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

Zheng G, Jia X, Peng C, Deng Y, Yin J, Zhang Z, Li N, Deng M, Liu X, Liu H, Lu M, Wang C, Gu Y, He Z - Oncotarget (2015)

Bottom Line: We found that levels of miR-491-3p were decreased in multidrug-resistant tongue cancer (TC) cells.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.Levels of miR-491-3 and Rictor or mTORC2 activity negatively correlated in TC tissues.

View Article: PubMed Central - PubMed

Affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.

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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Related in: MedlinePlus

miR-491-3p sensitized tongue cancer cells to chemotherapy(A) overexpressed miR-491-3p via transfection of miR-491-3p mimics sensitized Tca8113/PYM cells to PYM and cDDP, detected by MTS assay to determing proliferation and hochest stain to determining apoptosis respectively. (B–D) functional inhibition of miR-491-3p with specific inhibitor attenuated the sensitivity of Tca8113, SCC-25 and CAL-27 cell lines to PYM and cDDP, detected by MTS assay and hochest stain respectively.
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Figure 2: miR-491-3p sensitized tongue cancer cells to chemotherapy(A) overexpressed miR-491-3p via transfection of miR-491-3p mimics sensitized Tca8113/PYM cells to PYM and cDDP, detected by MTS assay to determing proliferation and hochest stain to determining apoptosis respectively. (B–D) functional inhibition of miR-491-3p with specific inhibitor attenuated the sensitivity of Tca8113, SCC-25 and CAL-27 cell lines to PYM and cDDP, detected by MTS assay and hochest stain respectively.

Mentions: MiR-491-3p expression was significantly down regulated in the chemo-resistant Tca8113/PYM cells. To investigate whether the reduction of miR-491-3p played a causal role in the development of drug resistance, we used a gain- or loss-of-function approach in a series of tongue cancer cell lines. As shown in Figure 1C, miR-491-3p expression was relatively higher in chemo-sensitive SCC-25 and CAL-27 tongue cancer cell lines than that in Tca8113/PYM cells. Increased miR-491-3p via transfection of miR-491-3p mimics significantly enhanced the sensitivity of Tca8113/PYM cells to PYM- and cDDP-induced growth inhibition and apoptosis (Figure 2A). Inversely, the sensitivity of Tca8113 (Figure 2B), SCC-25 (Figure 2C) and CAL-27 (Figure 2D) cells to PYM or cDDP was dramatically decreased upon inhibition of miR-491-3p with specific inhibitor, accompanied with reduced apoptosis-induced by PYM or cDDP.


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

Zheng G, Jia X, Peng C, Deng Y, Yin J, Zhang Z, Li N, Deng M, Liu X, Liu H, Lu M, Wang C, Gu Y, He Z - Oncotarget (2015)

miR-491-3p sensitized tongue cancer cells to chemotherapy(A) overexpressed miR-491-3p via transfection of miR-491-3p mimics sensitized Tca8113/PYM cells to PYM and cDDP, detected by MTS assay to determing proliferation and hochest stain to determining apoptosis respectively. (B–D) functional inhibition of miR-491-3p with specific inhibitor attenuated the sensitivity of Tca8113, SCC-25 and CAL-27 cell lines to PYM and cDDP, detected by MTS assay and hochest stain respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466660&req=5

Figure 2: miR-491-3p sensitized tongue cancer cells to chemotherapy(A) overexpressed miR-491-3p via transfection of miR-491-3p mimics sensitized Tca8113/PYM cells to PYM and cDDP, detected by MTS assay to determing proliferation and hochest stain to determining apoptosis respectively. (B–D) functional inhibition of miR-491-3p with specific inhibitor attenuated the sensitivity of Tca8113, SCC-25 and CAL-27 cell lines to PYM and cDDP, detected by MTS assay and hochest stain respectively.
Mentions: MiR-491-3p expression was significantly down regulated in the chemo-resistant Tca8113/PYM cells. To investigate whether the reduction of miR-491-3p played a causal role in the development of drug resistance, we used a gain- or loss-of-function approach in a series of tongue cancer cell lines. As shown in Figure 1C, miR-491-3p expression was relatively higher in chemo-sensitive SCC-25 and CAL-27 tongue cancer cell lines than that in Tca8113/PYM cells. Increased miR-491-3p via transfection of miR-491-3p mimics significantly enhanced the sensitivity of Tca8113/PYM cells to PYM- and cDDP-induced growth inhibition and apoptosis (Figure 2A). Inversely, the sensitivity of Tca8113 (Figure 2B), SCC-25 (Figure 2C) and CAL-27 (Figure 2D) cells to PYM or cDDP was dramatically decreased upon inhibition of miR-491-3p with specific inhibitor, accompanied with reduced apoptosis-induced by PYM or cDDP.

Bottom Line: We found that levels of miR-491-3p were decreased in multidrug-resistant tongue cancer (TC) cells.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.Levels of miR-491-3 and Rictor or mTORC2 activity negatively correlated in TC tissues.

View Article: PubMed Central - PubMed

Affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.

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.

Show MeSH
Related in: MedlinePlus