Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2

Abstract

Recently, the effect of endocrine-disrupting chemicals on the cancer procession has been a concern. Nonylphenol (NP) is a common environmental estrogen that has been shown to enhance the proliferation of colorectal cancer (CRC) cells in our previous studies; however, the underlying mechanism remains unclear. In this study, we confirmed the increased concentration of NP in the serum of patients with CRC. RNA sequencing was used to explore the differentially expressed genes after NP exposure. We found 16 upregulated genes and 12 downregulated genes in COLO205 cells after NP treatment. Among these differentially expressed genes, we found that coiled-coil domain containing 80 (CCDC80) was downregulated by NP treatment and was associated with CRC progression. Further experiments revealed that the overexpression of CCDC80 significantly suppressed NP-induced cell proliferation and recovered the reduced cell apoptosis. Meanwhile, the overexpression of CCDC80 significantly inhibited the activation of ERK1/2 induced by NP treatment. ERK1/2 inhibitor (PD98059) treatment also suppressed NP-induced CRC cell growth, but the overexpression of CCDC80 did not enhance the effect of ERK1/2 inhibitor. Taken together, NP treatment significantly inhibited the expression of CCDC80, and the overexpression of CCDC80 suppressed NP-induced CRC cell growth by inhibiting the activation of ERK1/2. These results suggest that NP could induce CRC cell growth by influencing the expression of multiple genes. CCDC80 and ERK1/2 inhibitors may be suitable therapeutic targets in NP-related CRC progression.

Nonylphenol Promoted Epithelial–Mesenchymal Transition in Colorectal Cancer Cells by Upregulating the Expression of Regulator of Cell Cycle

“…In addition, we found that the expression of RGCC in tumor tissues is positively correlated with the concentration of NP in patients’ serum (Figure H). The tumor tissue sample from our previous study also demonstrated that NP treatment could increase RGCC expression in vivo (Figure I).…”

“…The protein expression of the treated cells was analyzed using western blotting, as previously described. , The primary antibodies used were anti-E-cadherin (ab40772, Abcam,1:800), anti-N-cadherin (ab76011, Abcam,1:800), anti-vimentin (ab92547, Abcam,1:800), anti-ERK (ab184699, Abcam,1:800), anti-p-ERK (ab201015, Abcam,1:800), anti-RGCC (ab221098, Abcam,1:1000), and anti-GAPDH (5174, Cell Signaling Technology, 1:10 000). The IOD was analyzed using Image-Pro Plus 6.0 software (Media Cybernetics, MD).…”

“…RNA sequencing analysis suggested that the expression of many genes was changed in CRC COLO205 cells after NP treatment, including CCDC80 and response gene to complement 32 (RGC32). 7 RGC32, also called the regulator of cell cycle (RGCC), was confirmed to be an oncogene, which upregulated in many types of cancers, including CRC, 8 lung cancer, 9 and tongue squamous cell carcinoma, 10 inducing cancer cell proliferation and epithelial−mesenchymal transition (EMT). 8,11 EMT has been demonstrated as an early step in cancer metastasis.…”

“…Our previous study found a higher concentration of serum NP in patients with CRC than in healthy individuals in both men and women, and NP induced CRC cell proliferation. RNA sequencing analysis suggested that the expression of many genes was changed in CRC COLO205 cells after NP treatment, including CCDC80 and response gene to complement 32 (RGC32) …”

Delivery of Engineered Primary Tumor-Derived Exosomes Effectively Suppressed the Colorectal Cancer Chemoresistance and Liver Metastasis

“…The role of CCDC80 has been controversial in cancer research. Previous research indicated that the presence or high expression of CCDC80 might act as a protective factor in tumorigenesis. − Recent studies have reported that CCDC80 inactivation promotes AOM/DSS-induced colorectal carcinogenesis in mice . However, other studies have shown that CCDC80 may act as a prognostic stemness biomarker in CRC and that high expression of CCDC80 contributes to drug resistance and tumor immune evasion .…”