TY - JOUR
T1 - Growth factor–independent 1 is a tumor suppressor gene in colorectal cancer
AU - Chen, Min Shan
AU - Lo, Yuan Hung
AU - Chen, Xi
AU - Williams, Christopher S.
AU - Donnelly, Jessica M.
AU - Criss, Zachary K.
AU - Patel, Shreena
AU - Butkus, Joann M.
AU - Dubrulle, Julien
AU - Finegold, Milton J.
AU - Shroyer, Noah F.
N1 - Funding Information:
The authors thank the Texas Medical Center Digestive Disease Center for their support with funding from the NCI (P30DK56338), the Intestinal Stem Cell Consortium with funding from the NIH through grants (U01 DK103168 and U01 DK103168-03S), NIH grants R01 CA142826 (N.F. Shroyer) and F99 CA212433 (Y.-H. Lo). We thank the Integrated Microscopy Core at Baylor College of Medicine for their support with funding from the NIH (NCI-CA125123 and NIDDK-56338-13/15) and CPRIT (RP150578), the Cytometry
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Growth factor–independent 1 (GFI1) is a zinc finger transcriptional repressor responsible for controlling secretory cell differentiation in the small intestine and colon. GFI1 plays a significant role in the development of human malignancies, including leukemia, lung cancer, and prostate cancer. However, the role of GFI1 in colorectal cancer progression is largely unknown. Our results demonstrate that RNA and protein expression of GFI1 are reduced in advanced-stage nonmucinous colorectal cancer. Subcutaneous tumor xenograft models demonstrated that the reexpression of GFI1 in 4 different human colorectal cancer cell lines inhibits tumor growth. To further investigate the role of Gfi1 in de novo colorectal tumorigenesis, we developed transgenic mice harboring a deletion of Gfi1 in the colon driven by CDX2-cre (Gfi1 F/F ; CDX2-cre) and crossed them with Apc Min/þ mice (Apc Min/þ ; Gfi1 F/F ; CDX2-cre). Loss of Gfi1 significantly increased the total number of colorectal adenomas compared with littermate controls with an APC mutation alone. Furthermore, we found that compound (Apc Min/þ ; Gfi1 F/F ; CDX2-cre) mice develop larger adenomas, invasive carcinoma, as well as hyperplastic lesions expressing the neuroendocrine marker chromogranin A, a feature that has not been previously described in APC-mutant tumors in mice. Collectively, these results demonstrate that GFI1 acts as a tumor suppressor gene in colorectal cancer, where deficiency of Gfi1 promotes malignancy in the colon. Implications: These findings reveal that GFI1 functions as a tumor suppressor gene in colorectal tumorigenesis.
AB - Colorectal cancer is the third most common cancer and the third leading cause of cancer death in the United States. Growth factor–independent 1 (GFI1) is a zinc finger transcriptional repressor responsible for controlling secretory cell differentiation in the small intestine and colon. GFI1 plays a significant role in the development of human malignancies, including leukemia, lung cancer, and prostate cancer. However, the role of GFI1 in colorectal cancer progression is largely unknown. Our results demonstrate that RNA and protein expression of GFI1 are reduced in advanced-stage nonmucinous colorectal cancer. Subcutaneous tumor xenograft models demonstrated that the reexpression of GFI1 in 4 different human colorectal cancer cell lines inhibits tumor growth. To further investigate the role of Gfi1 in de novo colorectal tumorigenesis, we developed transgenic mice harboring a deletion of Gfi1 in the colon driven by CDX2-cre (Gfi1 F/F ; CDX2-cre) and crossed them with Apc Min/þ mice (Apc Min/þ ; Gfi1 F/F ; CDX2-cre). Loss of Gfi1 significantly increased the total number of colorectal adenomas compared with littermate controls with an APC mutation alone. Furthermore, we found that compound (Apc Min/þ ; Gfi1 F/F ; CDX2-cre) mice develop larger adenomas, invasive carcinoma, as well as hyperplastic lesions expressing the neuroendocrine marker chromogranin A, a feature that has not been previously described in APC-mutant tumors in mice. Collectively, these results demonstrate that GFI1 acts as a tumor suppressor gene in colorectal cancer, where deficiency of Gfi1 promotes malignancy in the colon. Implications: These findings reveal that GFI1 functions as a tumor suppressor gene in colorectal tumorigenesis.
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U2 - 10.1158/1541-7786.MCR-18-0666
DO - 10.1158/1541-7786.MCR-18-0666
M3 - Article
C2 - 30606770
AN - SCOPUS:85063109936
VL - 17
SP - 697
EP - 708
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 3
ER -