Dataset Information

MiR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer.

ABSTRACT: Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, investigation about molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The molecular mechanisms responsible for the chemoresistance of cervical cancer were investigated by the use of doxorubicin (Dox)-resistant HeLa/Dox and SiHa/Dox cells. Our data showed that chemoresistant cells exhibited significantly higher glucose consumption, lactate production rate, and ATP levels than that of their parental cells. Among metabolic and glycolytic related genes, the expression of PDK4 was upregulated in Dox-resistant cells. Knockdown of PDK4 can decrease glucose consumption, lactate production rate, and ATP levels and further sensitize resistant cervical cancer cells to Dox treatment. By screening microRNAs (miRNAs), which can regulate expression of PDK4, we found that miR-16-5p was downregulated in chemoresistant cells. Overexpression of miR-16-5p can decrease the expression of PDK4 and sensitize the resistant cells to Dox treatment. Xenograft models confirmed that knockdown of PDK4 can increase chemotherapy efficiency for in vivo tumor growth. Collectively, our data suggested that miR-16-5p/PDK4-mediated metabolic reprogramming is involved in chemoresistance of cervical cancer.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC7301169 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer.

Zhao Zhao Z Ji Mei M Wang Qianqing Q He Nannan N Li Yue Y

Molecular therapy oncolytics 20200523

Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, investigation about molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The molecular mechanisms responsible for the chemoresistance of cervical cancer were investigated by the use of doxorubicin (Dox)-resistant HeLa/Dox and SiHa/Dox cells. Our data showed that chemoresistant cells exhibited significantly higher glucose consumption, lactate production rate, and ATP levels t ...[more]

PMID: 32577500

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Project description:Neuroblastoma (NB) is the most common extracranial solid malignancy in children. Despite current aggressive treatment regimens, the prognosis for high-risk NB patients remains poor, with the survival of less than 40%. Amplification/stabilization of MYCN oncogene, in NB is associated with a high risk of recurrence. Thus, there is an urgent need for novel therapeutics. The deregulated expression of microRNA (miR) is reported in NB; nonetheless, its effect on MYCN regulation is poorly understood. First, we identified that miR-15a-5p, miR-15b-5p, and miR-16-5p (hereafter miR-15a, miR-15b or miR-16) were down-regulated in patient-derived xenografts (PDX) with high MYCN expression. MiR targeting sequences on MYCN mRNA were predicted using online databases such as TargetScan and miR database. The R2 database, containing 105 NB patients, showed an inverse correlation between MYCN mRNA and deleted in lymphocytic leukemia (DLEU) 2, a host gene of miR-15. Moreover, overexpression of miR-15a, miR-15b or miR-16 significantly reduced the levels of MYCN mRNA and N-Myc protein. Conversely, inhibiting miR dramatically enhanced MYCN mRNA and N-Myc protein levels, as well as increasing mRNA half-life in NB cells. By performing immunoprecipitation assays of argonaute-2 (Ago2), a core component of the RNA-induced silencing complex, we showed that miR-15a, miR-15b and miR-16 interact with MYCN mRNA. Luciferase reporter assays showed that miR-15a, miR-15b and miR-16 bind with 3'UTR of MYCN mRNA, resulting in MYCN suppression. Moreover, induced expression of miR-15a, miR-15b and miR-16 significantly reduced the proliferation, migration, and invasion of NB cells. Finally, transplanting miR-15a-, miR-15b- and miR-16-expressing NB cells into NSG mice repressed tumor formation and MYCN expression. These data suggest that miR-15a, miR-15b and miR-16 exert a tumor-suppressive function in NB by targeting MYCN. Therefore, these miRs could be considered as potential targets for NB treatment.

Dataset Information

MiR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer.

Publications

miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer.

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