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001-es BibID:BIBFORM111320
035-os BibID:(cikkazonosító)102505 (WoS)000878597600003 (Scopus)85140235949
Első szerző:Czikora Ágnes (molekuláris biológus)
Cím:Cystathionine beta-synthase overexpression drives metastatic dissemination in pancreatic ductal adenocarcinoma via inducing epithelial-to-mesenchymal transformation of cancer cells / Ágnes Czikora, Katalin Erdélyi, Tamás Ditrói, Noémi Szantó, Eszter Petra Jurányi, Szilárd Szanyi, József Tóvári, Tamás Strausz, Péter Nagy
Megjegyzések:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancer types with a constant rise in global incidence. Therefore, better understanding of PDAC biology, in order to design more efficient diagnostic and treatment modalities, is a priority.Here we found that the expression levels of cystathionine beta-synthase (CBS), a transsulfuration enzyme, is markedly elevated in metastatic PDAC cells compared to cell lines isolated from non-metastatic primary tumors. On human immunohistochemical samples from PDAC patients we also found higher CBS staining in cancerous ductal cells compared to in non-tumor tissue, which was further elevated in the lymph node metastasis of the same patients. In mice, orthotopically injected CBS-silenced T3M4 cells induced fewer liver metastases compared to control cells indicating important roles for CBS in PDAC cancer cell invasion and malignant transformation. Wound healing and colony formation assays in cell culture confirmed that CBS-deficient metastatic T3M4 and non-metastatic BxPC3 primary tumor cells migrate slower and have impaired anchorage-independent growth capacities compared to control T3M4 cells. CBS silencing in T3M4 cells lowered WNT5a and SNAI1 gene expression down to levels that were observed in BxPC3 cells as well as resulted in an increase in E-cadherin and a decrease in Vimentin signals in mouse tumors when injected orthotopically. These observations suggested a primary role for the epithelial to mesenchymal transformation of cancer cells in CBS-mediated tumor aggres-siveness. Under normal conditions, STAT3, an upstream regulator of Wnt signaling pathways, was less phos-phorylated and more oxidized in shCBS T3M4 and BxPC3 compared to control T3M4 cells, which is consistent with decreased transcriptional activity at lower CBS levels due to less protection against oxidation. Sulfur metabolome analyses suggested that this CBS-mediated protection against oxidative modifications is likely to be related to persulfide/sulfide producing activities of the enzyme rather than its canonical function to produce cystathionine for cysteine synthesis. Taken together, CBS overexpression through regulation of the EMT plays a significant role in PDAC cancer cell invasion and metastasis.
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Hydrogen sulfide
Pancreatic ductal adenocarcinoma
Cystathionine beta-synthase
Epithelial-to-mesenchymal transition
Megjelenés:Redox Biology. - 57 (2022), p.1-14. -
További szerzők:Erdélyi Katalin (1978-) (molekuláris biológus, biokémikus) Ditrói Tamás (1989-) (vegyész) Szántó Noémi Jurányi Eszter Petra Szanyi Szilárd Tóvári József Strausz Tamás Nagy Péter (1976-) (vegyész)
Pályázati támogatás:2022-2.1.1-NL-2022-00010
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