circular RNAs 0000515 and 0011385 as potential biomarkers for disease monitoring and determining prognosis in pancreatic ductal adenocarcinoma

Abstract Background Circular RNAs (circRNAs) are becoming a unique member of non-coding RNAs (ncRNAs) with emerging evidence of their regulatory roles in various cancers. However, with regards to pancreatic ductal adenocarcinoma (PDAC), circRNAs biological functions remain largely unknown and worth investigation for potential therapeutic innovation. Methods In our previous study, next-generation sequencing was used to identify differentially expressed circRNAs in 3 pairs of PDAC and adjacent normal tissues. Further validation of circRHOBTB3 expression in PDAC tissues and cell lines and gain-and-loss function experiments verified the oncogenic role of circRHOBTB3. The mechanism of circRHOBTB3 regulatory role was validated by pull-down assays, RIP, luciferase reporter assays. The autophagy response of PANC-1 and MiaPaca-2 cells were detected by mCherry-GFP-LC3B labeling and confocal microscopy, transmission electron microscopy and protein levels of LC3B or p62 via Western blot. Results circRHOBTB3 is highly expressed in PDAC cell lines and tissues, which also promotes PDAC autophagy and then progression in vitro and in vivo. Mechanistically, circRHOBTB3 directly binds to miR-600 and subsequently acts as a miRNA-sponge to maintain the expression level of miR-600-targeted gene NACC1, which facilitates the autophagy response of PDAC cells for adaptation of proliferation via Akt/mTOR pathway. Moreover, the RNA-binding protein FUS (FUS) directly binds to pre-RHOBTB3 mRNA to mediate the biogenesis of circRHOBTB3. Clinically, circRHOBTB3, miR-600 and NACC1 expression levels are correlated with the prognosis of PDAC patients and serve as independent risk factors for PDAC patients. Conclusions FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.

Download Full-text

CircMYOF triggers progression and facilitates glycolysis via the VEGFA/PI3K/AKT axis by absorbing miR-4739 in pancreatic ductal adenocarcinoma

Cell Death Discovery ◽

10.1038/s41420-021-00759-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Dandan Zheng ◽

Xianxian Huang ◽

Juanfei Peng ◽

Yanyan Zhuang ◽

Yuanhua Li ◽

...

Keyword(s):

Glucose Metabolism ◽

Pancreatic Ductal Adenocarcinoma ◽

Circular Rna ◽

Ductal Adenocarcinoma ◽

Luciferase Reporter ◽

Circular Rnas ◽

Loss Of Function ◽

Competing Endogenous Rna ◽

Rnase R

AbstractEmerging evidence has demonstrated that circular RNAs (circRNAs) take part in the initiation and development of pancreatic ductal adenocarcinoma (PDA), a deadly neoplasm with an extremely low 5-year survival rate. Reprogrammed glucose metabolism is a key feature of tumour development, including PDA. In this research, we evaluated the role of circRNAs in reprogrammed glucose metabolism in PDA. RNA sequencing under various glucose incubation circumstances was performed. A new circMYOF was identified. Sanger sequencing and RNase R treatment confirmed its circular RNA characteristics. Real-time PCR indicated that it was highly expressed in PDA clinical specimens and cell lines. Gain-of- and loss-of-function assays showed that circMYOF induced progression in PDA. Mechanistically, RNA pull-down and luciferase reporter experiments elucidated that circMYOF, as a competing endogenous RNA for miR-4739, facilitated glycolysis via the VEGFA/PI3K/AKT pathway. Taken together, our findings indicate that circMYOF may work as a desirable biomarker and therapeutic target for PDA patients.

Download Full-text

Circular RNA Expression Profile of Pancreatic Ductal Adenocarcinoma Revealed by Microarray

Cellular Physiology and Biochemistry ◽

10.1159/000453186 ◽

2016 ◽

Vol 40 (6) ◽

pp. 1334-1344 ◽

Cited By ~ 57

Author(s):

Haimin Li ◽

Xiaokun Hao ◽

Huimin Wang ◽

Zhengcai Liu ◽

Yong He ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Expression Profile ◽

