Journal
JOURNAL OF CANCER
Volume 12, Issue 18, Pages 5622-5632Publisher
IVYSPRING INT PUBL
DOI: 10.7150/jca.58824
Keywords
DNA-PKcs; NEAT1; miR-101; pancreatic ductal adenocarcinoma
Categories
Funding
- Jiangsu Natural Science Foundation Project [BK20191142, BK20131095]
- Scientific Research Project of Jiangsu Provincial Health Commission [Z2018022]
- Six One Project Top Talent Research Project of Jiangsu Province [LGY2018016]
- Major scientific research project of Wuxi Municipal Health Commission [Z201805]
- Research team construction funding project of Jiangnan University School of Medicine [1286010242190110]
- Translational Medicine Research Project of Wuxi Municipal Health Commission [ZM002, ZM008]
- Special Funding of Science and Education Enhancing Health of Wuxi [QNRC015, ZDRC039]
- Young Researcher Grants Program of Wuxi Health and Family Planning Commission [Q201621]
- Science and Technology Bureau guidance project of Wuxi [CSZ0N1709]
- Medical Core Member Science Fund of The Third Hospital [2016-2018-10221]
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The study revealed that the upregulation of DNA-PKcs in PDAC cells is promoted by NEAT1 and miR-101, leading to the malignant behaviors of the cells. NEAT1 functions as an oncogene influencing cell proliferation, migration, and invasion.
Background: Although we previously revealed that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and important for gemcitabine resistance, the role of DNA-PKcs in the progression and metastasis of PDAC remain unclear. To date, the upstream signaling events stimulating DNA-PKcs overexpression in PDAC are still not well characterized. Methods: Expression of DNA-PKcs was measured by western blot. The levels of miRNA-101 and lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) were detected by real-time PCR. Cell viability was determined by CCK-8. Cell migration and cell invasion were measured by transwell assay. The regulatory relationship between NEAT1 and miR-101 was determined by a luciferase assay. Results: DNA-PKcs expression was significantly elevated in human PDAC tissues and cells. DNA-PKcs overexpression was correlated with TNM stage and lymph node metastasis. Higher expression of DNA-PKcs was closely correlated with patients of worse overall survival (OS). DNA-PKcs knockdown suppresses malignant behaviors of PDAC cells. Further study showed that miRNA-101 level was decreased in PDAC tissues and cells, which could be responsible for DNA-PKcs overexpression and DNA-PKcs mediated oncogenic actions in PDAC cells. Moreover, NEAT1 functions as an oncogene influencing cell proliferation, migration and invasion in part by serving as a competing endogenous RNA (ceRNAs) modulating miR-101 expression, leading to up-regulation of DNA-PKcs. Conclusion: These findings suggest that NEAT1/miR-101-dependent up-regulation of DNA-PKcs promotes the malignant behaviors of PDAC cells. The NEAT1/miR-101/DNA-PKcs axis may serve as a viable prognostic marker and therapeutic target for PDAC.
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