TFAP2C promotes stemness and chemotherapeutic resistance in colorectal cancer via inactivating hippo signaling pathway.

Abstract

BACKGROUND:

Aberrant expression of transcription Factor AP-2 Gamma (TFAP2C) has been reported to be implicated in malignant process of many cancers. The purpose of this study is to investigate the clinical significance and biological roles of TFAP2C in colorectal cancer (CRC).

METHODS:

TFAP2C expression was evaluated by real-time PCR, Western blot and immunohistochemistry (IHC) respectively in clinical CRC tissues. Statistical analysis was performed to explore the correlation between TFAP2C expression and clinicopathological features, and overall and progression-free survival in CRC patients. In vitro and in vivo assays were performed to assess the biological roles of TFAP2C in CRC cells. Western blot, luciferase and Chromatin immunoprecipitation (ChIP) assays were used to identify the underlying pathway mediating the biological roles of TFAP2C in CRC.

RESULTS:

TFAP2C is robustly upregulated in CRC tissues and cells, and high expression of TFAP2C correlates with advanced clinicopathological features, poor prognosis and disease progression in CRC patients. Furthermore, upregulating TFAP2C enhances spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and reduces the apoptosis induced by 5-fluorouracil in colorectal cancer cells in vitro, and promotes stemness and chemoresistance of CRC cells in vivo; while silencing TFAP2C yields an opposite effect. Importantly, downregulation of TFAP2C dramatically restores chemotherapeutic sensitivity of CRC cells to 5-FU in vivo. Our results further demonstrate that TFAP2C promotes stemness and chemoresistance of CRC cells to 5-FU by inhibiting Hippo signaling via transcriptionally upregulating ROCK1 and ROCK2 in CRC cells.

CONCLUSION:

Our findings indicate that TFAP2C may serve as a novel prognostic factor in CRC patients, and a therapeutic target for the treatment of CRC, suggesting that silencing TFAP2C in combination with 5-FU may be an effective therapeutic strategy to improve survival in CRC patients.

• Authors: Xu Wang, Di Sun, Jiandong Tai, Si Chen, Miao Yu, Dong Ren, Lei Wang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 37 Issue 1 Pg. 27 (Feb 13 2018) ISSN: 1756-9966 [Electronic] England
• PMID: 29439714 (Publication Type: Journal Article)

Chemical References

• TFAP2C protein, human
• Transcription Factor AP-2
• Protein Serine-Threonine Kinases
• ROCK1 protein, human
• ROCK2 protein, human
• rho-Associated Kinases
• Fluorouracil

Topics

• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (genetics, metabolism, mortality, pathology)
• Drug Resistance, Neoplasm (genetics)
• Female
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Hippo Signaling Pathway
• Humans
• Immunohistochemistry
• Mice
• Neoplastic Stem Cells (metabolism)
• Protein Binding
• Protein Serine-Threonine Kinases (metabolism)
• Signal Transduction
• Transcription Factor AP-2 (genetics, metabolism)
• rho-Associated Kinases (genetics, metabolism)