lncRNA Up-Regulated in Nonmuscle Invasive Bladder Cancer Facilitates Tumor Growth and Acts as a Negative Prognostic Factor of Recurrence.

While lncRNAs (long noncoding RNAs) have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle invasive bladder cancer remain largely unknown. We identified a lncRNA termed lncRNA-UNMIBC (up-regulated in nonmuscle invasive bladder cancer) and evaluated its prognostic value in patients with primary nonmuscle invasive bladder cancer. We analyzed the expression of lncRNA-UNMIBC in the tissues of 75 cases of primary nonmuscle invasive bladder cancer and adjacent normal mucosa by quantitative real-time polymerase chain reaction. Data were compared with clinicopathological parameters using the Kaplan-Meier method and multivariate Cox regression analysis. The functions of lncRNA-UNMIBC were assessed by silencing the lncRNA in vitro and in vivo. RNA immunoprecipitation was performed to assay whether lncRNA-UNMIBC could be physically associated with EZH2 (enhancer of zeste homolog 2) and SUZ12 (SUZ12 polycomb repressive complex 2 subunit), which are core components of PRC2 (polycomb repressive complex 2). Chromatin immunoprecipitation was done to examine histone modification status. The expression level of lncRNA-UNMIBC was up-regulated in the tissues of 45 cases of primary nonmuscle invasive bladder cancer compared with normal mucosa. Kaplan-Meier estimates showed that lncRNA-UNMIBC expression was significantly associated with recurrence (log rank test p = 0.0151). We also found that lncRNA-UNMIBC had a key role in G0/G1 arrest. Furthermore, RNA and chromatin immunoprecipitation assays demonstrated that lncRNA-UNMIBC was physically associated with EZH2 and SUZ12, leading to an altered histone H3 lysine 27 methylation status of target genes. These findings indicate that lncRNA-UNMIBC can facilitate tumor growth and may act as a negative prognostic factor of recurrence.

Zhang S ，Zhong G ，He W ，Yu H ，Huang J ，Lin T ... -  《-》

linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer.

The human genome encodes many long intergenic noncoding RNAs (lincRNAs). However, their biological functions, molecular mechanisms and prognostic values associated with bladder cancer remain to be elucidated. Here we investigated a lincRNA termed linc-UBC1 (Up-regulated in bladder cancer 1) and evaluated its prognostic value in bladder cancer patients. Expression of linc-UBC1 was evaluated by quantitative reverse transcription PCR (qRT-PCR) in 102 bladder cancer tissue samples and normal adjacent tissues. The functions of linc-UBC1 on cell proliferation, migration, invasion, colony formation, tumorigenicity and metastatic potential were evaluated by knockdown strategy in vitro and in vivo. RNA immunoprecipitation (RIP) was performed to confirm that linc-UBC1 physically associates with EZH2 and SUZ12, core components of polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation (ChIP) was conducted to examine histone modification status. qRT-PCR confirmed that linc-UBC1 expression is up-regulated in 60 cases (58.8%) in bladder cancer tissues compared with normal adjacent tissues, and its overexpression correlates with lymph node metastasis and poor survival. Further functional analysis demonstrated that knockdown of linc-UBC1 attenuates bladder cancer cell proliferation, motility, invasion, colony formation ability, tumorigenicity and metastatic potential. Importantly, the inhibitory effect of linc-UBC1 on cell proliferation was also observed in primary bladder cancer cells obtained from patients. RIP and ChIP assay confirmed that linc-UBC1 physically associates with PRC2 complex and regulates histone modification status of target genes. Frequently overexpressed linc-UBC1 physically associates with PRC2 complex, and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer.

He W ，Cai Q ，Sun F ，Zhong G ，Wang P ，Liu H ，Luo J ，Yu H ，Huang J ，Lin T ... -  《-》

Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans.

