Type: dissertation
Abstract: Pancreatic cancer (PC) is an aggressive malignancy with few treatment options, and improved treatment strategies are urgently required.TYRO3, a member of the TAM receptor tyrosine kinase family, is a known oncogene; however, the relationship between TYRO3 expression and PC chemoresistance remains to be elucidated.We performed gain-and loss-of-function experiments on TYRO3 to examine whether it is involved in chemoresistance in PC cells.TYRO3 knockdown decreased cell viability and enhanced apoptosis following treatment of PC cells with gemcitabine and 5-fluorouracil (5-FU).In contrast, no such effects were observed in TYRO3overexpressing PC cells.It is known that autophagy is associated with cancer chemoresistance.We then examined effects of TYRO3 on autophagy in PC cells.TYRO3 overexpression increased LC3 mRNA levels and induced LC3 puncta in PC cells.Inhibition of autophagy by chloroquine mitigated cell resistance to gemcitabine and 5-FU.In a xenograft mouse model, TYRO3 silencing significantly increased sensitivity of the cells to gemcitabine and 5-FU.To further investigate the involvement of autophagy in patients with PC, we immunohistochemically analyzed LC3 expression in the tissues of patients who underwent pancreatectomy and compared it with disease prognosis and TYRO3 expression.LC3 expression was negatively and positively correlated with prognosis and TYRO3 expression, respectively.Furthermore, LC3-and TYRO3-positive patients had a significantly worse prognosis among patients with PC who received chemotherapy after recurrence.These results indicated that the TYRO3-autophagy signaling pathway confers PC resistance to gemcitabine and 5-FU, and could be a novel therapeutic target to resolve PC chemoresistance.Abbreviations PC pancreatic cancer RTKs receptor tyrosine kinases 5-FU 5-fluorouracil LC3 microtubule-associated protein 1A/1B-light chain 3 ATG5 autophagy related gene 5 BECN1 beclin1 ACTB actin beta CQ chloroquine CA19-9 carbohydrate antigen 19-9 GAS6 growth arrest-specific 6
Author: Hara,Kazushi
Institution: Tottori University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Molecular mechanisms underlying the promotion of epithelial barrier function by fat-soluble food components via regulating cell polarity, The TYRO3 role in pancreatic cancer via selective sutophagy., Cell damage suppression mechanism via cell polarity control by a novel inflammatory response signal pathway
OpenAlex ID: W7145707721