Dataset Information

The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.

ABSTRACT: HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC4484423 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.

Cheng Yating Y Jutooru Indira I Chadalapaka Gayathri G Corton J Christopher JC Safe Stephen S

Oncotarget 20150501 13

HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOT ...[more]

PMID: 25912306

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Project description:BackgroundThe human genome encodes many long non-coding RNAs (lncRNAs). However, their biological functions, molecular mechanisms, and the prognostic value associated with pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. Here, we identify a fundamental role for the lncRNA HOXA transcript at the distal tip (HOTTIP) in the progression and chemoresistance of PDAC.MethodsHigh-throughput microarrays were performed to detect the expression profiles of lncRNAs and messenger RNAs in eight human PDAC tissues and four pancreatic tissues. Quantitative real-time PCR was used to determine the levels of HOTTIP and HOXA13 transcripts in PDAC cell lines and 90 PDAC samples from patients. HPDE6 cells (immortalized human pancreatic ductal epithelial cells) and corresponding adjacent non-neoplastic tissues were used as controls, respectively. The functions of HOTTIP and HOXA13 in cell proliferation, invasion, and epithelial-mesenchymal transition were evaluated by targeted knockdown in vitro. CCK-8 assays, colony formation assays, and xenografts in nude mice were used to investigate whether targeted silencing of HOTTIP could sensitize pancreatic cancer cells to gemcitabine. Immunohistochemistry was performed to investigate the relationship between HOXA13 expression and patient outcome.ResultsMicroarray analyses revealed that HOTTIP was one of the most significantly upregulated lncRNAs in PDAC tissues compared with pancreatic tissues. Quantitative PCR further verified that HOTTIP levels were increased in PDAC cell lines and patient samples compared with controls. Functionally, HOTTIP silencing resulted in proliferation arrest by altering cell-cycle progression, and impaired cell invasion by inhibiting epithelial-mesenchymal transition in pancreatic cancer. Additionally, inhibition of HOTTIP potentiated the antitumor effects of gemcitabine in vitro and in vivo. Furthermore, knockdown of HOXA13 by RNA interference (siHOXA13) revealed that HOTTIP promoted PDAC cell proliferation, invasion, and chemoresistance, at least partly through regulating HOXA13. Immunohistochemistry results revealed that higher HOXA13 expression was correlated with lymph node metastasis, poor histological differentiation, and decreased overall survival in PDAC patients.ConclusionsAs a crucial tumor promoter, HOTTIP promotes cell proliferation, invasion, and chemoresistance by modulating HOXA13. Therefore, the HOTTIP/HOXA13 axis is a potential therapeutic target and molecular biomarker for PDAC.

Project description:Long non-coding RNA (lncRNA) ADAM metallopeptidase with thrombospondin type 1 motif 9 antisense RNA 2 (ADAMTS9-AS2) is involved in various types of cancer, such as ovarian cancer, lung cancer and clear cell renal cell carcinoma. However, the roles of ADAMTS9-AS2 in liver cancer are not completely understood. The present study aimed to determine the functional role of ADAMTS9-AS2 in human liver cancer and investigate the potential underlying molecular mechanisms. The expression levels of ADAMTS9-AS2 and ADAMTS9 were determined following ADAMTS9-AS2 overexpression and knockdown. The results indicated that ADAMTS9-AS2 overexpression and knockdown increased and decreased ADAMTS9 mRNA and protein expression levels, respectively, indicating that alterations in ADAMTS9 expression corresponded with ADAMTS9-AS2 expression. Subsequently, the effects of ADAMTS9-AS2 on liver cancer cell proliferation, migration and invasion were analyzed by performing Cell Counting Kit-8, wound healing and Transwell assays, respectively. The results demonstrated that ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion. Finally, the effect of ADAMTS9 on PI3K/AKT/mTOR signaling pathway-associated proteins [AKT, phosphorylated-AKT, phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit β (PIK3CB), mTOR and phosphorylated-mTOR], several key autophagy-related proteins [light chain 3-I/II (LC3-I/II), beclin 1 (BECN1) and sequestosome 1 (SQSTM1)] and apoptosis-related proteins (Bax and Bcl-2) was detected via western blotting. The results suggested that ADAMTS9-AS2 downregulated the phosphorylation of AKT and mTOR, the protein expression level of PIK3CB, as well as the expression levels of autophagy protein SQSTM1 and antiapoptotic protein Bcl-2. By contrast, ADAMTS9-AS2 upregulated the expression levels of autophagy proteins LC3-II and BECN1, and the proapoptotic protein Bax. Collectively, ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion via inhibiting the PI3K/AKT/mTOR signaling pathway. The present study provided a novel insight into the role of ADAMTS9-AS2 in liver cancer.

Dataset Information

The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.

Publications

The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.

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