In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain largely unknown. Differentially expressed lncRNAs between HBV-related HCC and paired peritumoral tissues were identified by microarray and validated using quantitative real-time polymerase chain reaction. Liver samples from patients with HBV-related HCC were analyzed for levels of a specific differentially expressed lncRNA High Expression In HCC (termed lncRNA-HEIH); data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. The effects of lncRNA-HEIH were assessed by silencing and overexpressing the lncRNA in vitro and in vivo. The expression level of lncRNA-HEIH in HBV-related HCC is significantly associated with recurrence and is an independent prognostic factor for survival. We also found that lncRNA-HEIH plays a key role in G(0) /G(1) arrest, and further demonstrated that lncRNA-HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of EZH2 target genes. Together, these results indicate that lncRNA-HEIH is an oncogenic lncRNA that promotes tumor progression and leads us to propose that lncRNAs may serve as key regulatory hubs in HCC progression.

Yang F ，Zhang L ，Huo XS ，Yuan JH ，Xu D ，Yuan SX ，Zhu N ，Zhou WP ，Yang GS ，Wang YZ ，Shang JL ，Gao CF ，Zhang FR ，Wang F ，Sun SH ... -  《-》

TGF-β-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12.

TGF-β promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT). However, the underlying mechanisms causing this are not entirely clear. Long noncoding RNAs (lncRNA) have been shown to play important regulatory roles in cancer progression. The lncRNA malat1 (metastasis associated lung adenocarcinoma transcript 1) is a critical regulator of the metastasis phenotype of lung cancer cells. We, therefore, investigated whether TGF-β regulates malat1 expression to promote tumor metastasis of bladder cancer. The expression levels of malat1 and EMT markers were assayed in specimens of bladder cancer. The role of malat1 in regulating bladder cancer metastasis was evaluated in cell and animal models. TGF-β induces malat1 expression and EMT in bladder cancer cells. malat1 overexpression is significantly correlated with poor survival in patients with bladder cancer. malat1 and E-cadherin expression is negatively correlated in vitro and in vivo. malat1 knockdown inhibits TGF-β-induced EMT. malat1 is associated with suppressor of zeste 12 (suz12), and this association results in decrease of E-cadherin expression and increase of N-cadherin and fibronectin expression. Furthermore, targeted inhibition of malat1 or suz12 suppresses the migratory and invasive properties induced by TGF-β. Finally, we demonstrated that malat1 or suz12 knockdown inhibits tumor metastasis in animal models. These data suggest that malat1 is an important mediator of TGF-β-induced EMT, and suggest that malat1 inhibition may represent a promising therapeutic option for suppressing bladder cancer progression.

Fan Y ，Shen B ，Tan M ，Mu X ，Qin Y ，Zhang F ，Liu Y ... -  《-》

LncRNA TP73-AS1 predicts the prognosis of bladder cancer patients and functions as a suppressor for bladder cancer by EMT pathway.

Long noncoding RNAs (lncRNAs) have been identified to have more and more important roles in tumorigenesis and may be novel biomarker for cancer therapy. LncRNA TP73-AS1 is a novel identified lncRNA that has been demonstrated to be increased in several cancers, however, its function in bladder cancer remains unknown. The aim of this work was to examine the expression and role of lncRNA TP73-AS1 in bladder cancer. The expression levels of lncRNA TP73-AS1 in bladder cancer tissues and cell lines were determined by quantitative real-time PCR (qRT-PCR), and its clinical significance was assessed by statistical analysis. Moreover, by gain-of-function assay, the effect of TP73-AS1 on proliferation, cell cycle, apoptosis, migration and invasion was examined in bladder cancer cells. We identified that the expression level of TP73-AS1 was significantly down-regulated in bladder cancer tissues and cells compared to adjacent non-tumor tissues. Kaplan-Meier survival analysis found that patients with low TP73-AS1 expression level had shorter overall survival and progression-free survival than those with high TP73-AS1 expression. Moreover, we showed that overexpression of TP73-AS1 could inhibit cell growth, arrest cell cycle, reduce cell migration and invasion, and promote cell apotosis in vitro study. In addition, overexpression of TP73-AS1 diminished epithelial-mesenchymal transition (EMT) through inhibiting the expression of vimentin, snail, MMP-2, and MMP-9 and upregulating the expression levels of E-cadherin. Collectively, our findings for the first time elucidated that lncRNA TP73-AS1 may serve as a tumor suppressor participated in bladder cancer progression, which provided a promising therapy strategy for patients with bladder cancer.

Tuo Z ，Zhang J ，Xue W 《-》