- 作者: Yi-Chih Tsai, Kung Hung Cheng, Shih Sheng Jiang, John R. Hawse, Shun En Chuang, Su Liang Chen, Tze-Sing Huang & Hui-Ju Ch’ang
- 作者服務機構: 1.Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA 2.Department of Oncology, School of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3.Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 4.National Institute of Cancer Research, National Health Research Institutes, R1-2034, 35 Keyan Road, Zhunan, Miaoli County, 35053, Taiwan 5.Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- 中文摘要:
- 英文摘要:
Background Pancreatic adenocarcinoma (PDAC) is well known for its rapid distant metastasis and local destructive
behavior. Loss of Krüppel-like factor 10 (KLF10) contributes to distant migration of PDAC. The role of KLF10 in modu‑
lating tumorigenesis and stem cell phenotypes of PDAC is unclear.
Methods Additional depletion of KLF10 in KC (LSL: KrasG12D; Pdx1-Cre) mice, a spontaneous murine PDAC model,
was established to evaluate tumorigenesis. Tumor specimens of PDAC patients were immune-stained of KLF10 to
correlate with local recurrence after curative resection. Conditional overexpressing KLF10 in MiaPaCa and stably
depleting KLF10 in Panc-1 (Panc-1-pLKO-shKLF10) cells were established for evaluating sphere formation, stem cell
markers expression and tumor growth. The signal pathways modulated by KLF10 for PDAC stem cell phenotypes were
disclosed by microarray analysis and validated by western blot, qRT-PCR, luciferase reporter assay. Candidate targets to
reverse PDAC tumor growth were demonstrated in murine model.
Results KLF10, defcient in two-thirds of 105 patients with resected pancreatic PDAC, was associated with rapid
local recurrence and large tumor size. Additional KLF10 depletion in KC mice accelerated progression from pan‑
creatic intraepithelial neoplasia to PDAC. Increased sphere formation, expression of stem cell markers, and tumor
growth were observed in Panc-1-pLKO-shKLF10 compared with vector control. Genetically or pharmacologically
overexpression of KLF10 reversed the stem cell phenotypes induced by KLF10 depletion. Ingenuity pathway analysis
and gene set enrichment analysis showed that Notch signaling molecules, including Notch receptors 3 and 4, were
over-expressed in Panc-1-pLKO-shKLF10. KLF10 transcriptionally suppressed Notch-3 and -4 by competing with E74like ETS transcription factor 3, a positive regulator, for promoter binding. Downregulation of Notch signaling, either
genetically or pharmacologically, ameliorated the stem cell phenotypes of Panc-1-pLKO-shKLF10. The combination
of metformin, which upregulated KLF10 expression via phosphorylating AMPK, and evodiamine, a non-toxic Notch-3
methylation stimulator, delayed tumor growth of PDAC with KLF10 defciency in mice without prominent toxicity.
Conclusions These results demonstrated a novel signaling pathway by which KLF10 modulates stem cell pheno‑
types in PDAC through transcriptionally regulating Notch signaling pathway. The elevation of KLF10 and suppression
of Notch signaling may jointly reduce PDAC tumorigenesis and malignant progression. - 中文關鍵字:
- 英文關鍵字: Krüppel-like factor 10, Notch signaling, Notch-3/4, ELF3, Pancreatic adenocarcinoma