Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) is highly aggressive with poor prognosis. Long non-coding RNAs (lncRNAs), a group of non-coding RNAs, play important roles in the progression of PDAC. This study aimed to investigate the potential involvement of lncRNA CCAT2 in PDAC tumorigenesis.MethodsExpression of CCAT2 was detected by quantitative real-time PCR (qRT-PCR) in 80 human PDAC tissues and three PDAC cell lines. The effects of CCAT2 silencing in PANC-1 cells on cell proliferation and invasion were studied using MTT assay and transwell assay, respectively. The effect of CCAT2 silencing on tumorigenesis was assessed by PANC-1 xenograft in vivo. Using si-KRAS, the role of KRAS to regulate CCAT2 was evaluated by qRT-PCR and luciferase reporter assay. The involvement of MEK/ERK and PI3K/AKT signaling in CCAT2 regulation was investigated by pathway inhibitors PD98059 and LY294002, respectively.ResultsCCAT2 was significantly elevated in high-grade PDAC tissues and higher CCAT2 expression was correlated with lower survival rate in PDAC patients. CCAT2 was up-regulated in PDAC cell lines, as compared with normal pancreatic cells. Silencing of CCAT2 inhibited cell proliferation and invasion in PANC-1 cells in vitro, and attenuated tumorigenesis of PANC-1 xenograft in vivo. Furthermore, CCAT2 was regulated by KRAS through MEK/ERK signaling pathway.ConclusionsCCAT2 is an oncogenic lncRNA in PDAC likely regulated by the KRAS-MEK/ERK pathway. It could be a potential diagnostic biomarker and therapeutic target for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive with poor prognosis
CCAT2 is upregulated in PDACs and predicts patients with poor survival We first categorized 80 human PDAC tissue samples into low-grade (n = 35) or high-grade (n = 45) (Fig. 1a), and used quantitative real-time PCR (qRT-PCR) to detect their endogenous CCAT2 expression
CCAT2 levels were significantly higher in the high-grade PDAC tissues than those in the low-grade PDACs (P = 0.004) (Fig. 1b, Table 1)
Summary
Long non-coding RNAs (lncRNAs), a group of non-coding RNAs, play important roles in the progression of PDAC. KRAS, as a small GTPase, couples various growth-factor receptors on the cell membrane to intracellular signaling pathways and transcription factors, controlling diverse cellular processes [4]. Most KRAS mutations impairs intrinsic GTPase activity of KRAS, resulting in an aberrant protein that is constitutively activating downstream oncogenic signaling pathways, including PI3K/AKT and MEK/ERK [5]. Aberrant KRAS constantly activates a wide range of transcription factors, promoting cell proliferation, survival, transformation, adhesion, and migration [6]. KRAS signaling is perceived as the major driving force of PDAC [7], intensive effort to explore KRAS as effective therapeutic target in PDAC has largely failed to reach the clinic [8]. There is an urgent need to develop alternative strategies to effectively target KRAS signaling, such as blocking KRAS downstream pathways, KRAS downstream effectors or KRAS upstream modulators
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