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Long non-coding RNA UCA1 promotes glycolysis by upregulating hexokinase 2 through the mTOR-STAT3/microRNA143 pathway.

Li Z, Li X, Wu S, Xue M, Chen W - Cancer Sci. (2014)

Bottom Line: Emerging evidence has shown that long non-coding RNAs (lncRNAs) act as key regulators of multiple cancers.In this study, we show that lncRNA UCA1 promotes glycolysis in bladder cancer cells, and that UCA1-induced hexokinase 2 (HK2) functions as an important mediator in this process.We further show that UCA1 activates mTOR to regulate HK2 through both activation of STAT3 and repression of microRNA143.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Medicine, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.

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(a, b) Long non-coding RNA UCA1 induces hexokinase 2 (HK2) mRNA expression through the mTOR–STAT3 pathway in stable bladder cancer cells. Western blot analysis of p-STAT3 protein levels in UMUC-2 cells transfected with pcDNA3.1/UCA1 (pcDNA-U) or pcDNA3.1/Mock (pcDNA-M) plasmids and 5637 cells transfected with pRNAT-U6.1/Neo-shUCA (pRNAT-U) and pRNAT-U6.1/Neo-Nc (pRNAT-N) plasmids. (a) Overexpression of UCA1. (b) Knockdown of UCA1. (c, f) Quantitative PCR analysis of HK2 mRNA levels in pcDNA-U cells. (c) Cells were treated with rapamycin or DMSO. (f) Cells were transfected with STAT3 siRNA or negative control (NC). (d, e, g, h) Glucose consumption and lactate production analysis in pcDNA-U cells. (d, e) Cells were treated with rapamycin or DMSO. (g, h) Cells were transfected with STAT3 siRNA or NC. The average values ± SD of three separate experiments were plotted. *P < 0.05.
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fig03: (a, b) Long non-coding RNA UCA1 induces hexokinase 2 (HK2) mRNA expression through the mTOR–STAT3 pathway in stable bladder cancer cells. Western blot analysis of p-STAT3 protein levels in UMUC-2 cells transfected with pcDNA3.1/UCA1 (pcDNA-U) or pcDNA3.1/Mock (pcDNA-M) plasmids and 5637 cells transfected with pRNAT-U6.1/Neo-shUCA (pRNAT-U) and pRNAT-U6.1/Neo-Nc (pRNAT-N) plasmids. (a) Overexpression of UCA1. (b) Knockdown of UCA1. (c, f) Quantitative PCR analysis of HK2 mRNA levels in pcDNA-U cells. (c) Cells were treated with rapamycin or DMSO. (f) Cells were transfected with STAT3 siRNA or negative control (NC). (d, e, g, h) Glucose consumption and lactate production analysis in pcDNA-U cells. (d, e) Cells were treated with rapamycin or DMSO. (g, h) Cells were transfected with STAT3 siRNA or NC. The average values ± SD of three separate experiments were plotted. *P < 0.05.

Mentions: Our previous studies showed that UCA1 played a pivotal role in bladder cancer progression by activating the PI3K–Akt–mTOR pathway.(13) In addition, a recent study showed that STAT3 is a direct transcriptional activator for HK2.(21) Taking into account that STAT3 is a known downstream effector of mTOR,(22,23) we speculated that the UCA1 upregulated HK2 through activation of mTOR–STAT3 signaling. As expected, we found that the phosphorylation of STAT3 was positively related to UCA1 in stable cell lines (Fig. 3a,b). Furthermore, HK2 mRNA levels were reduced by rapamycin (Fig. 3c), whereas knockdown of STAT3 completely abolished the induction of HK2 transcript levels (Fig. 3f). Consistent with an important role of the mTOR–STAT3 pathway in mediating the upregulation of HK2 transcription by UCA1, we found that the rates of glucose consumption and lactate production were significantly decreased by rapamycin or STAT3 siRNA (Fig. 3d,e,g,h). Collectively, these results reveal that UCA1 promotes HK2 mRNA transcription through activation of the mTOR–STAT3 pathway.


