ABSTRACT
The angiotensin-converting enzyme 2 (ACE2) is a primary cell surface viral binding receptor for SARS-CoV-2, so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19. In the current study, we utilized islet organoids derived from human embryonic stem cells (hESCs), animal models and COVID-19 patients to discover that fibroblast growth factor 7 (FGF7) enhances ACE2 expression within the islets, facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion. Using hESC-derived islet organoids, we demonstrated that FGF7 interacts with FGF receptor 2 (FGFR2) and FGFR1 to upregulate ACE2 expression predominantly in ß cells. This upregulation increases both insulin secretion and susceptibility of ß cells to SARS-CoV-2 infection. Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation, subsequently reducing viral infection and replication in the islets. Furthermore, retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms. Finally, animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels, resulting in a reduction of insulin concentrations in situ. Taken together, our research offers a potential regulatory strategy for ACE2 by controlling FGF7, thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.
Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Fibroblast Growth Factor 7 , Islets of Langerhans , Organoids , Animals , Humans , Male , Mice , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , COVID-19/pathology , Fibroblast Growth Factor 7/genetics , Fibroblast Growth Factor 7/metabolism , Human Embryonic Stem Cells/metabolism , Insulin Secretion/genetics , Islets of Langerhans/metabolism , Islets of Langerhans/virology , Islets of Langerhans/pathology , Organoids/virology , Organoids/metabolism , Organoids/pathology , SARS-CoV-2/geneticsABSTRACT
Cancer cell resistance presents a significant clinical challenge. The mechanisms underlying drug resistance in cancer cells are intricate and remain incompletely understood. Notably, tumor cell resistance often coincides with the epithelial-mesenchymal transition (EMT). In this study, we observed an elevation in autophagy levels following the development of drug resistance in oesophageal cancer cells. Inhibition of autophagy led to a reduction in drug-resistant cell migration and the inhibition of EMT. Furthermore, we identified an upregulation of SIRT1 expression in drug-resistant oesophageal cancer cells. Subsequent inhibition of SIRT1 expression in drug-resistant cells resulted in the suppression of autophagy levels, migration ability, and the EMT process. Our additional investigations revealed that a SIRT1 inhibitor effectively curbed tumor growth in human oesophageal cancer xenograft model mice (TE-1, TE-1/PTX) without evident toxic effects. This mechanism appears to be associated with the autophagy levels within the tumor tissue.
Subject(s)
Autophagy , Esophageal Neoplasms , Sirtuin 1 , Animals , Humans , Mice , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Esophageal Neoplasms/drug therapy , Sirtuin 1/metabolismABSTRACT
Background: Breast cancer and thyroid cancer are two prevalent malignancies in women, and a potential association between the two diseases has been suggested. Methods: This retrospective case-control study was conducted involving 97 patients with breast cancer and thyroid cancer (BC-TC group) and 97 age-matched patients with breast cancer alone (BC group). Thyroid hormone levels, including triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH), were analyzed in healthy controls, BC patients, and BC-TC patients. Results: BC-TC patients exhibited a higher rate of estrogen receptor (ER) and progesterone receptor (PR) positivity compared to BC patients. Serum T3 levels were significantly decreased in BC and BC-TC patients compared to healthy controls. However, there was no significant difference in T3 levels between BC and BC-TC patients. Serum TSH levels were significantly higher in BC-TC patients compared to BC patients. Conclusion: ER positivity, PR positivity, and serum TSH levels greater than 4.45 mU/L were independent risk factors for primary thyroid cancer in breast cancer patients.