Gankyrin Contributes to Tumorigenesis and Chemoresistance in Sporadic Colorectal Cancer.
Adenomatous Polyposis Coli Protein
/ genetics
Adult
Aged
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Bevacizumab
/ pharmacology
Biomarkers, Tumor
/ metabolism
Carcinogenesis
/ pathology
Chemotherapy, Adjuvant
/ methods
Colorectal Neoplasms
/ mortality
Disease Models, Animal
Drug Resistance, Neoplasm
Female
Humans
Male
Mice
Mice, Transgenic
Middle Aged
Prognosis
Progression-Free Survival
Proteasome Endopeptidase Complex
/ metabolism
Proto-Oncogene Proteins
/ metabolism
Transcription Factors
/ genetics
Bevacizumab
Bmi1
Extracellular signal-regulated protein kinase
Interleukin-6
V-Akt murine thymoma viral oncogene homolog
c-Myc
Journal
Digestion
ISSN: 1421-9867
Titre abrégé: Digestion
Pays: Switzerland
ID NLM: 0150472
Informations de publication
Date de publication:
2019
2019
Historique:
received:
22
05
2018
accepted:
23
10
2018
pubmed:
5
12
2018
medline:
27
2
2020
entrez:
5
12
2018
Statut:
ppublish
Résumé
Although Gankyrin is overexpressed in many malignancies, the role of Gankyrin for tumorigenesis and chemoresistance remains to be elucidated in sporadic colorectal cancer (CRC). We investigate whether Gankyrin affects Adenomatous polyposis coli (Apc) inactivation-induced tumorigenesis and therapeutic response to anti-angiogenic agents. Epithelial cell-specific APC and/or Gankyrin-deficient mice were used. The patients with metastatic CRC (n = 53) who were enrolled in this study underwent resection of primary cancer followed by systemic chemotherapy containing bevacizumab. We determined whether gene expression in CRC tissues before chemotherapy is associated with radiological responses. Deletion of Gankyrin in epithelial cell reduced the expression of c-Myc, a critical mediator of the APC signaling pathway, and interleukin-6. Gankyrin deficiency decreased the expression of Bmi1, a downstream molecule of c-Myc, and the activity of V-Akt murine thymoma viral oncogene homolog and extracellular signal-regulated protein kinase, leading to reduced Apc inactivation-induced tumorigenesis. Of 53 patients, 38 (72%) had increased Gankyrin expression in tumor cells. The enhanced Gankyrin expression in tumor cells was associated with unfavorable progression-free survival (log-rank test p = 0.026). Gankyrin in epithelial cell contributes to the development of sporadic CRC and the expression could serve as a biomarker to predict therapeutic response in patients with metastatic CRC.
Sections du résumé
BACKGROUND
BACKGROUND
Although Gankyrin is overexpressed in many malignancies, the role of Gankyrin for tumorigenesis and chemoresistance remains to be elucidated in sporadic colorectal cancer (CRC).
AIMS
OBJECTIVE
We investigate whether Gankyrin affects Adenomatous polyposis coli (Apc) inactivation-induced tumorigenesis and therapeutic response to anti-angiogenic agents.
METHODS
METHODS
Epithelial cell-specific APC and/or Gankyrin-deficient mice were used. The patients with metastatic CRC (n = 53) who were enrolled in this study underwent resection of primary cancer followed by systemic chemotherapy containing bevacizumab. We determined whether gene expression in CRC tissues before chemotherapy is associated with radiological responses.
RESULTS
RESULTS
Deletion of Gankyrin in epithelial cell reduced the expression of c-Myc, a critical mediator of the APC signaling pathway, and interleukin-6. Gankyrin deficiency decreased the expression of Bmi1, a downstream molecule of c-Myc, and the activity of V-Akt murine thymoma viral oncogene homolog and extracellular signal-regulated protein kinase, leading to reduced Apc inactivation-induced tumorigenesis. Of 53 patients, 38 (72%) had increased Gankyrin expression in tumor cells. The enhanced Gankyrin expression in tumor cells was associated with unfavorable progression-free survival (log-rank test p = 0.026).
CONCLUSION
CONCLUSIONS
Gankyrin in epithelial cell contributes to the development of sporadic CRC and the expression could serve as a biomarker to predict therapeutic response in patients with metastatic CRC.
Identifiants
pubmed: 30513515
pii: 000494969
doi: 10.1159/000494969
doi:
Substances chimiques
Adenomatous Polyposis Coli Protein
0
Antineoplastic Agents, Immunological
0
Biomarkers, Tumor
0
PSMD10 protein, human
0
Proto-Oncogene Proteins
0
Transcription Factors
0
adenomatous polyposis coli protein, mouse
0
gankyrin protein, mouse
0
Bevacizumab
2S9ZZM9Q9V
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
192-200Informations de copyright
© 2018 S. Karger AG, Basel.