SMUG1 promoted the progression of pancreatic cancer via AKT signaling pathway through binding with FOXQ1.
10.1097/CM9.0000000000003640
- Author:
Zijian WU
1
;
Wei WANG
1
;
Jie HUA
1
;
Jingyao ZHANG
2
;
Jiang LIU
1
;
Si SHI
1
;
Bo ZHANG
1
;
Xiaohui WANG
3
;
Xianjun YU
1
;
Jin XU
1
Author Information
1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
2. Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
3. Department of General Surgery, Beijing Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
- Publication Type:Journal Article
- Keywords:
DNA damage;
Forkhead box Q1;
Gemcitabine;
Myelocytomatosis viral oncogene homolog;
Pancreatic cancer;
Protein kinase B;
Single-strand selective monofunctional uracil DNA glycosylase
- MeSH:
Humans;
Pancreatic Neoplasms/pathology*;
Forkhead Transcription Factors/genetics*;
Signal Transduction/genetics*;
Animals;
Cell Line, Tumor;
Proto-Oncogene Proteins c-akt/metabolism*;
Cell Proliferation/physiology*;
Mice;
Uracil-DNA Glycosidase/genetics*;
Female;
Male;
Gemcitabine;
Mice, Nude;
Apoptosis/physiology*;
Deoxycytidine/analogs & derivatives*;
Cell Movement/genetics*
- From:
Chinese Medical Journal
2025;138(20):2640-2656
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Pancreatic cancer is a lethal malignancy prone to gemcitabine resistance. The single-strand selective monofunctional uracil DNA glycosylase (SMUG1), which is responsible for initiating base excision repair, has been reported to predict the outcomes of different cancer types. However, the function of SMUG1 in pancreatic cancer is still unclear.
METHODS:Gene and protein expression of SMUG1 as well as survival outcomes were assessed by bioinformatic analysis and verified in a cohort from Fudan University Shanghai Cancer Center. Subsequently, the effect of SMUG1 on proliferation, cell cycle, and migration abilities of SMUG1 cells were detected in vitro . DNA damage repair, apoptosis, and gemcitabine resistance were also tested. RNA sequencing was performed to determine the differentially expressed genes and signaling pathways, followed by quantitative real-time polymerase chain reaction and Western blotting verification. The cancer-promoting effect of forkhead box Q1 (FOXQ1) and SMUG1 on the ubiquitylation of myelocytomatosis oncogene (c-Myc) was also evaluated. Finally, a xenograft model was established to verify the results.
RESULTS:SMUG1 was highly expressed in pancreatic tumor tissues and cells, which also predicted a poor prognosis. Downregulation of SMUG1 inhibited the proliferation, G1 to S transition, migration, and DNA damage repair ability against gemcitabine in pancreatic cancer cells. SMUG1 exerted its function by binding with FOXQ1 to activate the Protein Kinase B (AKT)/p21 and p27 pathway. Moreover, SMUG1 also stabilized the c-Myc protein via AKT signaling in pancreatic cancer cells.
CONCLUSIONS:SMUG1 promotes proliferation, migration, gemcitabine resistance, and c-Myc protein stability in pancreatic cancer via protein kinase B signaling through binding with FOXQ1. Furthermore, SMUG1 may be a new potential prognostic and gemcitabine resistance predictor in pancreatic ductal adenocarcinoma.
