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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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AATBC knockdown inhibited tumorigenesis by bladder cancer cells in vivoA. AATBC expression level was evaluated by quantitative RT-PCR in UM-UC-3 after transfection with shRNAs and negative controls. Means ± SD were shown (n = 3) *P < 0.05 (vs. control). B-C. Images of tumorigenesis assay performed in NOD/SCID mice. D. Histological analysis of tumor weight in control and AATBC stable knockdown group (Student's t-test, P<0.05). Means ± SD were shown (n = 4). * P < 0.05 (vs. control).
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Figure 4: AATBC knockdown inhibited tumorigenesis by bladder cancer cells in vivoA. AATBC expression level was evaluated by quantitative RT-PCR in UM-UC-3 after transfection with shRNAs and negative controls. Means ± SD were shown (n = 3) *P < 0.05 (vs. control). B-C. Images of tumorigenesis assay performed in NOD/SCID mice. D. Histological analysis of tumor weight in control and AATBC stable knockdown group (Student's t-test, P<0.05). Means ± SD were shown (n = 4). * P < 0.05 (vs. control).

Mentions: To investigate the biological significance of AATBC knockdown on tumor growth in vivo, we proceeded with the research through the establishment of a subcutaneous xenograft tumor model in NOD/SCID mice. Firstly, Stable AATBC-knockdown in UM-UC-3 cells by lentiviral-mediated RNAi system was successfully established. Quantitative RT-PCR analysis confirmed that the lentivirus-transduced UM-UC-3 cells showed a significant decrease of AATBC in transcript levels. The inhibition efficiency was 79.3% ± 3.1% (Fig. 4A). Equal numbers of UM-UC-3 cells (5×106, per mice) stably expressing AATBC shRNA and negative control were injected subcutaneously into the flanks of NOD/SCID mice (n=4) (Fig. 4B). As expected, suppression of AATBC expression in UM-UC-3 cells treated with shRNA resulted in lower mean tumor mass compared to that of negative control group (0.36 g vs 1.085 g, P<0.05, Fig. 4C-D). The results in vivo indicated that the growth of xenografts was inhibited by AATBC shRNA treatment in UM-UC-3. This response of tumors to AATBC stable depletion revealed that AATBC might have tumor-promoting property in the carcinogenesis and progression of bladder cancer in vivo.


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)

AATBC knockdown inhibited tumorigenesis by bladder cancer cells in vivoA. AATBC expression level was evaluated by quantitative RT-PCR in UM-UC-3 after transfection with shRNAs and negative controls. Means ± SD were shown (n = 3) *P < 0.05 (vs. control). B-C. Images of tumorigenesis assay performed in NOD/SCID mice. D. Histological analysis of tumor weight in control and AATBC stable knockdown group (Student's t-test, P<0.05). Means ± SD were shown (n = 4). * P < 0.05 (vs. control).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4359217&req=5

Figure 4: AATBC knockdown inhibited tumorigenesis by bladder cancer cells in vivoA. AATBC expression level was evaluated by quantitative RT-PCR in UM-UC-3 after transfection with shRNAs and negative controls. Means ± SD were shown (n = 3) *P < 0.05 (vs. control). B-C. Images of tumorigenesis assay performed in NOD/SCID mice. D. Histological analysis of tumor weight in control and AATBC stable knockdown group (Student's t-test, P<0.05). Means ± SD were shown (n = 4). * P < 0.05 (vs. control).
Mentions: To investigate the biological significance of AATBC knockdown on tumor growth in vivo, we proceeded with the research through the establishment of a subcutaneous xenograft tumor model in NOD/SCID mice. Firstly, Stable AATBC-knockdown in UM-UC-3 cells by lentiviral-mediated RNAi system was successfully established. Quantitative RT-PCR analysis confirmed that the lentivirus-transduced UM-UC-3 cells showed a significant decrease of AATBC in transcript levels. The inhibition efficiency was 79.3% ± 3.1% (Fig. 4A). Equal numbers of UM-UC-3 cells (5×106, per mice) stably expressing AATBC shRNA and negative control were injected subcutaneously into the flanks of NOD/SCID mice (n=4) (Fig. 4B). As expected, suppression of AATBC expression in UM-UC-3 cells treated with shRNA resulted in lower mean tumor mass compared to that of negative control group (0.36 g vs 1.085 g, P<0.05, Fig. 4C-D). The results in vivo indicated that the growth of xenografts was inhibited by AATBC shRNA treatment in UM-UC-3. This response of tumors to AATBC stable depletion revealed that AATBC might have tumor-promoting property in the carcinogenesis and progression of bladder cancer in vivo.

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