Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis

Abstract

Evidence suggests that tripartite motif-containing 2 (TRIM2) is associated with carcinogenic effects in several malignancies. However, the expression patterns and roles of TRIM2 in pancreatic cancer are rarely studied. Our study demonstrated that TRIM2 was expressed in a high percentage of pancreatic tumors. High TRIM2 expression was negatively correlated with the outcome of pancreatic cancer. TRIM2 silencing significantly inhibited the proliferation, migration, invasion, and in vivo tumorigenicity of pancreatic cancer cells. Regarding the mechanism involved, TRIM2 activated ROS-related E2-related factor 2 (NRF2)/antioxidant response element (ARE) signaling and the integrin/focal adhesion kinase (FAK) pathway. Treatment of pancreatic cancer cells with the antioxidant N-acetyl-L-cysteine decreased ROS activity and expression level of NRF2 and ITGB7. Increased translocation of NRF2 protein into nucleus further rescued the inhibited ITGB7 transcription. Moreover, NRF2 bound to the potential ARE on the promoter region and enhanced the transcriptional activity of ITGB7, indicating the bridging effect of NRF2 between the two signaling pathways. In summary, our study provides evidence that upregulated TRIM2 in pancreatic cancer predicts short survival for pancreatic cancer patients. TRIM2 accelerates pancreatic cancer progression via the ROS-related NRF2/ITGB7/FAK axis.

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Fig. 1: TRIM2 expression is correlated with a poor prognosis of PDAC.
Fig. 2: TRIM2 is required for cell proliferation and metastasis in PDAC.
Fig. 3: TRIM2 influences redox balance in pancreatic cancer cells.
Fig. 4: TRIM2 regulates NRF2/ARE activation in PDAC.
Fig. 5: Silencing TRIM2 suppresses integrin/FAK signaling.
Fig. 6: ITGB7 transcription is regulated in an ROS-related NRF2-dependent manner.
Fig. 7: Increased TRIM2 in pancreatic cancer cells promoted cell progression by ROS-related NRF2/ITGB7/FAK axis.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (CN) (81871950 and 81972250); the China National Funds for Distinguished Young Scientists (CN) (81625016); the Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057).

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Conceptualization, XJY, QQS, XXW, SRJ and YQ; Methodology, QQS, GXF, XJY, ZY, ZZ and MQL; Statistical analysis, QQS, ZY, YQ and QFZ; Investigation, QQS, GXF, WYX, and WSL; Writing, QQS and YQ; Supervision, XJY, XWX and SRJ. All authors read and approved the final paper.

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Correspondence to Xiaowu Xu or Xianjun Yu.

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This study was approved by the Institutional Research Ethics Committee of Fudan University Shanghai Cancer Centre (ethical code: 050432-4-1212B) and written informed consent was obtained from all patients. All of the animal experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University (ethical code: 2019-JS-064).

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Sun, Q., Ye, Z., Qin, Y. et al. Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis. Oncogene (2020). https://doi.org/10.1038/s41388-020-01452-3

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