ROBO2 hampers malignant biological behavior and predicts a better prognosis in pancreatic adenocarcinoma

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is a fatalmalignant cancer with extremely poor prognosis and high mortality. Genome wide studies show that Slit/Robo signaling pathway takes a major effect in the oncogenesis and progression of pancreatic cancer. However, the function and mechanism of ROBO2 in the development of PDAC remains unclear.

Methods

In present study, we use Western blot and real-time polymerase chain reaction (RT-PCR) to detect the expression of ROBO2 in pancreatic cell lines. Cell proliferation,Transwellmigration and invasion were conducted inAsPC-1, MIA PaCa-2 and PANC-1cell lines. RNA sequencing, bioinformatics analysisand Western blot were used to explore its mechanism and potential target molecules. The expression of ROBO2 in 95 tumor tissues was detected by immunohistochemistry.

Results

ROBO2 expression was downregulated in PDAC cell lines and tissue samples. A high expression of ROBO2 was associated with better prognosis. Upregulation of ROBO2 inhibited PDAC cell proliferation, migration, and invasion. However, we found theoppositeresults in the ROBO2 downregulation group. In addition, the function of ROBO2 on cell proliferation was further affirmed by the animal model. Finally, the results of RNA sequencing indicated that ROBO2 partly promoted the antitumor activity by inhibiting ECM1 in PDAC.

Conclusions

Our work suggests that ROBO2 inhibits tumor progression in PDAC and may serve as a predictive biomarker and therapeutic target in PDAC.

Keywords:

• ROBO2
• SLIT / ROBO pathway
• pancreatic cancer
• cell proliferation
• invasion

Ethics declaration

All patients signed informed consent. All authors declare that all animal experiments were complied with the ARRIVE guidelines and be carried out in accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines, EU Directive 2010/63/EU for animal experiments.

Acknowledgments

The authors thank all of the staff from the Department of General Surgery and Department of Pathology, Peking Union Medical College Hospital.

Author contributions

MD designed concept of this manuscript. CD conducted the experiments and drafted the manuscript. YL and SW reviewed the manuscript and made revisions on the drafts. CX and CD contributed to verify the data analysis. LC scrutinized the data. YW and HZ prepared the pathological analysis. All authors approved the final version.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All raw data supporting this article are available to qualified researchers.

Additional information

Funding

This work was supported by the project of National Natural Science Foundation of China [81903150 & 82073238] the project of CAMS Innovation Fund for Medical Sciences [2016-I2M-3-005] the project of National Major Research and Development Programs of the Ministry of Science and Technology of China [2017YFC1308602].