Increased co-expression of PSMA2 and GLP-1 receptor in cervical cancer models in type 2 diabetes attenuated by Exendin-4: A translational case-control study
Dandan Mao,
Huanyi Cao,
Mai Shi,
Chi Chiu Wang,
Joseph Kwong,
Joshua Jing Xi Li,
Yong Hou,
Xing Ming,
Heung Man Lee,
Xiao Yu Tian,
Chun Kwok Wong,
Elaine Chow,
Alice Pik Shan Kong,
Vivian Wai Yan Lui,
Paul Kay Sheung Chan,
Juliana Chung Ngor Chan
Affiliations
Dandan Mao
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Huanyi Cao
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Mai Shi
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Chi Chiu Wang
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Joseph Kwong
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Joshua Jing Xi Li
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Yong Hou
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Xing Ming
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Heung Man Lee
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Xiao Yu Tian
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
Chun Kwok Wong
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Elaine Chow
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Alice Pik Shan Kong
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
Vivian Wai Yan Lui
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
Paul Kay Sheung Chan
Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.
Juliana Chung Ngor Chan
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China; Corresponding author at: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing St, Shatin, N.T., Hong Kong SAR, China.
Background: Type 2 diabetes (T2D) increases the risk of many types of cancer. Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects. Methods: We explored the co-expression of proteasome alpha 2 subunit (PSMA2) and GLP-1R in the Cancer Genome Atlas (TCGA) database and human cervical cancer specimens, supplemented by in vivo and in vitro studies using multiple cervical cancer cell lines. Findings: PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01). psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo. Exendin-4 decreased psma2 expression, tumour volume and Ki67 expression in vivo. There was no change in GLP-1R expression in 12 cancer types in TCGA database. However, GLP-1R expression (T2D vs non-T2D: 5.49 (3.0, 8.1) vs 1.00 (0.5, 1.5) fold change, P < 0.001) was increased and positively correlated with PSMA2 expression in T2D-related (r = 0.68) but not in non-T2D-related cervical cancer specimens. This correlation was corroborated by in vitro experiments where silencing glp-1r decreased psma2 expression. Exendin-4 attenuated phospho-p65 and -IκB expression in the NF-κB pathway. Interpretation: PSMA2 and GLP-1R expression in T2D-related cervical cancer specimens was increased and positively correlated, suggesting hyperglycaemia might promote cancer growth by increasing PSMA2 expression which could be attenuated by Exendin-4. Funding: This project was supported by Postdoctoral Fellowship Scheme, Direct Grant, Diabetes Research and Education Fund from the Chinese University of Hong Kong (CUHK)
