Limits...
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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LincRNAs are dysregulated in bladder cancerA. Heat map representing unsupervised hierarchical clustering of mRNAs expression level in bladder cancer (BCa) tissues compared with adjacent non tumor (ANT) tissues. Each column represents the indicated tissue sample, and each row indicates one mRNA. Red color scale represents higher expression level and green color represents lower expression level. B. Heat map representing unsupervised hierarchical clustering of lincRNAs expression level in BCa tissues compared with ANT tissues. C. High resolution of the heat map showing AATBC expression in the microarray analysis. The red rectangular indicates the hybridization signal (replicate probes) of AATBC in BCa and ANT tissues. D. Genomic location of AATBC and its neighboring protein coding genes. E. Quantitative RT-PCR analysis of AATBC expression level in 90 cases of BCa relative to ANT tissues. Fold change of >1.5 is defined as overexpression (AATBC high), and the rest is indicated as AATBC low. F. The AATBC expression level in bladder cancer cell lines (UM-UC-3, T24, EJ, 5637) is higher than normal urothelium cell line SV-HUC-1.
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Figure 1: LincRNAs are dysregulated in bladder cancerA. Heat map representing unsupervised hierarchical clustering of mRNAs expression level in bladder cancer (BCa) tissues compared with adjacent non tumor (ANT) tissues. Each column represents the indicated tissue sample, and each row indicates one mRNA. Red color scale represents higher expression level and green color represents lower expression level. B. Heat map representing unsupervised hierarchical clustering of lincRNAs expression level in BCa tissues compared with ANT tissues. C. High resolution of the heat map showing AATBC expression in the microarray analysis. The red rectangular indicates the hybridization signal (replicate probes) of AATBC in BCa and ANT tissues. D. Genomic location of AATBC and its neighboring protein coding genes. E. Quantitative RT-PCR analysis of AATBC expression level in 90 cases of BCa relative to ANT tissues. Fold change of >1.5 is defined as overexpression (AATBC high), and the rest is indicated as AATBC low. F. The AATBC expression level in bladder cancer cell lines (UM-UC-3, T24, EJ, 5637) is higher than normal urothelium cell line SV-HUC-1.

Mentions: To investigate the potential biological functions of lincRNAs in bladder cancer, we firstly examined the expression pattern (fold changes ≥ 2 and ≤0.5, p < 0.05) of lincRNAs and mRNAs in matched sets of muscle invasive bladder cancer tissues and adjacent non tumor tissues obtained from 5 patients. We used a microarray targeting 1238 Entrez protein coding genes and 151 lincRNAs (Agilent), as previously reported[15]. Hierarchical clustering was applied to analyze the systematic variations of lincRNAs expression in these 5 paired tissue specimens. Altogether, 30 lincRNAs were found to be up regulated more than two-fold, while 121 lincRNAs were down regulated more than two-fold (p < 0.05, Fig. 1A–B) in the bladder cancer tissues compared to the adjacent non tumor tissues. The microarray analysis of the expression pattern of lincRNAs clearly implicated that many lincRNAs are linked with bladder cancer. Some of these lincRNAs may have potential functions in the regulation of tumorigenesis and progression of bladder cancer or serve as molecular biomarkers.


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)

LincRNAs are dysregulated in bladder cancerA. Heat map representing unsupervised hierarchical clustering of mRNAs expression level in bladder cancer (BCa) tissues compared with adjacent non tumor (ANT) tissues. Each column represents the indicated tissue sample, and each row indicates one mRNA. Red color scale represents higher expression level and green color represents lower expression level. B. Heat map representing unsupervised hierarchical clustering of lincRNAs expression level in BCa tissues compared with ANT tissues. C. High resolution of the heat map showing AATBC expression in the microarray analysis. The red rectangular indicates the hybridization signal (replicate probes) of AATBC in BCa and ANT tissues. D. Genomic location of AATBC and its neighboring protein coding genes. E. Quantitative RT-PCR analysis of AATBC expression level in 90 cases of BCa relative to ANT tissues. Fold change of >1.5 is defined as overexpression (AATBC high), and the rest is indicated as AATBC low. F. The AATBC expression level in bladder cancer cell lines (UM-UC-3, T24, EJ, 5637) is higher than normal urothelium cell line SV-HUC-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: LincRNAs are dysregulated in bladder cancerA. Heat map representing unsupervised hierarchical clustering of mRNAs expression level in bladder cancer (BCa) tissues compared with adjacent non tumor (ANT) tissues. Each column represents the indicated tissue sample, and each row indicates one mRNA. Red color scale represents higher expression level and green color represents lower expression level. B. Heat map representing unsupervised hierarchical clustering of lincRNAs expression level in BCa tissues compared with ANT tissues. C. High resolution of the heat map showing AATBC expression in the microarray analysis. The red rectangular indicates the hybridization signal (replicate probes) of AATBC in BCa and ANT tissues. D. Genomic location of AATBC and its neighboring protein coding genes. E. Quantitative RT-PCR analysis of AATBC expression level in 90 cases of BCa relative to ANT tissues. Fold change of >1.5 is defined as overexpression (AATBC high), and the rest is indicated as AATBC low. F. The AATBC expression level in bladder cancer cell lines (UM-UC-3, T24, EJ, 5637) is higher than normal urothelium cell line SV-HUC-1.
Mentions: To investigate the potential biological functions of lincRNAs in bladder cancer, we firstly examined the expression pattern (fold changes ≥ 2 and ≤0.5, p < 0.05) of lincRNAs and mRNAs in matched sets of muscle invasive bladder cancer tissues and adjacent non tumor tissues obtained from 5 patients. We used a microarray targeting 1238 Entrez protein coding genes and 151 lincRNAs (Agilent), as previously reported[15]. Hierarchical clustering was applied to analyze the systematic variations of lincRNAs expression in these 5 paired tissue specimens. Altogether, 30 lincRNAs were found to be up regulated more than two-fold, while 121 lincRNAs were down regulated more than two-fold (p < 0.05, Fig. 1A–B) in the bladder cancer tissues compared to the adjacent non tumor tissues. The microarray analysis of the expression pattern of lincRNAs clearly implicated that many lincRNAs are linked with bladder cancer. Some of these lincRNAs may have potential functions in the regulation of tumorigenesis and progression of bladder cancer or serve as molecular biomarkers.

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