Downregulation of Notch3 links TIMP3 inhibition to suppress aggressive phenotypes of pancreatic ductal adenocarcinoma

Tai-Jan Chiu; Yi-Ju Chen; Jui Lan; Yen-Yang Chen; Yueh-Chiu Chen; Hsiao-Wu Lin; Hsin-Ting Tsai; Yu-Sheng Lin; Chang-Chun Hsiao; Chang-Han Chen

Downregulation of Notch3 links TIMP3 inhibition to suppress aggressive phenotypes of pancreatic ductal adenocarcinoma

Am J Cancer Res. 2021 Nov 15;11(11):5609-5624. eCollection 2021.

Authors

Tai-Jan Chiu^{1

2

3}, Yi-Ju Chen⁴, Jui Lan⁵, Yen-Yang Chen^{1

2}, Yueh-Chiu Chen^{1

2}, Hsiao-Wu Lin^{1

2}, Hsin-Ting Tsai⁶, Yu-Sheng Lin⁷, Chang-Chun Hsiao^{3

8}, Chang-Han Chen^{6

9}

Affiliations

¹ Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
² Kaohsiung Chang Gung Cholangiocarcinoma and Pancreatic Cancer Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 83301, Taiwan.
³ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Taoyuan 33302, Taiwan.
⁴ Department of Anatomic Pathology, E-Da Hospital, I-Shou University Kaohsiung 84001, Taiwan.
⁵ Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
⁶ Institute of Medicine, Chung Shan Medical University Taichung 40201, Taiwan.
⁷ State Key Laboratory of Optoelectronic Materials and Technologies, School of Electronics and Information Technology, Sun Yat-sen University Guangzhou 510060, China.
⁸ Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
⁹ Department of Medical Research, Chung Shan Medical University Hospital Taichung 40201, Taiwan.

PMID: 34873483
PMCID: PMC8640811

Abstract

Pancreatic ductal adenocarcinoma (PDAC), one of the most deadly digestive cancers, has a poor 5-year survival rate and is resistant to chemotherapeutic agents, such as gemcitabine. Notch3 plays an important role in cancer progression, and its expression facilitates chemoresistance in cancers. This study examined the clinical significance of Notch3 and explored the mechanisms through which it may affect disease progression in PDAC. We found Notch3 to be upregulated in PDAC patients in whom it correlated with lymph node stage and poor survival. In vitro and in vivo, functional assays indicated that silencing Notch3 could suppress the growth, migration, invasion of PDAC cells and sensitize PDAC cells to gemcitabine. QPCR array, which was performed to elucidate the Notch3-regulated pathway, revealed that inhibition of Notch3 decreased the transcription and secretion of TIMP3 in PDAC cells. Overexpression of TIMP3 reversed the impaired growth, migration, invasion, and chemosensitivity induced by Notch3 silencing. We also found a positive correlation between Notch3 mRNA expression and TIMP3 expression in patients with PDAC. We concluded that blocking Notch3/TIMP3 pathway could considered a potentially new therapeutic strategy for treating PDAC.

Keywords: Notch3; Pancreatic ductal adenocarcinoma; TIMP3; gemcitabine; motility.