Mammalian Cells ◽

Noncoding Rna ◽

Circular Rna ◽

Pathological Process ◽

Ductal Adenocarcinoma ◽

Circular Rnas ◽

Normal Tissues ◽

Polymerase Chain

Background/Aims: Circular RNAs (circRNAs) are a special novel type of a stable, diverse and conserved noncoding RNA in mammalian cells. Particularly in cancer, circRNAs have been reported to be widely involved in the physiological/pathological process of life. However, it is unclear whether circRNAs are specifically involved in pancreatic ductal adenocarcinoma (PDAC). Methods: We investigated the expression profile of circRNAs in six PDAC cancer samples and paired adjacent normal tissues using microarray. A high-throughput circRNA microarray was used to identify dysregulated circular RNAs in six PDAC patients. Bioinformatic analyses were applied to study these differentially expressed circRNAs. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm these results. Results: We revealed and confirmed that a number of circRNAs were dysregulated, which suggests a potential role in pancreatic cancer. Conclusions: this study demonstrates that clusters of circRNAs are aberrantly expressed in PDAC compared with normal samples and provides new potential targets for the future treatment of PDAC and novel insights into PDAC biology.

Download Full-text

The Role of Circular RNAs in Pancreatic Ductal Adenocarcinoma and Biliary-Tract Cancers

Cancers ◽

10.3390/cancers12113250 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3250

Author(s):

Christopher Limb ◽

Daniel S. K. Liu ◽

Morten T. Veno ◽

Eleanor Rees ◽

Jonathan Krell ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Biliary Tract ◽

Ex Vivo ◽

Expression Profiles ◽

Ductal Adenocarcinoma ◽

Circular Rnas ◽

Specific Expression ◽

Biliary Tract Cancers ◽

Cerna Network

Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies.

Download Full-text

Potential biomarkers of pancreatic ductal adenocarcinoma (PDAC)-associated diabetes

Pancreatology ◽

10.1016/j.pan.2015.05.136 ◽

2015 ◽

Vol 15 (3) ◽

pp. S30

Author(s):

Lucy Oldfield ◽

Claire Jenkinson ◽

Tejpal Purewal ◽

Robert Sutton ◽

John Neoptolemos ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Potential Biomarkers

Download Full-text

Inflammatory cytokines and angiogenic factors as potential biomarkers in South African pancreatic ductal adenocarcinoma patients: A preliminary report

Pancreatology ◽

10.1016/j.pan.2017.03.003 ◽

2017 ◽

Vol 17 (3) ◽

pp. 438-444 ◽

Cited By ~ 5

Author(s):

Yandiswa Y. Yako ◽

Martin Brand ◽

Martin Smith ◽

Deirdré Kruger

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

South African ◽

Inflammatory Cytokines ◽

Preliminary Report ◽

Angiogenic Factors ◽

Ductal Adenocarcinoma ◽

Potential Biomarkers

Download Full-text

Circ-ASH2L promotes tumor progression by sponging miR-34a to regulate Notch1 in pancreatic ductal adenocarcinoma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1436-0 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 16

Author(s):

Yan Chen ◽

Zhonghu Li ◽

Mengyun Zhang ◽

Bo Wang ◽

Jiaxin Ye ◽

...

Keyword(s):

Tumor Progression ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Invasion ◽

Lymphatic Invasion ◽

Tube Formation ◽

Regulatory Mechanisms ◽

Ductal Adenocarcinoma ◽

Circular Rnas ◽

Microarray Studies

Abstract Background Circular RNAs (circRNAs) have recently been shown to play important roles in different tumors. However, their detailed roles and regulatory mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not well understood. This study aimed to identify enriched circRNAs and detect their functions and mechanisms in PDAC cells and tissues. Methods circRNA-ASH2L (circ-ASH2L) was identified by circRNA microarray studies based on previous studies, and further detected in PDAC cells and samples by qRT-PCR. The functions of circ-ASH2L were identified by transwell, EdU, cell cycle or Tube formation assays. The regulatory mechanisms of circ-ASH2L were explored by WB, RIP, FISH, dual-luciferase assays, RNA pulldown or other assays. Results We identified a circRNA (circ-ASH2L) based on our previous studies, detected its expression in different malignant cells and found that circ-ASH2L was highly expressed in pancreatic cells or tumor tissues and correlated with tumor malignancy. Further studies revealed that circ-ASH2L promoted tumor invasion, proliferation and angiogenesis by regulating miR-34a, thus regulate Notch 1 expression. Circ-ASH2L served as a miRNA sponge for miR-34a and promoted tumor progression in vivo. Finally, we analyzed circ-ASH2L expression in clinical tissues and found that high circ-ASH2L expression was correlated with lymphatic invasion and TNM stage and was an independent risk factor for pancreatic patient survival. Conclusions circ-ASH2L play an important role in tumor invasion, and high circ-ASH2L may be a useful marker of PDAC diagnosis or progression.

Download Full-text