miR-15a/miR-16 cluster inhibits invasion of prostate cancer cells by suppressing TGF-β signaling pathway

Jin, Wei; Chen, Fangjie; Wang, Kefeng; Song, Yan; Fei, Xiang; Wu, Bin

doi:10.1016/j.biopha.2018.05.041

Cited by 60 publications

(44 citation statements)

References 29 publications

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“…We previously showed that either miR‐16 or miR‐302/367 cluster can downregulate SMAD3 expression in MDA‐MB‐231 and SK‐BR‐3 cells . Bioinformatic analyses using several databases including TargetScan, miRTarBase, and TarBase and previous reports have shown that some TGF‐β signaling factors such as TGFBR3 , TGFB1 , SMAD2 , SMAD3 , SMURF1 , ACVR2a , and TGFBR2 are miR‐16 targets . However, other studies indicate that miR‐16 may upregulate TGFBR2 through repression of KLF14, which is a TGFBR2 inhibitor because KLF14 is also a miR‐16 target …”

Section: Discussionmentioning

confidence: 99%

“…21,54 Bioinformatic analyses using several databases including TargetScan, miRTarBase, and TarBase and previous reports have shown that some TGF-β signaling factors such as TGFBR3, TGFB1, SMAD2, SMAD3, SMURF1, ACVR2a, and TGFBR2 are miR-16 targets. 55 However, other studies indicate that miR-16 may upregulate TGFBR2 through repression of KLF14, which is a TGFBR2 inhibitor 56 because KLF14 is also a miR-16 target. 57 As previously reported miR-302 or miR-302/367 clusters target some of the cell cycle regulators and induces cell cycle arrest at in G1/G2 phases.…”

Section: Discussionmentioning

confidence: 99%

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miR‐16 enhances miR‐302/367‐induced reprogramming and tumor suppression in breast cancer cells

2020

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Overexpression of either miR‐302 or miR‐302/367 cluster induces reprogramming of cancer cells and exerts tumor‐suppressive effects by induction of mesenchymal‐to‐epithelial transition, apoptosis and a less proliferative capacity. Several reports have described miR‐16 as a tumor suppressor microRNA (miRNA). Here, we studied the impact of exogenous induction of miR‐16 in MDA‐MB‐231 and SK‐BR‐3 breast cancer cells following overexpression of miR‐302/367 cluster and investigated whether transfection of these cells by a mature miR‐16 mimic could affect the reprogramming state of the cells and their tumorigenicity. miR‐16 enhanced the expression levels of OCT4A, SOX2, and NANOG, generally known as transcription or pluripotency factors, and suppressed proliferation and invasiveness of these cells. Meanwhile, inhibition of miR‐16 counteracted both the reprogramming effect and the antitumor function of miR‐302/367 in the breast cancer cells. Current results indicate that miR‐16 can work as an adjuvant to improve both cancer cell reprogramming and tumor‐suppressive function of miR‐302/367 cluster in MDA‐MB‐231 and SK‐BR‐3 cells, while its inhibition counteracts all of these effects. Combined application of miRNAs that share some common targets in cancer cell signaling pathways may provide new approaches for repression of multiple hallmarks of cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

miR‐16 enhances miR‐302/367‐induced reprogramming and tumor suppression in breast cancer cells

2020

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“…The interplay between TGF-β signaling and miRNA activity in prostate cancer has been documented by multiple studies. miR-15a/16 target and downregulate expressions of SMAD3 and ACVR2A, resulting in attenuated expression of TGF-β dependent genes, including MMP2, E-cadherin, Snail, and Twist, and leading to inhibition of EMT and invasion of prostate cancer cells [304]. Prostate tumors overexpress the TR4 transcription regulator, which attenuates the expression of miR-373-3p, leading to enhanced invasion of prostate cancer cells.…”

Section: Prostate Cancermentioning

confidence: 99%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

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“…From our bioinformatics analysis, we found that miR-15a/16 could target PD-L1 mRNA with a high probability of conservation in SGC7901. Reports indicate that miR-15a/16 is a critical tumor suppressor and plays a crucial role in the regulation of tumor proliferation, invasiveness, metastasis and angiogenesis 19,38,39 . Regarding the role of miR-15a/16 in tumor suppression, previous studies have shown that miR-15a/16 inhibit tumorigenesis in chronic lymphocytic leukemia 40 .…”

Section: Discussionmentioning

confidence: 99%

Exosome-delivered miR-15a/16 target PD-L1 to inhibit immune escape in gastric cancer

Yang¹,

Zhang

Zhang³

et al. 2020

Preprint

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Background: The programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway plays crucial role in various types of cancer. However, the underlying mechanism of PD-L1 expression dysregulation in GC has not been revealed. High expression of PD-L1 and low expression of miR-15a/16 often leads to poor prognosis of gastric cancer, therefore PD-L1 was regarded as a key target for the treatment of gastric cancer. This study aims to determine whether exosomes with miR-15a/16 could target PD-L1 and inhibit immune escape in gastric cancer (GC).Methods: The protein expression levels of PD-L1 in tumor tissues and normal tissues of patients were evaluated by Western blot (WB) and immunohistochemistry (IHC), then confirmed that PD-L1 was a target of miR-15a/16 by luciferase reporter assay. HEK293T cells were transfected with miR-15a/16, exosomes were isolated by sequential differential centrifugation then cultured with gastric cancer cell lines, the protein and RNA levels of the PD-L1 were determined by western blotting and real-time qPCR. A mouse xenograft model was adopted to assess the association between exosome loaded miR-15a/16 and tumor growth in vivo. Flow cytometry was performed to analysis the effect of exo-miR-15a/16 on CD8+T lymphocytes and INFγ+ of mice.Results: We found that compared to adjacent noncancerous tissues, PD-L1 protein expression was significantly increased while miR-15a/16 expression level was significantly inhibited in tumor tissues. In addition, we found that miR-15a/16 mimics could downregulate PD-L1 expression, while miR-15a/16 inhibitors enhanced PD-L1 expression in human gastric cancer cell line SGC7901. Exo-miR-15a/16 could target PD-L1 and inhibit immune escape in gastric cancer.Conclusions: Our study confirmed that miR-15a/16 in exosomes could suppress tumor growth and inhibit immune escape by targeting PD-L1 in vivo and in vitro, which might serve as a potential biomarker in monitoring the activity of gastric cancer.

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miR-15a/miR-16 cluster inhibits invasion of prostate cancer cells by suppressing TGF-β signaling pathway

Cited by 60 publications

References 29 publications

miR‐16 enhances miR‐302/367‐induced reprogramming and tumor suppression in breast cancer cells

miR‐16 enhances miR‐302/367‐induced reprogramming and tumor suppression in breast cancer cells

TGF-β and microRNA Interplay in Genitourinary Cancers

Exosome-delivered miR-15a/16 target PD-L1 to inhibit immune escape in gastric cancer

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