhanced apoptosis and inhibited cell cycle progression of a GC cell line by arresting the cells at t he G1 phase. These cellular effects were associated not only with decreased protein levels of c-Myc, PCNA, cyclins D, E, A, and B, as well as CDKs 2 and 6, but also with increased protein levels of the p21, p27, and p53. Knockdown of total SNHG16 lncRNAs also inhibited invasion and migration of the 2 GC cells in vitro. These results collectively suggest that SNHG16 may be oncogenic in GC by regulating cell cycle progression and may serve as a GC biomarker.

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“…First discovered in 2005 by Bentwich and colleagues, miR-506 belongs to an X-chromosome-linked miR cluster which is well conserved within primate species [7]. Several studies have identified miR-506 as an anti-cancer biomolecule in various cancer types, due to its abrupt dysregulation in various cancer phenotypes [8,9]. Moreover, miR-506's role as an anti-oncogenic miR is demonstrated by it targeting numerous biological pathways, such as through diminished epithelial-mesenchymal transition (EMT) mediated by TGF-β [10], inhibition of E-cadherin expression [11], targeting the PI3K/AKT pathway [12], and p53 response element activation [13].…”

Section: Introductionmentioning

confidence: 99%

Stable Dual miR-143 and miR-506 Upregulation Inhibits Proliferation and Cell Cycle Progression

Shrestha,

Lahooti,

Hossian

et al. 2024

IJMS

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The mainstays of lung cancer pathogenesis are cell cycle progression dysregulation, impaired apoptosis, and unregulated cell proliferation. While individual microRNA (miR) targeting or delivering is a promising approach that has been extensively studied, combination of miR targeting can enhance therapeutic efficacy and overcome limitations present in individual miR regulations. We previously reported on the use of a miR-143 and miR-506 combination via transient transfections against lung cancer. In this study, we evaluated the effect of miR-143 and miR-506 under stable deregulations in A549 lung cancer cells. We used lentiviral transductions to either up- or downregulate the two miRs individually or in combination. The cells were sorted and analyzed for miR deregulation via qPCR. We determined the miR deregulations’ effects on the cell cycle, cell proliferation, cancer cell morphology, and cell motility. Compared to the individual miR deregulations, the combined miR upregulation demonstrated a miR-expression-dependent G2 cell cycle arrest and a significant increase in the cell doubling time, whereas the miR-143/506 dual downregulation demonstrated increased cellular motility. Furthermore, the individual miR-143 and miR-506 up- and downregulations exhibited cellular responses lacking an apparent miR-expression-dependent response in the respective analyses. Our work here indicates that, unlike the individual miR upregulations, the combinatorial miR treatment remained advantageous, even under prolonged miR upregulation. Finally, our findings demonstrate potential advantages of miR combinations vs. individual miR treatments.

show abstract

Combination of miR‑143 and miR‑506 reduces lung and pancreatic cancer cell growth through the downregulation of cyclin‑dependent kinases

Cited by 9 publications

References 61 publications

Therapeutic miR-506-3p Replacement in Pancreatic Carcinoma Leads to Multiple Effects including Autophagy, Apoptosis, Senescence, and Mitochondrial Alterations In Vitro and In Vivo

Therapeutic miR-506-3p Replacement in Pancreatic Carcinoma Leads to Multiple Effects including Autophagy, Apoptosis, Senescence, and Mitochondrial Alterations In Vitro and In Vivo

SNHG16 lncRNAs are overexpressed and may be oncogenic in human gastric cancer by regulating cell cycle progression

Stable Dual miR-143 and miR-506 Upregulation Inhibits Proliferation and Cell Cycle Progression

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