Abstract

Growing evidence indicates that circular RNAs (circRNAs) are closely involved in tumorigenesis, but the association between circRNAs and pancreatic ductal adenocarcinoma (PDAC) is far from clear. Here, we focused on the functional investigation of circ-0005105, a newly identified circRNA, in PDAC progression. In the present study, we assessed circ-0005105 expression in PDAC tissues and cell lines with quantitative reverse transcription–polymerase chain reaction (qRT-PCR). The biological functions of circ-0005105 in cellular proliferation and invasion were identified through gain- and loss-of-function experiments in vitro and in vivo. The interaction between circ-0005105 and the microRNA (miR)-20a-3p–COL11A1 (collagen type XI alpha 1) axis was examined using luciferase reporter and RNA immunoprecipitation assays. We found that circ-0005105 expression was upregulated in both PDAC tissues and cell lines. Higher circ-0005105 expression correlated positively with the malignant clinical phenotype and poor prognosis of patients with PDAC. Gain- and loss-of-function analysis showed that circ-0005105 facilitated both in vitro and in vivo cellular proliferation and invasion. Mechanistically, circ-000510 served as a competing endogenous RNA (ceRNA) of miR-20a-3p and indirectly modulated COL11A1 expression, leading to activation of epithelial–mesenchymal transition (EMT). Rescue experiments suggested that the oncogenic activity of circ-0005105 was dependent on the modulation of the miR-20a-3p–COL11A1 axis. More importantly, COL11A1 overexpression was significantly associated with poor prognosis in PDAC, and silencing COL11A1 reduced PDAC cell tumorigenicity and metastasis. Taken together, our findings confirm for the first time that circ-0005105 has critical functions by regulating the miR-20a-3p–COL11A1 axis. In the clinic, circ-0005105 can act as a potential prognostic marker and therapeutic target in PDAC.

Highlights

  • Pancreatic ductal adenocarcinoma (PDAC) is gastrointestinal cancer with high mortality; it is known for being elusive to early detection and its unfavorable prognosis [1]

  • RESULTS circ-0005105 expression is upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines To identify the differentially expressed circRNAs in PDAC, we first analyzed public circRNA microarrays (GSE79634) obtained from the Gene Expression Omnibus (GEO) database, and found that circ-0005105 was among the most significantly differentially expressed circRNAs between tumor tissues (n = 10) and adjacent normal tissues (n = 10) (Fig. 1A)

  • We detected the subcellular localization of circ-0005105 in PANC-1 and SW1990 cells through fluorescence in situ hybridization (FISH) (Fig. 1F) and nuclear and cytoplasmic separation assay (Fig. 1G), Cell Death and Disease (2021)12:656

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Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is gastrointestinal cancer with high mortality; it is known for being elusive to early detection and its unfavorable prognosis [1]. Its high rates of regional invasion and systemic reoccurrence, involving peritoneal metastasis and retroperitoneal reoccurrence, compromise therapeutic efficacy [2]. It is crucial to elucidate the molecular mechanisms underlying progression and metastasis for treating PDAC. Non-coding RNAs (ncRNAs), consisting of various RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), participate significantly in cellular development and pathogenesis [4]. Increasing evidence suggests that circRNAs participate in various physiological and pathological processes [6]. They participate in the tumorigenesis and progression of several types of malignant tumors [7]. To our best knowledge, the specific molecular mechanisms underlying how circRNAs function in PDAC progression remain largely unknown

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