Long non-coding RNA UCA1 promotes glycolysis by upregulating hexokinase 2 through the mTOR-STAT3/microRNA143 pathway.

Li Z, Li X, Wu S, Xue M, Chen W - Cancer Sci. (2014)

(a, b) Long non-coding RNA UCA1 induces hexokinase 2 (HK2) mRNA expression through the mTOR–STAT3 pathway in stable bladder cancer cells. Western blot analysis of p-STAT3 protein levels in UMUC-2 cells transfected with pcDNA3.1/UCA1 (pcDNA-U) or pcDNA3.1/Mock (pcDNA-M) plasmids and 5637 cells transfected with pRNAT-U6.1/Neo-shUCA (pRNAT-U) and pRNAT-U6.1/Neo-Nc (pRNAT-N) plasmids. (a) Overexpression of UCA1. (b) Knockdown of UCA1. (c, f) Quantitative PCR analysis of HK2 mRNA levels in pcDNA-U cells. (c) Cells were treated with rapamycin or DMSO. (f) Cells were transfected with STAT3 siRNA or negative control (NC). (d, e, g, h) Glucose consumption and lactate production analysis in pcDNA-U cells. (d, e) Cells were treated with rapamycin or DMSO. (g, h) Cells were transfected with STAT3 siRNA or NC. The average values ± SD of three separate experiments were plotted. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4317864&req=5

fig03: (a, b) Long non-coding RNA UCA1 induces hexokinase 2 (HK2) mRNA expression through the mTOR–STAT3 pathway in stable bladder cancer cells. Western blot analysis of p-STAT3 protein levels in UMUC-2 cells transfected with pcDNA3.1/UCA1 (pcDNA-U) or pcDNA3.1/Mock (pcDNA-M) plasmids and 5637 cells transfected with pRNAT-U6.1/Neo-shUCA (pRNAT-U) and pRNAT-U6.1/Neo-Nc (pRNAT-N) plasmids. (a) Overexpression of UCA1. (b) Knockdown of UCA1. (c, f) Quantitative PCR analysis of HK2 mRNA levels in pcDNA-U cells. (c) Cells were treated with rapamycin or DMSO. (f) Cells were transfected with STAT3 siRNA or negative control (NC). (d, e, g, h) Glucose consumption and lactate production analysis in pcDNA-U cells. (d, e) Cells were treated with rapamycin or DMSO. (g, h) Cells were transfected with STAT3 siRNA or NC. The average values ± SD of three separate experiments were plotted. *P < 0.05.
Mentions: Our previous studies showed that UCA1 played a pivotal role in bladder cancer progression by activating the PI3K–Akt–mTOR pathway.(13) In addition, a recent study showed that STAT3 is a direct transcriptional activator for HK2.(21) Taking into account that STAT3 is a known downstream effector of mTOR,(22,23) we speculated that the UCA1 upregulated HK2 through activation of mTOR–STAT3 signaling. As expected, we found that the phosphorylation of STAT3 was positively related to UCA1 in stable cell lines (Fig. 3a,b). Furthermore, HK2 mRNA levels were reduced by rapamycin (Fig. 3c), whereas knockdown of STAT3 completely abolished the induction of HK2 transcript levels (Fig. 3f). Consistent with an important role of the mTOR–STAT3 pathway in mediating the upregulation of HK2 transcription by UCA1, we found that the rates of glucose consumption and lactate production were significantly decreased by rapamycin or STAT3 siRNA (Fig. 3d,e,g,h). Collectively, these results reveal that UCA1 promotes HK2 mRNA transcription through activation of the mTOR–STAT3 pathway.

Bottom Line: Emerging evidence has shown that long non-coding RNAs (lncRNAs) act as key regulators of multiple cancers.In this study, we show that lncRNA UCA1 promotes glycolysis in bladder cancer cells, and that UCA1-induced hexokinase 2 (HK2) functions as an important mediator in this process.We further show that UCA1 activates mTOR to regulate HK2 through both activation of STAT3 and repression of microRNA143.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Medicine, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.

Show MeSH
Related in: MedlinePlus