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Int J Biol Sci 2020; 16(14):2648-2662. doi:10.7150/ijbs.48358 This issue Cite

Research Paper

Jagged2 progressively increased expression from Stage I to III of Bladder Cancer and Melatonin-mediated downregulation of Notch/Jagged2 suppresses the Bladder Tumorigenesis via inhibiting PI3K/AKT/mTOR/MMPs signaling

Yen-Ta Chen^1,2, Chi-Ruei Huang^2,3, Chia-Lo Chang⁴, John Y. Chiang^5,6, Chi-Wen Luo⁷, Hong-Hwa Chen^4✉, Hon-Kan Yip^{2,3,8,9,10,11✉}

1. Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
2. Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
3. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
4. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
5. Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan.
6. Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung, Taiwan.
7. Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
8. Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital Kaohsiung, Taiwan.
9. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
10. Department of Nursing, Asia University Taichung, Taiwan.
11. Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, Fujian, China.

✉ Corresponding author: Hong-Hwa Chen, MD. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan., No.123, Dapi Rd., Niaosong Dist., Kaohsiung City 83301, Taiwan. Tel.: +886-7-7317123; Fax: +886-7-7354309; E-mail: ma2561org.tw. Hon-Kan Yip, MD. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123, Dapi Road, Niaosung Dist., Kaohsiung city, 83301, Taiwan. Tel.: +886-7-7317123; Fax: +886-7-7322402; E-mail: han.gunghinet.net. More

Abstract

Background: This study assessed the expression of Jagged2 in human bladder cancer (BC) tested the hypothesis that melatonin (Mel) inhibited the tumorigenesis of BC cells mainly through downregulating the Notch/Jagged2 and PI3K/AKT/mTOR/MMPs^(2&9) signaling pathways.

Methods and Results: Tissue array from BC patients showed that the gene and protein expressions of JAG2/Jagged2 were significantly upregulated from T1 to T3 (primary tumor size) and from stage I to III (all p<0.001). In vitro study showed that in BC cell line of UMUC3, the cellular and protein expressions of Jagged2 were significantly attenuated in Mel-treated UMUC3 and further attenuated in UMUC3 shRNA silenced Notch/JAG2 (UMUC3^KD) than in UMUC3 only (all p<0.0001). The protein expressions of Notch/Jagged2/MMPs^(2&9)/PI3K/p-AKT/mTOR/p53/ratio of LC3BII/LC3B-I were significantly progressively reduced from UMUC3 to UMUC3+Mel/1.0mM, further to UMUC3+Mel/2.0mM and furthermore to UMUC3^KD (all p<0.0001). The cell proliferation/invasion/colony formation/healing-process were significantly inhibited in Mel-treated/2.0mM UMUC3 and further significantly inhibited in UMUC3^KD regardless of Mel treatment as compared with UMUC3 only (all p<0.0001). By day 28 after UMUC3 implanted into nude mouse back, the BC weight/volume were significantly reduced in UMUC3+Mel (100 mg/kg/day) and furthermore reduced in UMUC3^KD (all p<0.0001) as compared with UMUC3 only (all p<0.0001). The cellular (MMPs^(2&9)/Notch/Jagged2) and protein (Notch/Jagged2/PI3K/p-AKT/mTOR/MMPs^(2&9)) exhibited a similar trend, whereas the PTEN protein level exhibited an opposite pattern of PI3K among three groups (all p<0.0001).

Conclusion: Notch/Jagged-PI3K/p-AKT/mTOR/MMPs is one essential signaling pathway for BC survival, proliferation and invasion that were remarkably suppressed by Mel treatment.

Keywords: Notch/Jagged2, bladder cancer, cell-stress signaling, matrix metalloproteinases

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