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Knockdown of a novel lincRNA AATBC suppresses proliferation and induces apoptosis in bladder cancer.

Zhao F, Lin T, He W, Han J, Zhu D, Hu K, Li W, Zheng Z, Huang J, Xie W - Oncotarget (2015)

Bottom Line: We also found that inhibition of AATBC resulted in cell proliferation arrest through G1 cell cycle mediated by cyclin D1, CDK4, p18 and phosphorylated Rb.Furthermore, JNK inhibitor SP600125 could attenuate the apoptotic effect achieved by AATBC knockdown, confirming the involvement of JNK signaling in the induced apoptosis.Moreover, mouse xenograft model revealed that knockdown of AATBC led to suppress tumorigenesis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

ABSTRACT
Long intergenic noncoding RNAs (lincRNAs) play important roles in regulating various biological processes in cancer, including proliferation and apoptosis. However, the roles of lincRNAs in bladder cancer remain elusive. In this study, we identified a novel lincRNA, which we termed AATBC. We found that AATBC was overexpressed in bladder cancer patient tissues and positively correlated with tumor grade and pT stage. We also found that inhibition of AATBC resulted in cell proliferation arrest through G1 cell cycle mediated by cyclin D1, CDK4, p18 and phosphorylated Rb. In addition, inhibition of AATBC induced cell apoptosis through the intrinsic apoptosis signaling pathway, as evidenced by the activation of caspase-9 and caspase-3. The investigation for the signaling pathway revealed that the apoptosis following AATBC knockdown was mediated by activation of phosphorylated JNK and suppression of NRF2. Furthermore, JNK inhibitor SP600125 could attenuate the apoptotic effect achieved by AATBC knockdown, confirming the involvement of JNK signaling in the induced apoptosis. Moreover, mouse xenograft model revealed that knockdown of AATBC led to suppress tumorigenesis in vivo. Taken together, our study indicated that AATBC might play a critical role in pro-proliferation and anti-apoptosis in bladder cancer by regulating cell cycle, intrinsic apoptosis signaling, JNK signaling and NRF2. AATBC could be a potential therapeutic target and molecular biomarker for bladder cancer.

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Effect of AATBC knockdown on cell cycle arrestA. Flow cytometric analysis of cell cycle arrest 48 hours after treatment of siRNAs and negative controls in UM-UC-3 and EJ cells. Data represented as means ± SD (n = 3). *P < 0.05 (vs. control). B. Western blotting analysis of the expression of cell cycle-related proteins.
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Figure 3: Effect of AATBC knockdown on cell cycle arrestA. Flow cytometric analysis of cell cycle arrest 48 hours after treatment of siRNAs and negative controls in UM-UC-3 and EJ cells. Data represented as means ± SD (n = 3). *P < 0.05 (vs. control). B. Western blotting analysis of the expression of cell cycle-related proteins.

Mentions: For the purpose of better understanding the role of AATBC in proliferation, we employed the EdU incorporation assay to examine the effects of AATBC inhibition on the DNA synthesis during cell growth. The result showed that the proportion of S-phase cells (EdU-positive cells) was decreased in siRNA treated groups, suggesting reduced DNA synthetic activity resulted from AATBC depletion (Fig. 2D). Furthermore, we transfected the cancer cells with siRNAs before analyzing the impact on the cell cycle distribution by flow cytometry. Both UM-UC-3 and EJ cells treated with siRNAs show apparent increases in the percentage of cells in G1 phase with concomitant decreases in the percentage of cells in the S phase when compared with negative controls (Fig. 3A), which was consistent with EdU assay. These results proved that AATBC knockdown could lead to a cell cycle arrest in G1 phase, which was responsible for the suppressed proliferation.


Knockdown of a novel lincRNA AATBC suppresses proliferation and induces apoptosis in bladder cancer.

Zhao F, Lin T, He W, Han J, Zhu D, Hu K, Li W, Zheng Z, Huang J, Xie W - Oncotarget (2015)

Effect of AATBC knockdown on cell cycle arrestA. Flow cytometric analysis of cell cycle arrest 48 hours after treatment of siRNAs and negative controls in UM-UC-3 and EJ cells. Data represented as means ± SD (n = 3). *P < 0.05 (vs. control). B. Western blotting analysis of the expression of cell cycle-related proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359217&req=5

Figure 3: Effect of AATBC knockdown on cell cycle arrestA. Flow cytometric analysis of cell cycle arrest 48 hours after treatment of siRNAs and negative controls in UM-UC-3 and EJ cells. Data represented as means ± SD (n = 3). *P < 0.05 (vs. control). B. Western blotting analysis of the expression of cell cycle-related proteins.
Mentions: For the purpose of better understanding the role of AATBC in proliferation, we employed the EdU incorporation assay to examine the effects of AATBC inhibition on the DNA synthesis during cell growth. The result showed that the proportion of S-phase cells (EdU-positive cells) was decreased in siRNA treated groups, suggesting reduced DNA synthetic activity resulted from AATBC depletion (Fig. 2D). Furthermore, we transfected the cancer cells with siRNAs before analyzing the impact on the cell cycle distribution by flow cytometry. Both UM-UC-3 and EJ cells treated with siRNAs show apparent increases in the percentage of cells in G1 phase with concomitant decreases in the percentage of cells in the S phase when compared with negative controls (Fig. 3A), which was consistent with EdU assay. These results proved that AATBC knockdown could lead to a cell cycle arrest in G1 phase, which was responsible for the suppressed proliferation.

Bottom Line: We also found that inhibition of AATBC resulted in cell proliferation arrest through G1 cell cycle mediated by cyclin D1, CDK4, p18 and phosphorylated Rb.Furthermore, JNK inhibitor SP600125 could attenuate the apoptotic effect achieved by AATBC knockdown, confirming the involvement of JNK signaling in the induced apoptosis.Moreover, mouse xenograft model revealed that knockdown of AATBC led to suppress tumorigenesis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

ABSTRACT
Long intergenic noncoding RNAs (lincRNAs) play important roles in regulating various biological processes in cancer, including proliferation and apoptosis. However, the roles of lincRNAs in bladder cancer remain elusive. In this study, we identified a novel lincRNA, which we termed AATBC. We found that AATBC was overexpressed in bladder cancer patient tissues and positively correlated with tumor grade and pT stage. We also found that inhibition of AATBC resulted in cell proliferation arrest through G1 cell cycle mediated by cyclin D1, CDK4, p18 and phosphorylated Rb. In addition, inhibition of AATBC induced cell apoptosis through the intrinsic apoptosis signaling pathway, as evidenced by the activation of caspase-9 and caspase-3. The investigation for the signaling pathway revealed that the apoptosis following AATBC knockdown was mediated by activation of phosphorylated JNK and suppression of NRF2. Furthermore, JNK inhibitor SP600125 could attenuate the apoptotic effect achieved by AATBC knockdown, confirming the involvement of JNK signaling in the induced apoptosis. Moreover, mouse xenograft model revealed that knockdown of AATBC led to suppress tumorigenesis in vivo. Taken together, our study indicated that AATBC might play a critical role in pro-proliferation and anti-apoptosis in bladder cancer by regulating cell cycle, intrinsic apoptosis signaling, JNK signaling and NRF2. AATBC could be a potential therapeutic target and molecular biomarker for bladder cancer.

Show MeSH
Related in: MedlinePlus