A novel mechanism driving poor-prognostic gastric cancer: overexpression of the transcription factor Krüppel-like factor 16 promotes growth and metastasis of gastric cancer through regulating the Notch pathway

Ding-Ping Sun; Yu-Feng Tian; Chih-Chan Lin; Shih-Ting Hung; Yih-Huei Uen; You-Cheng Hseu; Chia-Lin Chou; Li-Chin Cheng; Wen-Ching Wang; Yi-Yu Kuang; Chia-Lang Fang; Kai-Yuan Lin

A novel mechanism driving poor-prognostic gastric cancer: overexpression of the transcription factor Krüppel-like factor 16 promotes growth and metastasis of gastric cancer through regulating the Notch pathway

Am J Cancer Res. 2021 Jun 15;11(6):2717-2735. eCollection 2021.

Authors

Ding-Ping Sun^{1

2}, Yu-Feng Tian¹, Chih-Chan Lin³, Shih-Ting Hung³, Yih-Huei Uen^{4

5

6}, You-Cheng Hseu^{7

8

9}, Chia-Lin Chou¹, Li-Chin Cheng¹, Wen-Ching Wang¹, Yi-Yu Kuang³, Chia-Lang Fang^{10

11}, Kai-Yuan Lin^{3

12}

Affiliations

¹ Department of Surgery, Chi Mei Medical Center Tainan 71004, Taiwan.
² Department of Food Science and Technology, Chia Nan University of Pharmacy and Science Tainan 71710, Taiwan.
³ Department of Medical Research, Chi Mei Medical Center Tainan 71004, Taiwan.
⁴ Department of Surgery, Asia University Hospital Taichung 41354, Taiwan.
⁵ Department of Biotechnology, Asia University Taichung 41354, Taiwan.
⁶ Department of Surgery, Tainan Municipal An-Nan Hospital Tainan 70965, Taiwan.
⁷ Department of Cosmeceutics, China Medical University Taichung 40402, Taiwan.
⁸ Department of Health and Nutrition Biotechnology, Asia University Taichung 41354, Taiwan.
⁹ Chinese Medicine Research Center, China Medical University Taichung 40402, Taiwan.
¹⁰ Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University Taipei 11031, Taiwan.
¹¹ Department of Pathology, Taipei Medical University Hospital, Taipei Medical University Taipei 11031, Taiwan.
¹² Department of Biotechnology, Chia Nan University of Pharmacy and Science Tainan 71710, Taiwan.

PMID: 34249424
PMCID: PMC8263687

Abstract

Gastric cancer (GC) is one of the most common malignant tumors worldwide and has high rates of morbidity and mortality. This study investigated the role of Krüppel-like factor 16 (KLF16) in GC. Real-time polymerase chain reaction, Western blotting, and immunohistochemistry were used to examine the expression of KLF16 in gastric cells and tissues. Gene overexpression and silencing were applied to study the involvement of KLF16 in GC cell growth and metastasis along with its underlying mechanism. The results indicate that KLF16 overexpression is significantly associated with nodal status, distant metastasis, staging, degree of differentiation, vascular invasion, and patient survival. Multivariate Cox proportional hazards regression model analysis revealed that the overexpression of KLF16 is an independent prognostic biomarker of GC. The in vitro study revealed that up-regulated KLF16 accelerates cell growth and metastasis, whereas the inhibition of KLF16 suppresses these cellular activities. The results of an animal study also indicated that the overexpression and silencing of KLF16 accelerate and repress xenograft proliferation and metastasis. Further studies of affected cell growth and metastasis revealed that KLF16 modulates the cell cycle and epithelial-mesenchymal transition through transcriptional regulation of microfibrillar-associated protein 5. Collectively, these results reveal that KLF16 overexpression is a potential prognostic biomarker and therapeutic target for the treatment of GC.

Keywords: Gastric cancer; KLF16; MFAP5; Notch pathway; prognosis.