Growth factor–independent 1 is a tumor suppressor gene in colorectal cancer

Min Shan Chen, Yuan Hung Lo, Xi Chen, Christopher S. Williams, Jessica M. Donnelly, Zachary K. Criss, Shreena Patel, Joann M. Butkus, Julien Dubrulle, Milton J. Finegold, Noah F. Shroyer

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)697-708
Number of pages12
JournalMolecular Cancer Research
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Chen, M. S., Lo, Y. H., Chen, X., Williams, C. S., Donnelly, J. M., Criss, Z. K., Patel, S., Butkus, J. M., Dubrulle, J., Finegold, M. J., & Shroyer, N. F. (2019). Growth factor–independent 1 is a tumor suppressor gene in colorectal cancer. Molecular Cancer Research, 17(3), 697-708. https://doi.org/10.1158/1541-7786.MCR-18-0666