The miR-491-3p/mTORC2/FOXO1 regulatory loop modulates chemo-sensitivity in human tongue cancer

Oncotarget
Guopei ZhengZhimin He

Abstract

We found that levels of miR-491-3p were decreased in multidrug-resistant tongue cancer (TC) cells. Induction of miR-491-3p expression sensitized TC cells to chemotherapy. In agreement, functional inhibition of miR-491-3p enhanced resistance of TC cells to chemotherapy. We found that miR-491-3p directly targeted mTORC2 component Rictor and inhibited mTORC2 activity, which was increased in resistant TC cells with high p-Akt(Ser473), p-SGK1(Ser422) and p-FOXO1(Thr24) levels. Inhibition of mTORC2 activity via either Rictor knockdown or mTOR inhibitor in turn sensitized TC cells to chemotherapy. In agreement, overexpression of Rictor increased the mTORC2 activity and induced resistance of TC cells to chemotherapy. As a feedback loop, mTORC2 downregulated miR-491-3p expression by inactivating FOXO1, which otherwise would transcriptionally induce miR-491-3p expression. Levels of miR-491-3 and Rictor or mTORC2 activity negatively correlated in TC tissues. Finally, low levels of miR-491-3p and highly expressed Rictor were associated with poor prognosis in tongue cancer patients. These data provide a rationale for targeted intervention on miR-491-3p/mTORC2 axis to enhance the efficacy of chemotherapy against tongue cancer.

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Citations

Aug 30, 2017·Molecular Medicine Reports·Junhu DuanLonghua Rao
Oct 24, 2017·BioMed Research International·Lin-Lin WangShui-Long Guo
Jun 29, 2016·Oncology Reports·Ye-Gong XieXu-Chen Cao
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Feb 12, 2020·Molecular Medicine·Deze ZhaoHelei Hou
Jun 17, 2021·Molecular Biology Reports·M Janaki Ramaiah, K Rohil Kumar

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Methods Mentioned

BETA
transfection
PCR
Assay
Protein Assay
electrophoresis
immunoprecipitation
ChIP

Software Mentioned

SPSS
Exiqon
JASPAR

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