Abstract
BackgroundAberrant 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).MethodsTFAP2C 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.ResultsTFAP2C 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.ConclusionOur 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.
Highlights
Aberrant expression of transcription Factor Activator protein-2 (AP-2) Gamma (TFAP2C) has been reported to be implicated in malignant process of many cancers
We find that Transcription Factor AP-2 Gamma (TFAP2C) is significantly upregulated in colorectal cancer (CRC) tissues and cells and high expression of TFAP2C correlates with advanced clinicopathological features, poor prognosis and disease progression in CRC patients
TFAP2C is upregulated in colorectal cancer cell lines and tissues Through analyzing several colorectal cancer RNA sequencing datasets from The Cancer Genome Atlas (TCGA) and ArrayExpress, we found that TFAP2C expression was dramatically elevated in CRC tissues compared with the adjacent normal colorectal tissues (Fig. 1a and Additional file 5: Figure S1)
Summary
Aberrant expression of transcription Factor AP-2 Gamma (TFAP2C) has been reported to be implicated in malignant process of many cancers. Multiple studies have shown that CSCs play crucial roles in the induction and maintenance of chemotherapeutic resistance in several human cancers [8, 9]. Accumulating literatures have shown that AP-2 proteins play crucial roles in the development of therapeutic resistance in the treatment of cancers. Low expression of TFAP2E due to hypermethylation was significantly associated with nonresponse to chemotherapy in colorectal cancer [17]. These studies have indicated that different members of AP-2 proteins have stimulatory or inhibitory affect on chemotherapeutic response in cancer treatment, which may be environment and tumor type dependent
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