Purpose. The present study was aimed at investigating the effects of dioxin-like pentachlorobiphenyls (PCBs) on aryl hydrocarbon receptor (AHR)/ nuclear factor erythroid 2–related factor 2 (NRF-2) pathway and related long noncoding RNAs (lncRNAs) and endothelial cell-specific molecule 1 (ESM-1) in thyrocytes. Methods. Primary human thyrocytes were exposed to increasing doses (5 and 10 µM) of 2,3’,4,4’,5-pentachlorobiphenyl (PCB-118) and 3,3',4',4',5 pentachlorobiphenyl (PCB-126) for 24 h. Cell culture and medium were collected to assess: mRNA levels of AHR, NRF-2, CYP1A1 lncRNAs (HOTAIR, MALAT-1, MEG-3), ESM-1, metalloproteinases (MMP) -3, MMP-9 and IL-1β by qPCR; protein levels of AHR and ESM-1 by western blot and ELISA, and ROS production by a commercial kit. Results. Treatment with PCB-126 and PCB-118 at both doses significantly increased mRNA levels of AHR, NRF-2, CYP1A1, MMP-3, MMP-9, IL-1β and ROS production. Furthermore, PCBs, especially PCB-118, enhanced ESM-1, HOTAIR and MALAT-1 expression and reduced MEG-3 mRNA levels. Discussion. PCBs are chemical pollutants able to promote inflammation and carcinogenesis. Our data demonstrated that PCB-118 and PCB-126 may induce AHR/NRF-2 pathway activation with a consequent ROS production and inflammatory responses in thyrocytes. This condition led to an increase in ESM-1, a circulating proteoglycan involved in angiogenesis and overexpressed in several tumors, and MMP-3 and MMP-9 that cause ECM remodeling. Furthermore, PCBs can induce epigenetic modifications by increasing lncRNAs MALAT-1 and HOTAIR expression, associated with cell proliferation and tumor growth, and reduce anti-oncogenic lncRNA MEG3. Conclusion. These results suggest new mechanisms underlying toxic effects of PCBs exposure on thyrocytes, indicating ESM-1 and lncRNAs as putative key factors of thyroid tumorigenesis.
Dioxin-like pentachlorobiphenyls promote extra-cellular matrix remodeling by increasing the expression of endothelial cell-specific molecule 1 and metalloproteinases, and induce epigenetic modifications in thyrocytes
Aurelio Minuti;Federica Aliquo;Rosaria Ruggeri;Martina Lagana;Marta Ragonese;Angela Avenoso;Giuseppe M. Campo;Salvatore Campo;Salvatore Cannavò;Michele Scuruchi;Angela D’Ascola.
2022-01-01
Abstract
Purpose. The present study was aimed at investigating the effects of dioxin-like pentachlorobiphenyls (PCBs) on aryl hydrocarbon receptor (AHR)/ nuclear factor erythroid 2–related factor 2 (NRF-2) pathway and related long noncoding RNAs (lncRNAs) and endothelial cell-specific molecule 1 (ESM-1) in thyrocytes. Methods. Primary human thyrocytes were exposed to increasing doses (5 and 10 µM) of 2,3’,4,4’,5-pentachlorobiphenyl (PCB-118) and 3,3',4',4',5 pentachlorobiphenyl (PCB-126) for 24 h. Cell culture and medium were collected to assess: mRNA levels of AHR, NRF-2, CYP1A1 lncRNAs (HOTAIR, MALAT-1, MEG-3), ESM-1, metalloproteinases (MMP) -3, MMP-9 and IL-1β by qPCR; protein levels of AHR and ESM-1 by western blot and ELISA, and ROS production by a commercial kit. Results. Treatment with PCB-126 and PCB-118 at both doses significantly increased mRNA levels of AHR, NRF-2, CYP1A1, MMP-3, MMP-9, IL-1β and ROS production. Furthermore, PCBs, especially PCB-118, enhanced ESM-1, HOTAIR and MALAT-1 expression and reduced MEG-3 mRNA levels. Discussion. PCBs are chemical pollutants able to promote inflammation and carcinogenesis. Our data demonstrated that PCB-118 and PCB-126 may induce AHR/NRF-2 pathway activation with a consequent ROS production and inflammatory responses in thyrocytes. This condition led to an increase in ESM-1, a circulating proteoglycan involved in angiogenesis and overexpressed in several tumors, and MMP-3 and MMP-9 that cause ECM remodeling. Furthermore, PCBs can induce epigenetic modifications by increasing lncRNAs MALAT-1 and HOTAIR expression, associated with cell proliferation and tumor growth, and reduce anti-oncogenic lncRNA MEG3. Conclusion. These results suggest new mechanisms underlying toxic effects of PCBs exposure on thyrocytes, indicating ESM-1 and lncRNAs as putative key factors of thyroid tumorigenesis.Pubblicazioni consigliate
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