Dataset Information

MicroRNA-3648 Is Upregulated to Suppress TCF21, Resulting in Promotion of Invasion and Metastasis of Human Bladder Cancer.

ABSTRACT: Although microRNAs (miRNAs) are well-known for their potential in cancer, the function and mechanisms of miR-3648 have barely been explored in any type of cancer. We show here that miR-3648 is upregulated in human BC tissues in comparison with adjacent non-tumor tissues. Functional studies showed that inhibition of miR-3648 expression in the human invasive BC UMUC3 and T24T cell lines decreased migration and invasion in vitro and suppressed lung metastasis in vivo, whereas miR-3648 overexpression promoted BC cell migration and invasion. A bioinformatics screen and mRNA 3' UTR luciferase reporter assay showed that transcription factor 21 (TCF21) was a direct target of miR-3648, and the results obtained from using a miR-3648 inhibitor revealed that miR-3648 inhibited TCF21 protein expression by reduction of its mRNA stability. Further, Kisspeptin 1 (KISS1) was identified as a TCF21 downstream effector responsible for miR-3648-mediated BC invasion and lung metastasis. Collectively, the present results suggest that miR-3648 is overexpressed and plays an oncogenic role in mediation of BC invasion and metastasis through directing the TCF21/KISS1 axis, revealing miR-3648 as a potential biomarker for BC prognosis and a target for BC therapy.

SUBMITTER: Sun W

PROVIDER: S-EPMC6506626 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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MicroRNA-3648 Is Upregulated to Suppress TCF21, Resulting in Promotion of Invasion and Metastasis of Human Bladder Cancer.

Sun Wenrui W Li Shi S Yu Yuan Y Jin Honglei H Xie Qipeng Q Hua Xiaohui X Wang Shuai S Tian Zhongxian Z Zhang Huxiang H Jiang Guosong G Huang Chuanshu C Huang Haishan H

Molecular therapy. Nucleic acids 20190414

Although microRNAs (miRNAs) are well-known for their potential in cancer, the function and mechanisms of miR-3648 have barely been explored in any type of cancer. We show here that miR-3648 is upregulated in human BC tissues in comparison with adjacent non-tumor tissues. Functional studies showed that inhibition of miR-3648 expression in the human invasive BC UMUC3 and T24T cell lines decreased migration and invasion in vitro and suppressed lung metastasis in vivo, whereas miR-3648 overexpressio ...[more]

PMID: 31071528

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Project description:BackgroundMetformin, a traditional first-line anti-hyperglycemic agent for diabetes, recently exhibits better antitumor effect in hepatocellular carcinoma (HCC). However, its resistance and tolerance mechanism in HCC remains largely unknown. Here, we investigated whether increased matrix stiffness attenuated the intervention effects of metformin on HCC invasion and metastasis, and explored its underlying molecular mechanism.MethodsFN-coated gel substrates with 6, 10, and 16 kPa, which simulated the stiffness of normal, fibrotic, and cirrhotic liver tissues respectively, were established to evaluate matrix stiffness-mediated effects on HCC cells. Alterations in morphology, proliferation, motility, and invasive/metastatic-associated genes (PTEN, MMP2, MMP9) of HCC cells grown on different-stiffness substrates were comparatively analyzed before and after metformin intervention. Subsequently, the underlying molecular mechanism by which higher matrix stiffness attenuates antitumor effects of metformin in HCC was further elucidated.ResultsMetformin significantly inhibited proliferation, migration, and invasion of HCC cells. Compared with the controls on lower-stiffness substrate, HCC cells grown on higher-stiffness substrate exhibited an obvious resistance to intervention effects of metformin on proliferation, migration, invasion and metastasis. High stiffness stimulation significantly activated the miR-17-5p/PTEN/PI3K/Akt signaling pathway in HCC cells via integrin β1 and in turn resulted in MMP2 and MMP9 upregulation. Meanwhile, integrin β1 knockdown or PI3K inhibitor partially reversed the activation of the above signaling molecules. For HCC cells grown on the same-stiffness substrate, metformin remarkably upregulated PTEN expression and suppressed the activation of the PI3K/Akt/MMP pathway, but no effect on integrin β1 expression. Importantly, the increase in fold of PTEN expression and decrease in folds of Akt phosphorylation level and MMP2 and MMP9 expressions in the treated HCC cells with metformin on 16-kPa stiffness substrate were evidently weakened compared with those in the controls on the 6-kPa stiffness substrate.ConclusionsIncreased matrix stiffness significantly attenuates the inhibitory effect of metformin on HCC invasion and metastasis, and a common pathway of PTEN/PI3K/Akt/MMPs activated by mechanical stiffness signal and inactivated by metformin contributes to matrix stiffness-caused metformin resistance. To the best of our knowledge, this is the first report to clarify the mechanism of metformin intervention resistance from the perspective of tumor biophysical microenvironment.

Dataset Information

MicroRNA-3648 Is Upregulated to Suppress TCF21, Resulting in Promotion of Invasion and Metastasis of Human Bladder Cancer.

Publications

MicroRNA-3648 Is Upregulated to Suppress TCF21, Resulting in Promotion of Invasion and Metastasis of Human Bladder Cancer.

Similar Datasets

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