Abstract
ObjectivePancreatic cancer is associated with poor prognosis and dismal survival rates. This study aims to investigate roles of lncRNA UCA1-loaded exosomes secreted by pancreatic stellate cells (PSCs) in Gemcitabine (Gem) resistance of pancreatic cancer under hypoxia, which involves the methylation of SOCS3 and EZH2 recruitment.MethodsThe exosomes were isolated from PSCs and hypoxic PSCs (HPSCs), and co-cultured with pancreatic cancer cells transduced with manipulated lncRNA UCA1, EZH2, and SOCS3. The interaction among lncRNA UCA1, EZH2, and SOCS3 was characterized by RIP and ChIP assays. Next, MTT assay, flow cytometry and TUNEL staining and Transwell assay were used to detect cell viability, apoptosis, invasion, and migration. Gem-resistant pancreatic cancer cell line (GemMIA-R3) was established, which was applied in a mouse xenograft model of pancreatic cancer, with MTT assay to determine Gem sensitivity.ResultsLncRNA UCA1 was highly expressed, while SOCS3 was poorly expressed in pancreatic cancer tissues. Hypoxia induced activation of PSCs and promoted release of exosomes. LncRNA UCA1 delivered by hypoxic PSC-derived exosomes (HPSC-EXO) regulated histone methylation level in SOCS3 gene region through recruitment of EZH2. In vitro and in vivo experimental results confirmed that lncRNA UCA1-loaded HPSC-EXO promoted malignant phenotypes, inhibited apoptosis, and promoted Gem resistance of pancreatic cancer cells as well as tumorigenesis in mice.ConclusionUnder hypoxic conditions, exosomes secreted by hypoxia-induced PSCs deliver lncRNA UCA1 into pancreatic cancer cells, where lncRNA UCA1 recruits EZH2 and regulates histone methylation level in SOCS3 gene region, thereby augmenting pancreatic cancer resistance to Gem.
Highlights
Pancreatic cancer has a poor prognosis and accounts for about 3% of new cancer cases each year [1]
PANC-1 cells with long noncoding RNAs (lncRNAs) UCA1 knockdown were more sensitive to Gem while further co-culture with HPSC-EXO reversed this sensitivity to a certain extent. These results reveal that lncRNA UCA1 can be transferred to pancreatic cancer cells by HPSC-EXO, thereby promoting the malignant phenotypes of pancreatic cancer cells and their resistance to Gem
LncRNA UCA1 expression was found to be increased in hypoxic pancreatic cancer cells, and enriched in exosomes derived from hypoxic pancreatic cancer cells, and it was established that lncRNA UCA1 knockout restricted angiogenesis and tumor growth [7]. These results suggested that hypoxic pancreatic cancer cell-derived exosome-mediated angiogenesis was dependent on lncRNA UCA1
Summary
Pancreatic cancer has a poor prognosis and accounts for about 3% of new cancer cases each year [1]. Pancreatic stellate cells (PSCs) are the main cell components of pancreatic cancer, which produce large number of extracellular matrix components [2]. Increasing evidence has shown that hypoxia is a key microenvironment factor to promote the activation of PSCs [3]. The accumulation of extracellular matrix leads to vascular collapse, impaired drug delivery and acquired chemoresistance, which may be induced by activated PSCs [4]. Various factors secreted by stromal cells have recently been reported to promote gemcitabine (Gem) resistance [5]. Gem is a nucleoside analogue, which has been the mainstay of pancreatic cancer chemotherapy for a long time. The clinical efficacy of Gem is limited due to its limited cellular uptake and impaired intracellular activation, resulting in low overall efficacy [6]. It is necessary to understand the biological characteristics of pancreatic cancer
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